Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[S:10][C:11]([CH:14]2N(C)CCN2C)=[CH:12][CH:13]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].S(=O)(=O)(O)[OH:22]>O>[CH2:6]([O:5][P:4]([C:9]1[S:10][C:11]([CH:14]=[O:22])=[CH:12][CH:13]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)c1ccc(C2N(C)CCN2C)s1
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(C=O)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.3 %

Procedure:
To a solution of [5-(1,3-dimethyl-imidazolidin-2-yl)-thiophen-2-yl]-phosphonic acid diethyl ester (17.2 g, 60.17 mmol) in water (20 ml) was added sulfuric acid (3 ml) over 5 mins. The reaction was stirred at r.t. for 20 min, diluted with water, extracted with EtOAc. The organic layer was washed with sat. NaHCO3, dried over MgSO4, filtrated, concentrated, purified by Biotage (80% EtOAc) to give (5-formyl-thiophen-2-yl)-phosphonic acid diethyl ester (7.2 g, 48.3%). 1H NMR (300 MHz, DMSO-d6): δ 10.02 (d, J=2.4 Hz, 1H), 8.09 (m, 1H), 7.75 (m, 1H), 4.05 (m, 4H), 1.24 (m, 6H). LC-MS m/z=249.4 [C9H13O4PS+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[C:3]([C:9]([O:11][CH3:16])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cc1ccc(Br)c(C(=O)O)n1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nc(C)ccc1Br
Temperature: 25 °C
Yield: 40 %

Procedure:
To the title compound of step A (10.3 g, 20 mmol) in MeOH (50 mL) was added thionyl chloride (4.4 mL, 60 mmol). The reaction was heated at reflux overnight, cooled to rt and concentrated. Purification via silica gel chromatography (0-15% EtOAc in heptane) gave the title compound (1.9 g, 40%). MS (ESI) mass calcd. for C8H8BrNO2, 230.1; m/z found 232 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([OH:39])=[O:38]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:36][CH2:35][CH2:34][C@H:33]4[C:37]([OH:39])=[O:38])=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(O)[C@@H]1CCCN1Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and (S)-pyrrolidine-2-carboxylic acid (111 mg; 0.97 mmol) to give Example 159 as an off-white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.77-8.74 (2H, m), 7.98-7.87 (3H, m), 7.76-7.69 (1H, m), 7.64-7.57 (4H, m), 7.52 (2H, t, J=8.5 Hz), 4.11 (1H, d, J=13.5 Hz), 3.72 (1H, d, J=13.5 Hz), 3.31 (1H, dd, J=8.9, 5.9 Hz), 3.04-2.96 (1H, m), 2.50 (1H, d, J=8.5 Hz), 2.16-2.07 (1H, m), 1.94-1.84 (1H, m), 1.84-1.73 (2H, m). LC/MS (Method C): 412 (M+H)+. HPLC (Method I) Rt 15.21 min (Purity: 95.3%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][OH:17])=[CH:10][CH:11]=2)[N:6]([CH3:18])[C:5]1=[O:19].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:17][CH2:16][C@@H:14]1[CH2:15][C@H:13]1[C:9]1[N:8]=[C:7]2[N:6]([CH3:18])[C:5](=[O:19])[N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:12]2=[CH:11][CH:10]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CO)nc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3COS(C)(=O)=O)nc21
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
1-(2,2-Dimethylpropyl)-5-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (31-4, 53.2 mg, 0.18 mmol, 1.0 equiv) was added to anhydrous DCM (1.8 mL) and cooled to −10° C. Triethylamine (108 μL, 0.77 mmol, 4.2 equiv) and methanesulfonyl chloride (32 μL, 0.40 mmol, 2.2 equiv) were added sequentially and the resulting reaction mixture was stirred for 1 min. Following this duration, TLC showed complete consumption of 31-4. The reaction mixture was partitioned between ethyl acetate (5 mL) and saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a clear, yellow oil. The crude product was carried forward without further purification.
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[CH:21][C:20]=1[C:28](=[O:30])[CH3:29].C([O-])(O)=O.[Na+]>C(Cl)Cl.O1CCOCC1.CN(C=O)C>[C:28]([C:20]1[C:19]([NH:18][C:9]([C:6]2[CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[O:8][N:7]=2)=[O:11])=[C:24]([Cl:25])[C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:30])[CH3:29]
Reactant: CC(C)c1cc(C(=O)O)no1
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(NC(=O)c2cc(C(C)C)on2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a stirred solution of 5-isopropylisoxazole-3-carboxylic acid (3.5 g, 22.6 mmol) in DCM (35 mL) was added anhydrous DMF (few drops) and oxalyl chloride (3.82 mL, 43.2 mmol) at 0° C. under nitrogen. At the end of the gas escape, the reaction mixture was allowed to warm up to room temperature. The mixture was stirred at room temperature for 2 hrs and was evaporated. Dioxane (70 mL) was added under nitrogen, followed by a solution of 1-(2-amino-3-chloro-4-methoxy-phenyl)-ethanone 201d (4.10 g, 20.6 mmol) in dioxane (15 mL). The reaction mixture was stirred at room temperature for 16 hrs. NaHCO3 was then added. The mixture was extracted with EtOAc. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was triturated in Et2O to yield compound 241d as a brown solid in 60% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.47 (s, 3H), 1.48 (s, 3H), 1.76 (brs, 1H), 2.57 (s, 3H), 3.34-3.40 (m, 1H), 3.98 (s, 3H), 6.86 (d, J=8.53 Hz, 1H), 7.64 (d, J=8.53 Hz, 1H), 8.07 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>ClCCl>[C:15]([NH:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1)([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:21]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NCc1nccs1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NCc1nccs1
Reaction time: 0.5 h

Procedure:
To a solution of 3.43 g (30 mmol) of 2-aminomethylthiazole and 3.34 g (33 mmol) of triethylamine in 60 ml of dichloromethane, a solution of 4.512 g of ethyl chloroxalate in 10 ml of dichloromethane was added dropwise with ice-cooling. The reaction solution was stirred for 30 minutes. 20 ml of water was added to the solution, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 ml×5). The organic layers were combined, washed with a small amount of a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The resultant was concentrated to dryness under reduced pressure to give solid 2-(ethoxalylamino)methylthiazole. To this was added 50 ml of phosphorus oxychloride with ice-cooling. The mixture was refluxed for 12 hours, cooled to room temperature, and concentrated to dryness under reduced pressure. To the residue were added 50 ml of water and 50 ml of dichloromethane to obtain a solution. 50 g of potassium carbonate was added to the solution little by little with ice-cooling. The reaction solution was stirred for 10 minutes, and then filtered to remove insoluble matters. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 ml×2). The combined organic layers were dried over anhydrous potassium carbonate, and purified by flash column chromatography using silica gel, eluting with ethyl acetate to give 4.68 g (yield 80%) of the title compound as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:14]>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[C:4]([NH:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=3)[CH2:21][CH2:22]2)[N:3]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: CC(=O)Nc1cc(Cl)nc(Cl)n1
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3cc(NC(C)=O)nc(Cl)n3)CC2)ccc1OC
Yield: 2.5 %

Procedure:
A solution of N-(2,6-dichloro-pyrimidin-4-yl)-acetamide (30.9 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 180° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.6 mg (3%) of the title compound. MS (ISP): 434.4 [M+H]+.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:31](=O)/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH3:36]>>[C:2]([OH:4])(=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:31][CH:32]=[CH:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC/C=C/C=O
Agent: [Br-]
Product: CCCC=CC=CCCCCCCC(=O)O
Yield: 43.9 %

Procedure:
This compound was synthesized from 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) and 2-trans-hexenal (1.96 g, 20 mmol) in 10% hexamethylphosphoric triamide (HMPA)-THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (1.97 g, 44%) as a yellow oil (bp 123-126° C./0.01 torr). IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 0.95 (t, 3 H), 1.35 (m, 8 H), 1.62 m, 2 H), 2.05 (m, 4 H), 2.32 (t, 2 H), 5.23 (m, 1 H), 5.60 (m, 1 H), 5.90 (m, 1 H), 6.05 (m, 1 H), 10.50 (bs, 1 H). Anal. Calcd. for C14H24O2 : C, 74.95, H, 10.78%; Found: C, 75.01, H, 10.80%.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13]C(OCC2C=CC=CC=2)=O)[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCC(NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCC(N)C1

Procedure:
A solution of 467 mg 3-benzyloxycarbonylamino-pyrrolidine-1-carboxylic acid butyl ester in 10 ml ethyl acetate was stirred in the presence of 50 mg Pd/C (10%) under an atmosphere of hydrogen (1 bar) for 12 h. The reaction mixture was filtrated, washed with ethyl acetate and concentrated to give the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:20]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2ccc(Cl)cc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)n(-c3ccc(Cl)cc3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 89A in analogy to the synthesis of the compound of Example 1. 31 mg (80% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[NH:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][N:24]=1)[C:20]#[N:21])[NH2:16].CC(O)=O>CCO>[CH2:11]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:15]([C:17]2[CH:18]=[C:19]([C:20]#[N:21])[CH:22]=[CH:23][N:24]=2)[N:16]=1)[CH3:12]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCC(=O)CC(=O)c1ccc(C)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1cc(-c2ccc(C)cc2)n(-c2cc(C#N)ccn2)n1
Yield: 176.6 %

Procedure:
To a solution of 1-(4-methylphenyl)pentane-1,3-dione (370 mg, 1.9 mmol) and 2-hydrazinylisonicotinonitrile (150 mg, 1.1 mmol, PREPARATION 2) in 10 mL EtOH was added 2 mL AcOH. The reaction mixture was heated under reflux conditions overnight before being cooled and concentrated to dryness. The residue was adjusted to pH>8 with saturated aq. K2CO3, then extracted by EtOAc (10 mL×3). The combined organic layers were washed with 20 mL brine, dried over Na2SO4, concentrated, and purified by flash column chromatography (PE/EtOAc=10/1) to give the title compound (560 mg, 77%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.33 (3H, m), 2.38 (3H, s), 2.76 (2H, m), 6.33 (1H, s), 7.15 (4H, m), 7.31 (1H, m), 7.82 (1H, s), 8.42 (1H, m). [M+H] Calc'd for C18H16N4, 289; Found, 289.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]5[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=5[F:42])=[O:33])=[CH:27][CH:26]=4)[CH:21]=[CH:20][N:19]=3)[NH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1.[OH-].[Na+].O.Cl>C1COCC1.CO>[F:42][C:36]1[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:35]=1[NH:34][C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]2[CH:21]=[CH:20][N:19]=[C:18]([C:16]3[NH:15][CH:14]=[C:13]([C:11]([N:8]4[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:43])=[O:2])[CH2:6][CH2:7]4)=[O:12])[CH:17]=3)[CH:23]=2)=[CH:26][CH:27]=1)=[O:33]
Reactant: COC(=O)CC1CCN(C(=O)c2c[nH]c(-c3cc(Oc4ccc(NC(=O)Nc5cc(C)ccc5F)cc4)ccn3)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CCC(CC(=O)O)CC5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl{1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperidin-4-yl}acetate (50 mg, 0.085 mmol) in THF/MeOH (5 ml/5 ml) was added 1M NaOH solution (3 ml, 3 mmol). The mixture was stirred at room temperature for one hour, and poured into 50 ml of water. 2M HCl was added until pH=4. The resulting precipitates were filtered, washed with water, and dried in vacuo to give {1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperidin-4-yl}acetic acid as white solid. Yield: 47 mg, 96%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[C:28]1([C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][O:30]1)=O.Cl>C1COCC1.O>[C:28]1(=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][C:7]2=[O:12])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][O:30]1
Reactant: O=C1OCc2ccccc21
Reactant: COc1ccc2c(c1)CC(=O)N2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(=C1OCc3ccccc31)C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a stirred solution of 5-methoxyoxindole (100 mg, 0.61 mmol) in anhydrous THF (5 ml) under nitrogen was added 1.0M LiHMDS/THF solution (1.3 ml, 1.3 mmol). The mixture was stirred at room temperature for 10 minutes, and phthalide (74 mg, 0.55 mmol) was added. The mixture was stirred at room temperature for 5 hours and was then poured into a mixture of THF (10 ml) and 2M HCl (10 ml). The mixture was heated at 45° C. for 30 minutes, cooled to room temperature, and poured into water (125 ml). The resulting solid was separated, washed with water and dried under vacuum to give 3-(3H-Isobenzofuran-1-ylidene)-5-methoxy-1,3-dihydro-indol-2-one (70 mg, 46%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])[CH:11]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[CH3:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:14]([CH:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:33]([C:29]3[N:28]([CH3:27])[CH:32]=[CH:31][N:30]=3)(=[O:35])=[O:34])[CH:13]=2)[CH2:9][CH:10]1[NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cn1ccnc1S(=O)(=O)Cl
Reactant: CCOC(=O)NC1Cc2ccc(OCCN)cc2C1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)NC1Cc2ccc(OCCNS(=O)(=O)c3nccn3C)cc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 6-(2-aminoethoxy)-1-benzyl-2,3-dihydro-1H-inden-2-ylcarbamate (44.7 mg, 0.126 mmol; see example 193.8) in dry dichloromethane (2 ml) was added 4-dimethylaminopyridine (18.49 mg, 0.151 mmol) followed by 1-methyl-1H-imidazole-2-sulfonyl chloride (22.78 mg, 0.126 mmol). The reaction mixture was stirred at room temperature for 1 h. Added dichloromethane and washed twice with 1N hydrochloric acid. The collected organic layers were washed with water, sodium bicarbonate and brine, dried, filtered and evaporated to obtain ethyl 1-benzyl-6-(2-(1-methyl-1H-imidazole-2-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate as a white foam. m=60 mg (95%)
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[F:15][C:16]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].O>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:13]([O:12][C:10]([C@H:7]1[CH2:6][CH2:5][C@@H:4]([O:3][C:20]2[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([F:15])[CH:21]=2)[CH2:9][CH2:8]1)=[O:11])[CH3:14]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 5.05 g, 126 mmol) was added in one portion to a stirred solution of ethyl 4-hydroxycyclohexanecarboxylate (20.7 g, 120 mmol) and 2,4-difluoronitrobenzene (19.1 g, 120.2 mmol) in DMA (100 mL) at 4° C. and the mixture was stirred at 4° C. for 1 h and then the reaction mixture was warmed to ambient temperature and stirred for 24 h. The reaction mixture was cooled to 0° C. and then water and ethyl acetate were added. The layers were separated and the organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to leave a yellow oil. The oil was purified by column chromatography, using a gradient of 20-50% ethyl acetate in isohexane as eluent, to give the title compound as a pale yellow solid (4.1 g, 11%).
Reaction SMILES: C1C2C(COC([N:18]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@H:19]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=3)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=O)C3C(=CC=CC=3)C=2C=CC=1.[OH:57][C:58]1[C:67]2[C:62](=[C:63]([OH:68])[CH:64]=[CH:65][CH:66]=2)[N:61]=[C:60]([C:69]([OH:71])=O)[CH:59]=1>>[OH:57][C:58]1[C:67]2[C:62](=[C:63]([OH:68])[CH:64]=[CH:65][CH:66]=2)[N:61]=[C:60]([C:69]([N:18]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@H:19]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([OH:37])[CH:31]=2)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=[O:71])[CH:59]=1
Reactant: O=C(O)c1cc(O)c2cccc(O)c2n1
Reactant: CNC(=O)CC[C@@H](C(=O)NCc1ccc(O)c(O)c1)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CNC(=O)CC[C@@H](C(=O)NCc1ccc(O)c(O)c1)N(C(=O)c1cc(O)c2cccc(O)c2n1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-methyltrityl-L-glutaminyl]-3,4-dihydroxybenzylamine (1.0 g, 1.4 mmol, example 26, step A) as described for example 26 using 4,8-dihydroxyquinoline-2-carboxylic acid (435 mg, 2.1 mmol) instead of4-hydroxy-3-nitrobenzoic acid. The crude material was purified by flash chromatography using a solvent gradient from 30% to 60% EtOAc/CH2Cl2/1% AcOH. The title compound was obtained as yellow crystals (100 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[C:4]([F:19])[CH:3]=1.[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[C:27]([NH2:30])[CH:28]=2)[NH:23][N:22]=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[C:27]([NH:30][C:16]([C:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[F:19])[CH2:13][C:12](=[O:14])[NH:11][C:10]=3[CH3:15])=[O:18])[CH:28]=2)[NH:23][N:22]=1
Reactant: Nc1cc2c(Cl)n[nH]c2cc1F
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2cc3c(Cl)n[nH]c3cc2F)C(c2ccc(Cl)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.6 %

Procedure:
The product of Example 3 Step 2 (191 mg, 0.668 mmol, 1.00 equiv), the product of Step 2 (125 mg, 0.668 mmol, 1.0 equiv), and EDC (153 mg, 0.802 mmol, 1.20 equiv) were suspended in 2.0 mL DMF. Et3N (0.112 mL, 0.802 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by reverse-phase HPLC (20-90% CH3CN/H2O—NH4OH to pH 10 over 13 minutes, retention time 7.79 min) to provide 20 mg (7%) of the title compound as a white solid. MS (ES+) m/e 452 [M+H]+
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)[NH2:2].ClC1C=NC=CN=1.NN.[C:18](O)([C:20]([F:23])([F:22])[F:21])=O.[OH-].[NH4+]>>[F:21][C:20]([F:23])([F:22])[C:18]1[N:4]2[CH:5]=[CH:6][N:7]=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: NNc1cnccn1
Reactant: O=C(O)C(F)(F)F
Agent: Clc1cnccn1
Agent: NN
Agent: [NH4+]
Product: FC(F)(F)c1nnc2cnccn12
Temperature: 140 °C
Reaction time: 18 h
Yield: 61.4 %

Procedure:
A mixture of 2-hydrazinopyrazine (820 mg, 7.45 mmol), prepared from 2-chloropyrazine and hydrazine using a procedure analogous to that described in the literature (P. J. Nelson and K. T. Potts, J. Org. Chem. 1962, 27, 3243, except that the crude product was extracted into 10% methanol/dichloromethane and filtered, and the filtrate was concentrated and purified by flash chromatography on silica gel, eluting with 100% ethyl acetate followed by 10% methanol in dichloromethane), TFA (2.55 g, 22.4 mmol), and polyphosphoric acid (10 mL) was heated to 140° C. with stirring for 18 h. The solution was added to ice and neutralized by the addition of ammonium hydroxide. The aqueous solution was extracted with ethyl acetate (3×), washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography (silica gel, 1:1 hexane:ethyl acetate, then 100% ethyl acetate) afforded the title compound as a solid (861 mg). 1H NMR (500 MHz, CDCl3) δ 8.17˜8.20 (m, 2H), 9.54 (s, 1H). LC/MS (M+1) 189.