Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].[Br-].[CH2:31]([Zn+])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH2:31]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1c(Br)c2ccccc2n1CCCOc1cccc2ccccc12
Reactant: [Zn+]Cc1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cc2ccccc2)c2ccccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 31C (100 mg), 0.5M benzyl zinc(II) bromide in THF (1.32 mL) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (18 mg) in THF (2 mL) was stirred at 60° C. for 16 hours. The mixture was diluted with ethyl acetate, and the organic phase was washed with water and brine and dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 0-8% ethyl acetate/hexanes.
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:9]1([Mg]Cl)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1.O1CCCC1.CN1CCCC1=O>[C:9]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCCCCl
Reactant: Cl[Mg]c1ccccc1
Agent: [Pd+2]
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCCCCCCc1ccccc1

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 0.027 g (0.12 mmol) of palladium (II) acetate and 7 ml of N-methylpyrrolidinone were weighed in the flask, followed by, stirring. Further, 0.072 g (0.12 mmol) of tricyclohexylphosphonium tetraphenylborate obtained in Example A-4 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 25° C. for 30 minutes. 0.404 g (3 mmol) of n-heptyl chloride was added, followed by stirring at 25° C. for 30 minutes. 2 ml (4.4 mmol) of 2.2M tetrahydrofuran solution of phenylmagnesium chloride was added dropwise at 25° C. over a period of 10 minutes, followed by stirring at 25° C. for 19 hours. After the completion of the reaction, 6 ml of tetrahydrofuran and 10 ml of saturated aqueous ammonium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.435 g of 1-phenylheptane (yield: 82 mol % based on n-heptyl chloride). The identification of the product was made by mass spectroscopy.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@H:14]([O:25]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[O:44][C@H:45]1[C@H:56]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C@@H:55]([CH2:65][O:66][C@H:67]2[O:99][C@H:98]([CH2:100][O:101]C(=O)C3C=CC=CC=3)[C@@H:88]([O:89]C(=O)C3C=CC=CC=3)[C@H:78]([O:79]C(=O)C3C=CC=CC=3)[C@@H:68]2[O:69]C(=O)C2C=CC=CC=2)[O:54][C@@H:47]([O:48][CH2:49][CH2:50][N:51]=[N+:52]=[N-:53])[C@@H:46]1[F:110])(=O)C1C=CC=CC=1.O(C)[Na]>CO>[C@H:11]1([O:44][C@H:45]2[C@H:56]([O:57][CH2:58][C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[C@@H:55]([CH2:65][O:66][C@H:67]3[O:99][C@H:98]([CH2:100][OH:101])[C@@H:88]([OH:89])[C@H:78]([OH:79])[C@@H:68]3[OH:69])[O:54][C@@H:47]([O:48][CH2:49][CH2:50][N:51]=[N+:52]=[N-:53])[C@@H:46]2[F:110])[O:12][C@H:13]([CH2:34][OH:35])[C@@H:14]([OH:25])[C@H:15]([OH:16])[C@@H:10]1[OH:9]
Reactant: [N-]=[N+]=NCCO[C@@H]1O[C@H](CO[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@H]1F
Agent: CO[Na]
Solvent: CO
Product: [N-]=[N+]=NCCO[C@@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@H]1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-azidoethyl 2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl-(1→3)-[2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl-(1→6)]-4-O-benzyl-2-deoxy-2-fluoro-β-D-glucopyranoside (5.0 g, 3.34 mmol) in CH3OH (40 mL) was added NaOCH3 (1.0 mL, 0.5 mmol, 0.5 M in CH3OH). After stirring at rt for 24 hr, amberlite IR 120 (H) ion exchange resin (pre-washed with CH3OH 3×30 mL) was added to the reaction mixture. After 15 min, the resin was filtered off and washed with CH3OH (3×5 mL). The filtrate was concentrated and the residue was taking into EtOAc (50 mL) and stirred for 2 hr. The solid was filtered, and washed with EtOAc (3×15 mL) and dried to give the title compound. UPLC Method B: calculated for C27H40FN3O15 665.24, observed m/e: 666.35 [M+1]; Rt=2.03 min.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[Sn](CCCC)(CCCC)CCCC.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][C:14]1[C:13]([O:12][CH2:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:26]2[N:25]([CH3:24])[CH:29]=[CH:28][CH:27]=2)[N:7]=3)=[CH:21][CH:20]=[C:19]([F:22])[C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cccc1-c1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Temperature: 120 °C
Yield: 33.3 %

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.10 g, 0.24 mmol) in 5 ml of anhydrous DMF was added 1-methyl-2-tributylstannanyl-1H-pyrrole (0.120 g, 0.32 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.004 g, 0.0037 mmol) was then added and the reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. The reaction mixture was then cooled to room temperature, added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate/Hexane (40:60) as the eluent to provide the title compound as yellow solid (0.032 g, 32%). 1H NMR (DMSO-d6, 400 MHz): δ 3.73 (s, 3H), 5.72 (s, 2H), 6.13 (br s, 1H), 6.40 (br s, 1H), 6.97 (s, 1H), 7.12 (m, 1H), 7.42 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H), 8.48 (s, 1H) and 8.75 (s, 1H). MS ES+ (401.26), HPLC (method I) Rt=15.61 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[CH2:12]([Sn](CCCC)(CCCC)C=C)[CH2:13]CC>C1(C)C=CC=CC=1.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>[CH:12]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1)=[CH2:13]
Reactant: Clc1ccc2ncccc2n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2ncccc2n1
Temperature: 140 °C
Yield: 57.1 %

Procedure:
2-chloro-1,5-naphthyridine (10-1) (35 g, 213 mmol) in toluene (420 mL) was treated with tributyl(vinyl)stannane (101 g, 93.4 mL, 319 mmol) and tetrakis(triphenylphosphine)palladium (36.9 g, 31.9 mmol). The mixture was heated at 140° C. under microwave irradiation for 20 min, then cooled and concentrated in vacuo. The residue was purified by silica gel flash column chromatography, eluting with 0-100% EtOAc/heptane. The fractions containing the desired product (10-2) were pooled, and after solvent removal in vacuo, 19 g (57%) of the product were obtained. LC/MS: m/z (M+H)=157.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6](=O)[CH2:5][CH2:4][N:3]1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].C([O-])(=O)C.[Na+].Cl.[CH3:23][O:24][NH2:25]>CO>[CH3:23][O:24]/[N:25]=[C:6]1/[C:2]([CH3:16])([CH3:1])[N:3]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:5]/1
Reactant: CON
Reactant: CC1(C)C(=O)CCN1C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CO/N=C1\CCN(C(=O)c2ccccc2)C1(C)C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of 2,2-dimethyl-1-(phenylcarbonyl)-3-pyrrolidinone (2.0602 g, 9.482 mmol) in MeOH (50 mL) was added sodium acetate (0.956 g, 11.38 mmol) and methoxyamine hydrochloride (0.950 g, 11.37 mmol). The mixture was stirred overnight and then concentrated in vacuo. The residue was dissolved in DCM (200 mL) and washed with sat. aq. NaHCO3 (50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford (3E)-2,2-dimethyl-1-(phenylcarbonyl)-3-pyrrolidinone O-methyloxime (1.9567 g, 84% yield) as a light yellow oil that solidified under high vacuum. LCMS: (M+H)+: 247.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:45]=[CH:46][CH:47]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:14]2[CH:15]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:42]5[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:50])=[O:51])[CH:45]=[CH:46][CH:47]=5)[CH:3]=4)[N:8]([S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=4)(=[O:26])=[O:25])[CH:9]=3)[CH:12]=[N:13]2)=[CH:18][CH:19]=1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccc(F)cc4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccc(F)cc4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 78.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.285 mmol) was coupled with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methane sulfonamide (intermediate 3) (127 mg, 0.427 mmol) in sodium carbonate (90.6 mg, 0.855 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (39.8 mg, 0.057 mmol) and toluene/ethanol/water (20/8/2 ml) to afford 138 mg (79% yield) of the pure product after column purification using 40% ethyl acetate in hexane as eluent. MS: m/z=616.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][NH:12][C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]2=[O:20])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1NCc2cccnc2N1c1cccc([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1N(Cc2ccccc2)Cc2cccnc2N1c1cccc([N+](=O)[O-])c1
Yield: 26.3 %

Procedure:
1-(3-Nitrophenyl)pyrido[2,3-d]pyrimidine-2(1H,3H)-one (300 mg, 1.1 mmole) was suspended in acetone (100 ml). To this suspension was added powdered K2CO3 (607 mg, 4.4 mmole) and benzyl bromide (282 mg, 1.65 mmole). The suspension was refluxed for 18 hours. The suspension was filtered, while still hot, to remove solid unreacted K2CO3, which was discarded. The solvents were removed from the filtrate and the residue was purified by preparative thin-layer chromatography (eluted with ethyl acetate) yielding 104 mg (0.289 mmole, 26% yield) of 1-(3-nitrophenyl)-3-benzylpyrido[2,3-d]pyrimidine-2(1H,3H)-one (mp 144°-145° C.), as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH3:13][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO.C(OCC)C>[C:1]([C:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:13])=[O:8])[CH:10]=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)c1cccc(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3.95 g (24.06 mmol) of 3-acetylbenzoic acid were initially charged in 100 ml of toluene and 75 ml of methanol. After dropwise addition of 4.12 g (36.09 mmol) of trimethylsilyldiazomethane 2M in diethyl ether at RT, an instant evolution of gas in the reaction solution was observed. Another 0.27 g (2.4 mmol) of trimethylsilyldiazomethane 2M in diethyl ether was added until the reaction solution remained yellow, and the mixture was stirred at RT for 10 min. The reaction solution was evaporated.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([O-:18])(=O)=[O:16].[Na+].CC(C)=O.P(Cl)(Cl)([Cl:26])=O>CN(C)C(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([Cl:26])(=[O:18])=[O:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
59 g of sodium 2-(2-methoxyethoxy)-5-nitrobenzenesulfonate prepared as described in Example 1 above was added to a mixture of 200 ml of acetone and 75 ml of phosphorus oxychloride. 75 ml of N,N-dimethylacetamide was added dropwise to the mixture with stirring while the reaction mixture was maintained at 30° to 40° C. After the completion of the addition, the mixture was allowed to stand with stirring until it cooled to room temperature (25° C.). The reaction mixture was then poured into 600 ml of ice water (0° C.), stirred for 30 minutes and the crystals thus-precipitated were recovered by filtration. The crystals were washed with water and air-dried. Yield: 56 g; Melting Point: 74° to 74.5° C.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6]CC)=O.[N:13]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[N+:14]=[N-:15]>C(O)C>[OH:6][C:4]1[N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:14]=[N:15][C:3]=1[C:2]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1O

Procedure:
Sodium metal (3.8 g, 164 mmol) was added to absolute ethanol (200 mL). The mixture was stirred under reflux until a clear solution was obtained. Diethyl malonate (26.3 g, 164 mmol) was added to this solution which was again heated to reflux, and a solution of 1-(azidomethyl)-4-methoxybenzene (i.e. the product of Step A, 25.5 g, 156 mmol) in ethanol (50 mL) was added at once. The reaction mixture was stirred at reflux for 24 h then the reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with water (100 mL) and acidified to pH 2 with 1 M aqueous hydrochloric acid, stirred for 30 min, and the solid was filtered off and washed with water. The solid was dried over phosphorus pentoxide. The solid was stirred in chloroform (500 mL) and the insoluble solids were filtered off. Hexanes (400 mL) were added to precipitate the product, which was removed by filtration and dried to afford the title compound (12.0 g) as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([N:19]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]3[C:27]([O:36][CH3:37])=[CH:28][CH:29]=[C:30]4[C:35]=3[N:34]=[CH:33][CH:32]=[CH:31]4)[CH2:21][CH2:20]2)[CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:37][O:36][C:27]1[C:26]([N:22]2[CH2:23][CH2:24][CH2:25][N:19]([CH:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]3)[CH2:15][C:16](=[O:18])[NH:45][CH2:44][CH2:43][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:20][CH2:21]2)=[C:35]2[C:30]([CH:31]=[CH:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1
Reactant: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: NCCN1CCCC1
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: O
Solvent: CN(C)C=O
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)NCCN2CCCC2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.5 %

Procedure:
(±)-3-[(tert-Butoxycarbonyl)piperidin-4-yl]-3-[4-(7-methoxyquinolin-8-yl)-[1,4]-diazepan-1-yl]propanoic acid (800 mg, 1.56 mmol), and 2-(pyrrolidin-1-yl)ethanamine (250 mg, 2.19 mmol) were suspended in anhydrous DMF (6 mL). N,N-Diisopropylethylamine (0.5 mL, 2.88 mmol) was added and the mixture was stirred at ambient temperature for 5 min followed by addition of HATU (761 mg, 2.00 mmol). After 1 h at ambient temperature, LC-MS and TLC indicated complete reaction (LC/MS [M+H]+609.7). Water (5 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (3×30 mL) and concentrated. The residue was purified by silica gel flash column chromatograph using 2 to 5% MeOH in DCM with 0.5% aqueous NH4OH to afford the title compound as a light yellow oil (480 mg, 50%): 1H NMR (400 MHz, CDCl3) δ 8.81 (dd, 1H, J=1.6 and 4 Hz), 8.03 (dd, 2H, J=1.6 and 8 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.29 (d, 1H, J=8.8 Hz), 7.22 (dd, 1H, J=4 and 8 Hz), 4.12 (br s, 2H), 3.96 (s, 3H), 3.51 (m, 4H), 3.38 (m, 3H), 3.20-2.80 (m, 4H), 2.70-2.40 (m, 5H), 2.24 (m, 1H), 1.98 (br, 1H), 1.80-1.55 (m, 11H), 1.46 (s, 9H), 1.34-1.16 (m, 3H). MS (ES) m/z 609.7 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].FC(F)(F)C(O)=O.[CH:19]([C:22]1[S:23][CH:24]=[C:25]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[N:26]=1)([CH3:21])[CH3:20].C(N(CC)CC)C>CC#N>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:37]1[CH2:38][CH2:39][C:33]2([O:32][CH2:31][CH2:30][N:29]([C:27]([C:25]3[N:26]=[C:22]([CH:19]([CH3:20])[CH3:21])[S:23][CH:24]=3)=[O:28])[CH2:34]2)[CH2:35][CH2:36]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCCCCCCCCBr
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 9-bromo-1-nonanol (0.316 g) in MeCN (3 mL) was added to solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.40 g) and triethylamine (0.395 mL) in MeCN (7 mL). The resulting mixture was stirred at 60° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine (×2), dried over sodium sulphate, filtered and evaporated in vacuo. The orange solid was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the subtitled compound as an off-white solid. Yield 0.325 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19]([CH3:21])=[N:18][C:17]=2[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[S:20][C:19]([CH3:21])=[N:18][C:17]=3[CH:22]=2)=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Cc1nc2cc(N)ccc2s1
Product: Cc1nc2cc(NC(=S)Nc3cc(Cl)ccc3C)ccc2s1
Yield: 29.3 %

Procedure:
Prepared using Method A from 4.5 g (24.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 4.02 g (24.5 mmol) of 5-amino-2-methylbenzothiazole to give 6.0 g of crude material. Soxhlet extraction with EtOAc gave 2.5 g of pure title compound as a tan solid (29% yield, m.p. 173-174° C. ).
Reaction SMILES: C1([NH:7][C:8](=[O:30])[C:9]2[CH:14]=[C:13]([OH:15])[C:12]([OH:16])=[CH:11][C:10]=2NC(C2SC3C=CC=CC=3C=2Cl)=O)C=CC=CC=1.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34]>C(Cl)Cl.N1C=CC=CC=1>[OH:15][C:13]1[C:12]([O:16][C:33]([C:32]([CH3:37])([CH3:36])[CH3:31])=[O:34])=[CH:11][CH:10]=[C:9]([CH:14]=1)[C:8]([NH2:7])=[O:30]
Reactant: O=C(Nc1ccccc1)c1cc(O)c(O)cc1NC(=O)c1sc2ccccc2c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(N)=O)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4,5-dihydroxybenzamide (0.09 g, 0.21 mmol) in CH2Cl2 (1 mL) and pyridine (1 mL) at 0° C. was added trimethylacetyl chloride (0.027 mL, 0.22 mmol). The solution was allowed to warm to ambient temperature with stirring. After 16 hours, the reaction mixture was partitioned between ethyl acetate and dilute HCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel to afford 0.038 g (40% yield) of N-phenyl-2-[((3-chlorobenzo b]thien-2-yl)carbonyl)amino]-5-hydroxy4-((1,1-dimethylethyl)carbonyl)oxybenzamide as a white solid; NMR(DMSO-d6) 12.2 (s, 1), 10.8 (s, 1), 10.4 (s, 1), 8.3 (s, 1), 8.2 (d, 1), 8.0 (d, 1), 7.6-7.7 (m, 4), 7.4 (t, 2), 7.1 (t, 1), 1.3 (s, 9) ppm.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1.C[Si](C)(C)Cl.Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].Cl>ClCCl.C(N(CC)CC)C>[CH:27]([S:28]([NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:11][CH:12]=1)(=[O:30])=[O:29])=[CH2:26]
Reactant: NCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: Br
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)NCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
276 mg of triethylamine was added to a dichloromethane suspension (4 ml) containing 100 mg of 6-[4-(3-aminopropoxy)phenyl]pyridazin-3(2H)-one hydrobromide and 37 mg of dimethylanitine, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, 86 mg of trimethylchlorosilane was added thereto, and the mixture was stirred at room temperature for 2 hours. Again, under ice cooling, a dichloromethane solution (1 ml) containing 65 mg of chloroethylsulfonyl chloride was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes. 5 ml of 1M hydrochloric acid was added to the mixture, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol (30: 1)) to obtain 73 mg of 6-[4-(3-vinylsulfonylaminopropoxy)phenyl]pyridazin-3 (2H) -one.