Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8]Br)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[I-].[Na+].[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:41]/[O:42][CH3:43])/[C:19]([NH:21][C@@H:22]2[C:39](=[O:40])[N:24]3[C:25]([C:36]([O-:38])=[O:37])=[C:26]([CH2:29][CH:30]4[O:34][C:33](=[O:35])[CH:32]=[CH:31]4)[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1.[Na+]>CC(C)=O.CN(C=O)C>[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:41]/[O:42][CH3:43])/[C:19]([NH:21][C@@H:22]2[C:39](=[O:40])[N:24]3[C:25]([C:36]([O:38][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:37])=[C:26]([CH2:29][CH:30]4[O:34][C:33](=[O:35])[CH:32]=[CH:31]4)[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CC3C=CC(=O)O3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCBr
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(CC3C=CC(=O)O3)CS[C@H]12)c1csc(N)n1

Procedure:
The title compound was prepared as described in Example 3, using pivaloyloxymethyl bromide (0.051 g) in acetone (1ml), sodium iodide (0.039 g) and sodium 7β-[2-(2-aminothiazol-4-yl)-2-Z-methoxyiminoacetamido]-3-[(5RS)-2,5-dihydro-2-oxofuran-5-ylmethyl]ceph-3-em-4-carboxylate (0.13 g) in DMF (2 mls).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].[CH3:15][C:16]([CH3:21])=[CH:17][CH:18](O)[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][CH:18]([CH:17]=[C:16]([CH3:21])[CH3:15])[CH3:19]
Reactant: CC(C)=CC(C)O
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CC(C)Oc1cc(Nc2nccs2)ccc1Cl
Reaction time: 1 h
Yield: 24 %

Procedure:
Following the procedure general for O-alkylation, Method C, 2-chloro-5-(thiazol-2-ylamino)phenol (50 mg, 0.22 mmol), 4-Methylpent-3-en-2-ol (23 mg, 0.23 mmol), Ph3P (58 mg, 0.22 mmol) were suspended in THF (0.07 mL). The reaction flask was lowered into a sonication bath and sonicated for several minutes giving a clear and highly viscous solution. While sonication, DEAD (0.043 mL, 0.22 mmol) was added slowly. The reaction mixture was stirred for 1 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 4/1) in 24% yield (16 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:8][C:7]2=[O:18].O.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl.[OH-].[Na+]>C(O)(C)C>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH:8][C:7]2=[O:18]
Reactant: O=c1cc(-c2ccccc2)oc2c(O)cccc12
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=c1cc(-c2ccccc2)oc2c(OCC3CO3)cccc12
Temperature: 70 °C
Yield: 99 %

Procedure:
8-Hydroxyflavone (17.9 g, 75 mmol) (see Awad et al, J. Org. Chem., 25, 1333 (1960)) was suspended in a solvent consisting of 22 ml of water and 135 ml of isopropanol. Epichlorohydrin (59 ml, 75 mmol) and NaOH (3.0 g, 75 mmol) were added and the reaction mixture was heated at 70° C. for 31/2 hours. The reaction mixture was then cooled and filtered, and the solvent was removed under reduced pressure. The residue was taken up in 600 ml of CH2Cl2, washed twice with 600 ml of H2O, dried and the remaining solvent was removed by evaporation. This gave 21.9 g of light tan solid (99% yield). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:5][CH:3]1O.CN(C=O)C.C(Br)(=O)C([Br:42])=O>ClCCl>[F:1][C@@H:2]1[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:5][CH:3]1[Br:42]
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1F
Reactant: O=C(Br)C(=O)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: F[C@H]1C(Br)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-Deoxy-2-fluoro-3,4,6-tri-O-benzyl glucopyranose (450 mg) was dissolved in dichloromethane (5.0 mL) and dry DMF (180 μL) was added. The reaction solution was cooled to 0° C. and oxalyl bromide (102 μL) was added. The resulting solution was stirred for 3-5 hours at 0° to 5° C. The solution was then diluted with dichloromethane (50 mL) and washed with water (2×50 mL), dried over sodium sulfate, filtered and evaporated to obtain the title compound.
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][NH:12][C:13]([C:15]1[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=1)=[O:14])([CH3:9])[CH3:8].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.CN1CCOCC1>CN(C=O)C>[Br-:1].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][NH:12][C:13]([C:15]2[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=2)=[O:14])([CH3:9])[CH3:8])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: C[N+](C)(CCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Br-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[N+](C)(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
A solution of (4-amino-butyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate N) (0.25 g, 0.60 mmol), 4-chlorobenzenesulfonyl chloride (0.125 g, 0.59 mmol) and N-methylmorpholine (0.3 mL, 2.73 mmol) in DMF (5 mL) is shaken at RT for 16 h. The reaction mixture is concentrated in vacuo, and the residue is purified by chromatography (basic alumina, 0-15% methanol in DCM) to obtain the title compound. M+ 504.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[N:9]=[CH:8][CH:7]=1>O1CCOCC1.N1C=CC=CC=1>[C:1]([NH:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[N:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cn1nccc(N)c1=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccnn(C)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
A solution of 2.7 ml of acetyl chloride in 20 ml of dioxane was added dropwise to a solution of 4.0 g (0.032 mol) of 5-amino-1-methyl-6-pyridazone in 100 ml of pyridine. After stirring for 12 hours at 25° C., the solvent was distilled off under reduced pressure, and the residue was taken up with methylene chloride, washed with sodium bicarbonate solution and dried. After the solvent had been stripped off under reduced pressure and the residue stirred with a small amount of diisopropyl ether, there was obtained 3.1 g (58.0%) of 5-acetylamino-1-methyl-6-pyridazone (active ingredient 1.001) of melting point 152°-153° C.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[C:19]([O:23][C:24]([N:26]1[C@H:30]([C:31]([OH:33])=O)[CH2:29][S:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[NH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C@H:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40]([OH:42])=[O:41]>CN(C=O)C.O>[C:47]([O:46][C:44]([NH:43][C@@H:39]([CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:31]([C@@H:30]1[CH2:29][S:28][CH2:27][N:26]1[C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:25])=[O:33])[C:40]([OH:42])=[O:41])=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (247 mg, 0.892 mmol) was added to a solution of (R)-3-(tert-butoxycarbonyl)thiazolidine-4-carboxylic acid (Compound tk81) (208 mg, 0.892 mmol) in DMF (1 ml), and the mixture was stirred at room temperature for 30 minutes. A solution of (S)-6-amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (220 mg, 0.892 mmol) in water (1 ml) was added dropwise at room temperature over 3 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes. The reaction solution was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol) to afford (S)-2-((tert-butoxycarbonyl)amino)-6-((R)-3-(tert-butoxycarbonyl)thiazolidine-4-carboxamido)hexanoic acid (Compound tk82) (156 mg, 38%).
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8](=[O:17])[CH2:9][CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.[CH3:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)(O)[O-].[Na+].C(O)(=O)C>[CH3:6][O:7][C:8](=[O:17])[CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([NH:19][CH3:18])[CH2:12][CH2:11]1
Reactant: CN
Reactant: COC(=O)CC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC1CCC(CC(=O)OC)CC1
Reaction time: 4 h
Yield: 35 %

Procedure:
To a tetrahydrofuran (60 mL) solution of (4-oxo-cyclohexyl)-acetic acid methyl ester (2.14 g) obtained in Example (1c), methylamine (2.0 M tetrahydrofuran solution, 12.5 mL), acetic acid (0.72 mL), and sodium triacetoxyborohydride (2.67 g) were added at room temperature. After 4 hours, the reaction mixture was diluted with saturated sodium bicarbonate (100 mL). The organic solvent was removed under reduced pressure. The aqueous mixture was subjected to extraction with dichloromethane (×3). The dichloromethane layer was dried over sodium sulfate and then concentrated. The residue was purified by column chromatography (NH silica gel, dichloromethane/methanol) to obtain the title compound (822 mg, 35%) as a brown oil.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH2:21]([NH:27][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: CCCCCCN
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCCCCNC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Yield: 33.8 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 1.11 g, 4.14 mmol), n-hexylamine (502 mg, 4.96 mmol), Ti(iPrO)4 (2.35 g, 8.27 mmol), TiCl4 (1.0M/DCM, 8.27 ml, 8.27 mmol), and NaBH3CN (520 mg, 8.27 mmol) gives the title compound (495 mg) as a tan solid. Mass spectrum (ion spray): m/z=354 (M+1); (HNMR (CDCl3): 8.59 (s, 1H), 8.16 (d, 1H), 7.38 (d, 1H), 6.99 (s, 1H), 6.96 (d, 1H), 6.94 (d, 1H), 5.92 (br. s, 2M, 4.24 (t, 1H), 3.01 (m, 1H), 2.83 (m, 1H), 2.73 (t, 2H), 2.45 (m, 1H), 1.88 (m, 1H), 1.53 (m, 3H), 1.32 (m, 5H), 0.89 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.C(N(CC)C(C)C)(C)C>C(OCCO)C>[C:19]([O:18][C:16]([NH:15][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[CH:7][CH:6]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: Clc1nccc2ccccc12
Solvent: CCOCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3ccccc23)cc1)NC(=O)OC(C)(C)C

Procedure:
A stirred solution of ethyl (S)-3-(4-aminophenyl)-2-(N-t-butyloxycarbonylamino)propanoate (3.08 g, 10.0 mmol), 1-chloroisoquinoline (1.80 g, 11.0 mmol) and N,N-diisopropylethylamine (1.42 g, 1.91 ml, 11.0 mmol) in 2-ethoxyethanol (1.0 ml) was heated at 130° for 4 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (120 ml) and saturated aqueous NaHCO3 (50 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (80 ml). The combined organic extracts were washed with brine (30 ml), dried (MgSO4) and evaporated in vacuo. The obtained dark oil was chromatographed (silica; 20-30% EtOAc/hexane) to afford the title compound as a pink oil which crystallised on standing (2.78 g, 64%). δH (CDCl3) 8.07 (1H, d, J 5.8 Hz), 7.93 (1H, d, J 8.4 Hz), 7.72 (1H, d, J 7.5 Hz), 7.63 (1H, d), 7.61 (2H, d, J 8.5 Hz), 7.51 (1H, t, J 6.8 Hz), 7.23 (1H, br s), 7.10 (1H, br s), 7.10 (2H, d, J 6.8 Hz), 5.02 (1H, br d, J 8.0 Hz), 4.54 (1H, br m), 4.16 (2H, t, J 7.1 Hz), 3.05 (2H, br m), 1.43 (9H, s), 1.25 (3H, t, J 7.1 Hz); m/z (ES+, 60V) 436 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH2:21][C:22]1[O:23][CH:24]=[CH:25][N:26]=1.C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: ClCc1ncco1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC1(C)C(=O)N(Cc2ncco2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 94.9 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 2-chloromethyl-oxazole (0.47 g; 4 mmol) and K2CO3 (1.1 g; 7.96 mmol) at RT for 18 h. After aqueous work-up the crude material (1.30 g) is de-acetylated in MeOH (30 ml) using DBU (280 μl) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-oxazol-2-ylmethyl-1,3-dihydro-indol-2-one (1.09 g) is obtained and used without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][NH:27]2)=[CH:23][CH:22]=1>CC(O)CCC>[ClH:2].[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([NH:20][C:3]3[C:12]4[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=4)[N:6]=[CH:5][CH:4]=3)[CH:29]=2)[CH:25]=[N:26]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COCCOc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Solvent: CCCC(C)O
Product: COCCOc1cc2nccc(Nc3ccc4cn[nH]c4c3)c2cc1OC
Yield: 54.8 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (300 mg, 1 mmol) (prepared as described for the starting material in Example 5), and 6-aminoindazole (130 mg, 0.97 mmol) in 2-pentanol (10 ml) was heated at reflux for 3 hours. The precipitate was collected by filtration, washed with acetone and dried under vacuum. The residue was purified by reverse phase column chromatography eluting with methanol/water containing 1% acetic acid (40/60). Concentrated hydrochloric acid (5 drops) was added to the combined fractions of the product and the volatiles were removed by evaporation to give 4-(1H-indazol-6-ylamino)-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (213 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[C:14]([CH3:38])=[C:15]([N:19]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=2)[CH2:20][CH2:21][CH3:22])[CH:16]=[CH:17][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:23][C:24]3[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=3)[CH2:20][CH2:21][CH3:22])[C:14]=2[CH3:38])=[CH:5][CH:4]=1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Reactant: COc1ccc(B(O)O)cc1
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(OC)cc2)c1C

Procedure:
Prepared from 4-methoxyphenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=O)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([NH:19][NH2:20])=[O:18].C(O)(=O)C>CCO>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[N:20][NH:19][C:17](=[O:18])[C:16]2[CH:21]=[CH:22][CH:23]=[C:14]([CH3:13])[CH:15]=2)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cccc(C(=O)NN)c1
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=NNC(=O)c1cccc(C)c1)c1cc(Cl)cc(Cl)c1O
Temperature: 60 °C
Yield: 92.8 %

Procedure:
A suspension of 1-(3,5-dichloro-2-hydroxyphenyl)-ethanone (0.100 g, 0.49 mmol), 3-methylbenzoic acid hydrazide (0.069 g, 0.46 mmol), and glacial acetic acid (0.3 mL) in EtOH (3 mL) was heated to 60° C. for 4 h The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with H2O to furnish the title material as a yellow solid (0.144 g, 93%): mp 221-223° C.; 1H NMR (400 MHz, DMSO) δ 14.48 (s, 1H), 11.54 (s, 1H), 7.79-7.72 (m, 2H), 7.68 (d, J=2.5 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.47-7.42 (m, 2H), 2.52 (s, 3H), 2.41 (s, 3H); ESIMS m/z 337 ([M+H]+), 335 ([M−H]−).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[C:8]([O:11][CH:12]=[CH:13][CH2:14][CH2:15][CH3:16])(=[O:10])[CH3:9].C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[C:8]([O:11][C@@H:12]1[NH:5][C:6](=[O:7])[C@H:13]1[CH2:14][CH2:15][CH3:16])(=[O:10])[CH3:9]
Reactant: CCCC=COC(C)=O
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC[C@@H]1C(=O)N[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 120 h
Yield: 3.4 %

Procedure:
Eight hundred microliters of chlorosulfonyl isocyanate was added to a solution of 1.28 g (10 mM) pent-1-enyl acetate in 5 ml methylene chloride at 0° under nitrogen. After stirring at 0° 5 days, the reaction mixture was added dropwise to a mixture of 5 g ice, 1.15 ml water, 2.82 g NaHCO3 and 1.0 g Na2SO3 and stirred at 0° for 30 minutes. The mixture was extracted with 2×25 ml methylene choride and the combined organic phases washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel in hexane/ethyl acetate to yield 60 mg trans 4-acetoxy-3-n-propylazetidin-2-one (3.4%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1cccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(N2CCNCC2)n1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A solution of 2-chloro-6-(trifluoromethyl)pyridine (1.0 g, 5.5 mmol), piperazine (1.4 g, 16.0 mmol), and triethylamine (1.5 mL, 11.0 mmol) were mixed in DMF (10 mL) in a dealed tube. The mixture was heated at 100° C. overnight. The reaction mixture was concentrated and chromatographed on silica gel (ethyl acetate to EA/MeOH/Et3N=9:1:0.5) to give 1.05 g of the desired product. MS calculated for C10H12F3N3: (M+H) 232.1; found 232.1.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:19][CH2:20][N:21]=[C:22]=[O:23]>O1CCCC1>[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:19][CH2:20][NH:21][C:22]2=[O:23])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=C=NCCCl
Reactant: CC(=O)c1sc(N)nc1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1sc(N2CCNC2=O)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of 5-acetyl-2-amino-4-methylthiazole (5.50 g, 35.20 mmol) in tetrahydrofuran (200 mL) was added triethylamine (15.0 mL, 107.6 mmol) and 2-chloroethyl isocyanate (3.90 mL, 45.70 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, and then heated to reflux for 27 hours. The solvent was removed in vacuo, and the residue was washed with water (200 mL) and ethyl acetate/hexanes (1/1, 50 mL) to afford the title compound in 99% yield (7.9 g): MS (ES+) m/z 226.1 (M+1).
Reaction SMILES: [ClH:1].FC1C=CC=C(F)C=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4C=NC=CC=4)=[CH:23][C:16]=23)=[C:10]([F:30])[CH:9]=1)=[O:6].Cl.FC1C=C([CH:64]([C:68]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=2)=[O:69])C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.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>[ClH:1].[F:30][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:64][C:68]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=2)=[O:69])[CH:13]=[CH:12][C:11]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][C:22]([CH3:24])=[CH:23][C:16]=12
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1c(F)cccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a mixture of 3-fluoro-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (20 mg, 0.078 mmol, Compound E of Example 292), 3-(4-fluorophenylamino)-3-oxopropanoic acid (20 mg, 1 mmol, Compound A of Example 25), and HATU (44 mg, 0.12 mmol) in DMF (0.5 mL) was added DIPEA (0.1 mL). The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired product (HCl salt, 12.5 mg, 34%) as a white solid. 1H NMR (CD3OD) δ 8.05 (d, 1H, J=7.2 Hz), 7.79 (dd, 1H, J=12.7, 2.8 Hz), 7.50–7.53 (m, 2H), 7.27–7.36 (m, 2H), 6.97 (m, 2H), 6.70 (d, 1H, J=6.6 Hz), 6.20 (s, 1H), 3.47 (s, 2H), 2.40 (s, 3H); LC/MS(ESI+) m/z 437 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[N:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1CCCCCCCCc1ccccc1
Reactant: CC(C)(C)N
Solvent: Cc1ccccc1
Product: CC(C)(C)N=Cc1ccccc1CCCCCCCCc1ccccc1
Yield: 93.4 %

Procedure:
A stirred solution of 2-(8-phenyloctyl)benzaldehyde (10 g, 0.034 mol), and t-butylamine (4.96 g, 0.068 mol) in toluene (100 mL) was refluxed under standard Dean-Stark conditions for 16 h. The solution was evaporated to an oil which was vacuum distilled (bp 260° C., 0.15 mm Hg) to afford the titled product (11.1 g, 94%): GC RT 19.8 min (DB-1, 30 m×0.53 mm, program, 100° C. for 5 min, 100°-260° C. at 15° C./min, hold at 260° C. for 12 min.); 1H NMR (CDCl3, 400 MHz) δ 8.58 (s, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.29-7.13 (m, 8H), 2.79 (t, J=7.5 Hz, 2H), 2.58 (t, J=7.5 Hz, 2H), 1.59-1.51 (m, 12H), 1.30 (s, 9H).