Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:33])=[C:8]2[C:16](=[C:17]([C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]1[O:13][CH2:14][O:15][C:11]=1[CH:10]=[CH:9]2)=[O:5])[CH3:2].[CH3:34][Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][CH3:34])=[C:8]2[C:16](=[C:17]([C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]1[O:13][CH2:14][O:15][C:11]=1[CH:10]=[CH:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2c3c(ccc2c1O)OCO3
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2c3c(ccc2c1OC)OCO3
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
Compound 33 (95 mg, 0.21 mmol) was dissolved in a mixture of MeOH (3 mL) and THF (6 mL). (Trimethylsilyl)diazomethane (2 M in hexanes, 0.6 mL, 1.2 mmol) was added to the solution. The mixture was stirred for 12 h at room temperature, and then concentrated in vacuo. The crude material was purified by column chromatography on silica gel using CH2Cl2 to afford 35 (97 mg, 99%) as a yellow oil. 1H NMR (CDCl3) δ 7.86 (d, 1H, H5, J=8.7 Hz), 7.26 (d, 1H, H6, J=8.7 Hz), 6.75-6.82 (m, 3H, H2′+H5′+H6′), 6.00 (AB, 2H, 3′,4′-OCH2O—, Δδ=11.7 Hz, J=1.2 Hz), 5.87 (AB, 2H, 7,8-OCH2O—, Δδ=9.0 Hz, J=1.2 Hz), 4.39 (q, 2H, OCH2CH3, J=7.2 Hz), 4.06 (s, 3H, 4-OCH3), 4.03 (q, 2H, OCH2CH3, J=7.2 Hz), 1.38, 1.04 (each t, 2×3H, 2×OCH2CH3, J=7.2 Hz); MS (EI) m/z 466 [M]+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CCC.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>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[C:3]([OH:9])=[CH:4][C:5]([OH:6])=[CH:7][CH:8]=1
Reactant: Oc1ccc(Br)c(O)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: COc1ccc(F)c(-c2ccc(O)cc2O)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 4-bromoresorcinol (10.1 g) in 1-butanol (200 mL) were added 2-fluoro-5-methoxyphenylboronic acid (10.8 g), tetrakis(triphenylphosphine)palladium(0) (3.00 g) and 2.0 M aqueous sodium carbonate solution (54 mL), and the mixture was stirred at 90° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.6 g) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH2:30]([OH:34])[CH2:31][CH2:32][CH3:33]>O1CCOCC1.CN(C=O)C>[CH2:30]([O:34][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-mopholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and butanol in dioxane and DMF. ES-MS m/e (%): 465 (M+Na+, 40), 443 (M+H+, 100).
Reaction SMILES: [P:1]([OH:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].C(O[O:14][C:15]([CH3:18])(C)C)(C)(C)C.[CH3:19][C:20]1[CH:25]2[C:26]([CH3:28])([CH3:27])[CH:23]([CH2:24]2)[CH2:22][CH:21]=1>>[CH2:3]([O:2][P:1]([CH:21]1[CH2:22][CH:23]([CH:26]([CH3:27])[CH3:28])[CH2:24][CH:25]([P:1](=[O:5])([O:14][CH2:15][CH3:18])[O:2][CH2:3][CH3:4])[CH:20]1[CH3:19])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: CC1=CCC2CC1C2(C)C
Reactant: CCOP(O)OCC
Reactant: CC(C)(C)OOC(C)(C)C
Product: CCOP(=O)(OCC)C1CC(C(C)C)CC(P(=O)(OCC)OCC)C1C
Temperature: 25 °C
Yield: 70 %

Procedure:
To a 5-liter vessel equipped with a mechanical stirrer was added 863 ml (6.7 mol) of diethyl hydrogen phosphite (DEHP). The stirred DEHP was heated to 140° and then 12.3 ml (0.067 mol) of di-tertiary-butyl peroxide was added. Finally, α-pinene, 211 ml (1.3 mol), was added dropwise over a period of 10-30 minutes while the reaction temperture was maintained at 140°-150°. This mixture was heated for 5 hours at 140°, cooled at room temperature, and then distilled in vacuo to yield 54.2 g (0.2 mol; 15.4%) of diethyl para-menth-6-en-2-ylphosphonate, bp=180°-185° (1.2 mm), and 376.5 g (0.91 mol, 70.0%) of tetraethyl-para-menthane-2,6-diyldiphosphonate), bp=198° (0.4 mm). The NMR spectrum showed an A2B3 pattern corresponding to the ethyl groups at 4.12δ and 1.35δ along with the remainder of the proton signals between 2.5δ and 0.8δ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.Cl.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28][NH2:29])[CH2:24][CH2:23]1>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:18])([CH3:17])[C:13](=[O:15])[N:28]([CH:25]3[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]3)[N:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NNC1CCNCC1
Reactant: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Temperature: 20 °C
Reaction time: 8 h

Procedure:
1000 g of methyl 3-(3,4-dimethoxyphenyl)-2,2-dimethyl-3-oxopropanoate (compound D1) are dissolved in 10.5 l of methanol. 2500 g piperidin-4-yl-hydrazine dihydrochloride, solved in 4 l of water are added rapidly. The mixture is heated to reflux and kept at reflux temperature for 4 days. The reaction mixture is cooled to 20° C., 10 l of water are added and then methanol is removed by distillation in vacuum. The aqueous solution is allowed to stand overnight at RT. The solution is cooled and aqueous sodium hydroxide (c=10 mol/l) (about 2 l) is added during 4 to 5 h by keeping the temperature below 20° C. and the pH should be higher than 13. The product crystallizes during adding of sodium hydroxyide. The mixture is stirred 1 h at 10° C., filtered over a filter press and washed with 0.51 of water. The product is dried at 50° C. in a circulating air dryer resulting in the title compound. (compound B1)
Reaction SMILES: [F:1][C:2]([F:15])([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)[CH:3]([F:5])[F:4].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>O.ClCCCl>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:2]([F:15])([F:1])[CH:3]([F:5])[F:4])[CH:8]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: FC(F)C(F)(F)Oc1cccc(CNc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
EX-220A) To a 1,2-dichloroethane (30 mL) solution of 3-(1,1,2,2-tetrafluoroethoxy)-benzaldehyde (2.00 g, 9.0 mmol) was added 3-bromoaniline (0.98 mL, 9.0 mmol), NaB(OAc)3H (2.48 g, 11.7 mmol) and acetic acid (0.57 mL, 10 mmol). The cloudy mixture was stirred at room temperature for 1 ; hour. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 3.27 g (96%) of the desired N-(3-bromophenyl)- [[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine product as a brown oil which was used without further purification. MS m/z=377 [M+].
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.CON(C)[C:21]([C:23]1[N:24]=[N:25][N:26]([CH2:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=2)[C:27]=1[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:22].Cl>C1COCC1.CCOCC.CCOC(C)=O>[F:44][C:41]([F:42])([F:43])[C:39]1[CH:40]=[C:35]([CH:36]=[C:37]([C:45]([F:46])([F:48])[F:47])[CH:38]=1)[CH2:34][N:26]1[C:27]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[C:23]([C:21]([C:14]2[N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[Cl:6])[CH:17]=[CH:16][N:15]=2)=[O:22])[N:24]=[N:25]1
Reactant: CON(C)C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Reactant: Clc1ccccc1-n1ccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1)c1nccn1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Add BuLi (0.80 mL, 1.28 mmol) to a −78° C. solution of 1-(2-chloro-phenyl)-1H-imidazole (200 mg, 1.12 mmol) in THF (3 mL). Stir at −78° C. for 20 min., then add a solution of 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid methoxy-methyl-amide (261 mg, 0.57 mmol) in THF (2 mL) via cannula. Stir the resulting solution at −78° C. for 10 min., then allow to warm to RT and stir for 2 h. Add 1N HCl (1.3 mL) and stir for 30 min. Dilute reaction with EtOAc (50 mL) and wash with water (20 mL), saturated NaHCO3 (20 mL) and brine (20 mL). Dry, filter and concentrate the organic solution and purify the crude material by silica gel chromatography (20% to 80% EtOAc/hexanes) to give a brown solid. Trituration with cold ether gives the title compound as a fine white powder. MS [ES] 577.2 (M+H)+. 1H NMR (400 MHz, CHCl3) δ 8.68 (dd, 1H, J=1.4, 4.8 Hz), 8.48 (d, 1H, J=1.8 Hz), 7.81 (s, 1H), 7.48 (m, 3H), 7.46 (m, 1H), 7.44 (m, 1H), 7.34 (m, 4H), 7.17 (m, 1H), 5.60 (s, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:16]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH2:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCCC1CCc2ccccc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2CCc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
15.73 g (82.5 mmol) of p-toluenesulphonyl chloride are added at room temperature while stirring to a solution of 13.36 g (75 mmol) of 2-(2-hydroxyethyl)chroman in 90 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. After stirring for a further 3 hours at room temperature, the reaction mixture is poured onto ice-water. The crystals formed are filtered off with suction, washed with water and dried in vacuo. There are obtained 8.68 g (34.7%) of 2-[2-(p-toluenesulphonyloxy)ethyl]chroman which melts at 57°-59°.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].C([Li])CCC.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH2:20][CH2:21][CH2:22][CH3:23])[CH3:19])=[O:17].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH2:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:3]#[C:2][CH2:1][OH:4])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN(C)C(=O)CCCCCBr
Reactant: C#CCO
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)CCCCCC#CCO
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
A solution of 1.77 ml of propargyl alcohol, 30 ml of tetrahydrofuran and 7.5 ml of hexamethyl phosphotriamide cooled to -60° C. was admixed with 37.5 ml of a 1.6M solution of butyllithium in hexane and after stirring for 45 minutes at -30° C., 7 g of the product of Step A in solution in 7 ml of tetrahydrofuran were added. The mixture was stirred for 16 hours at ambient temperature and then poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with 2N hydrochloric acid and with a saturated solution of sodium bicarbonate, dried and evaporated to dryness. The 5.78 g of residue were chromatographed on silica (eluant: methylene chloride-ethyl acetate 70-30, then methylene chloride-isopropanol 95-5) to obtain 1.65 g of the desired product.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.[NH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C1CCC(N=C=NC2CCCCC2)CC1>ClC(Cl)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
2.03 g of TEA was added to a mixture of 5.84 g of Boc-Phe-OH and 7.03 g of TosOH.β-Ala-OBzl in 80 ml of dichloroethane. 4.54 g of DCC was added to the solution at 0 ° C. After stirring for 3 hrs at 0 ° C. and overnight at room temperature, precipitated DCUrea was filtered off and the solvent was distilled in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 10% citric acid aqueous solution, water, 5% sodium hydrogencarbonate aqueous solution and brine. After dehydration over sodium sulfate anhydride, the solvent was evaporated to give 8.36 g of Boc-Phe-β-Ala-OBzl; yield 98%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:16](N)=O>O>[N:11]1([C:8]2[CH:7]=[C:3]3[C:2](=[CH:10][CH:9]=2)[N:1]=[CH:16][NH:6][C:4]3=[O:5])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: NC(=O)c1cc(-n2ccnc2)ccc1N
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2ccc(-n3ccnc3)cc12
Temperature: 160 °C

Procedure:
A mixture of 2-amino-5-(1-imidazolyl)benzamide (12.0 g) and formamide (30 ml) was heated at 160° C. for 3 hours. The mixture was cooled and added to water. The precipitate was filtered off and washed with water to give 6-(1-imidazolyl)-3,4-dihydroquinazolin-4-one (7.5 g); NMR Spectrum: (CD3SOCD3) 7.15 (s, 1H), 7.80 (s, 1H), 7.90 (s, 1H), 8.13 (m, 2H), 8.26 (d, 1H), 8.41 (s, 1H);
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:32]=[CH:31][C:30]([O:33]CC5C=CC=CC=5)=[CH:29][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].[OH-:42].C(Cl)(Cl)[Cl:44]>>[ClH:44].[OH:33][C:30]1[CH:31]=[CH:32][C:18]2[C:17]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:14][CH:13]=3)=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:12][CH2:11][CH2:10][C:9]([OH:8])=[O:42])=[CH:24][CH:23]=3)[S:20][C:19]=2[CH:29]=1
Reactant: ClC(Cl)Cl
Reactant: [OH-]
Reactant: O=C(c1ccc(OCCN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(OCc3ccccc3)ccc12
Agent: [NH4+]
Product: Cl
Product: O=C(O)CCCOc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Yield: 52 %

Procedure:
By essentially following the procedure described below in Example 25, Part B, the title compound was prepared as a foam starting from 6-benzyloxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part C) in 52% yield following MPLC (SiO2; 0.5% in CHCl3 sat'd with NH4OH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl[CH2:19]C1C=CC(C(O)=O)=CC=1.COC(=O)C1C=CC(CCl)=CC=1.CN1CCNCC1>>[CH3:19][O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([CH2:8][N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CN1CCNCC1
Agent: COC(=O)c1ccc(CCl)cc1
Product: COC(=O)c1ccc(CN2CCN(C)CC2)cc1

Procedure:
4-(4-methylpiperazin-1-ylmethyl)benzoic acid (17) is obtained as described in the following Scheme 5. 4-Chloromethylbenzoic acid (14) is first esterified to a methyl ester to protect an acid group in the following reaction. 4-Chloromethyl-benzoic acid methyl ester (15) is then allowed to react with 1-methylpiperazine to give 4-(4-methylpiperazin-1-ylmethyl)benzoic acid methyl ester (16). Methyl ester is cleaved by heating with potassium hydroxide in methanol. 4-(4-methylpiperazin-1-ylmethyl)benzoic acid is reacted as described above in Scheme 4 with aminopyridine derivatives (3) to result in N-4-(4-methylpiperazin-1-ylmethyl)benzamide derivatives of (13). By a similar manner other N-4-(piperazin-1-ylmethyl)benzamide derivatives of (13) can be prepared.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:27][O:28][CH3:29])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-].O>C1COCC1.O.CO>[C:30]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]3[CH2:21][CH2:22][C@H:23]([O:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:25]3)[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: COCO[C@H]1CC[C@H](N(c2cc(C3=CCCCC3)sc2C(=O)OC)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCO[C@H]1CC[C@H](N(c2cc(C3=CCCCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-methoxymethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (775 mg, 1.54 mmol) in THF:H2O:MeOH (3:1:2) (10 mL), was added LiOH in water (1N) (4.6 mL, 4.6 mmol). The reaction mixture was stirred at 70° C. for 5 h. The mixture was concentrated under reduced pressure on a rotary evaporator and the residue was treated with a solution of 0.1 N HCl and extracted in EtOAc. The EtOAc layer was dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by HPLC purification afforded 5-cyclohex-1-enyl-3-[(trans-4-methoxymethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (380 mg, 50%) as a foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:20]=[C:16]([C:17]([OH:19])=O)[C:15]([OH:21])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:22][C:23]([F:36])([F:35])[C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[NH2:27]>>[F:22][C:23]([F:35])([F:36])[C:24]1[CH:25]=[C:26]([NH:27][C:17](=[O:19])[C:16]2[CH:20]=[C:12]([N:11]=[N:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:15]=2[OH:21])[CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=1
Reactant: O=C(O)c1cc(N=Nc2ccc([N+](=O)[O-])cc2)ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(N=Nc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 11.3 %

Procedure:
Using 5-[(4-nitrophenyl)diazenyl]salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([O:8]S(C)(=O)=O)[CH2:6][CH2:5][N:4]([C:13]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:14])[CH2:3]1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36](O)[CH:37]=1)[N:34]=[C:33]([C:39]1[N:43]3[CH:44]=[CH:45][C:46]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[CH:47][C:42]3=[N:41][CH:40]=1)[CH:32]=[CH:31]2.C([O-])([O-])=O.[Cs+].[Cs+].O>CC(N(C)C)=O.CCOC(C)=O>[F:1][C@H:2]1[C@H:7]([O:8][C:36]2[CH:37]=[C:28]([F:27])[CH:29]=[C:30]3[C:35]=2[N:34]=[C:33]([C:39]2[N:43]4[CH:44]=[CH:45][C:46]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[CH:47][C:42]4=[N:41][CH:40]=2)[CH:32]=[CH:31]3)[CH2:6][CH2:5][N:4]([C:13]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:14])[CH2:3]1
Reactant: COCCOc1ccn2c(-c3ccc4cc(F)cc(O)c4n3)cnc2c1
Reactant: CS(=O)(=O)O[C@H]1CCN(C(=O)OCc2ccc3ccccc3c2)C[C@H]1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COCCOc1ccn2c(-c3ccc4cc(F)cc(O[C@@H]5CCN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5F)c4n3)cnc2c1
Temperature: 90 °C
Yield: 97.7 %

Procedure:
(3R,4S)-naphthalen-2-ylmethyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (170 mg, 0.44 mmol) (Example 20, Step F, derived from Peak 2), 6-fluoro-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (173 mg, 0.49 mmol) and Cs2CO3 (290 mg, 0.89 mmol) were weighed into a flask and suspended in 10 mL of DMA. The reaction was then heated to 90° C. overnight. The reaction was then cooled to ambient temperature, followed by workup with water and EtOAc. The combined organic phase was concentrated in vacuo, followed by flash column chromatography (1-10% MeOH/DCM) affording the desired product as a brown semi-solid (270 mg, 0.43 mmol, 95%). MS APCI (+) m/z 639.2 and 640.1 (M+1/+3) detected.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2)([CH3:21])[CH3:20]
Reactant: Oc1cccc2ncccc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc2ncccc12
Temperature: 80 °C
Yield: 91 %

Procedure:
To a mixture of quinolin-5-ol (2.00 g, 13.8 mmol) and K2CO3 (7.62 g, 55.1 mmol) in DMF (20 mL) was added 2-iodopropane (2.76 mL, 27.6 mmol). The reaction mixture was heated at 80° C. overnight before it was partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. The crude material was purified by column chromatography (10-20% EtOAc-Hex) to provide 5-isopropoxyquinoline (91%) as a light yellow oil. ESI-MS m/z calc 187.1. found 188.3 (M+1)+. Retention time: 1.06 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.O>O1CCCC1>[Cl:1][C:2]1[C:11]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(C(C)(C)C#N)c1Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of methyl 2-chloro-3-(1-cyano-1-methylethyl)benzoate (1.67 g, 7.02 mmol) in tetrahydrofuran (24 mL)/methanol (8 mL)/water (8 mL) was added lithium hydroxide•monohydrate (501 mg, 11.9 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and 6N hydrochloric acid (2.8 mL) was added dropwise to the residue. The precipitate was collected by filtration, and washed with water to give the title compound (1.43 g, 91%) as a white powder.