Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[CH3:9][O:10]S([O-])(=O)=O.C([N+](CC)(CC)C)C.[C:23](OC(=O)C)(=[O:25])C>C(O)(=O)C>[CH3:23][O:25][CH:8]([O:10][CH3:9])[C:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1
Reactant: COS(=O)(=O)[O-]
Agent: CC[N+](C)(CC)CC
Solvent: CC(=O)O
Product: COC(OC)c1cccc(C)c1

Procedure:
Electrolyte: 900 g (8.49 mol) of m-xylene, 180 g of triethylmethylammonium methyl sulfate, 180 g of acetic anhydride and 4740 g of acetic acid
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15](Cl)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C([NH:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][N:44](C(=O)C(F)(F)F)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)=O>C(#N)C>[C:7]1([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:39][CH:40]=2)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ccc(N2CCN(C(=O)C(F)(F)F)CC2)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)Nc1ccc(N2CCNCC2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
To an ice cooled and stirred solution of 4-(4-aminophenyl)piperazine (4.29 g, 24.2 mmol) in dichloromethane (100 mL) containing Et3N (7.42 mL, 52.5 mmol) was added trifluoroacetic anhydride (7.52 mL, 53.2 mmol) in dichloromethane (25 mL) over a 5 minute period. The mixture was allowed to warm to room temperature and stirred two days, then stirred with ice water. The pink solid that separated was isolated by filtration, washed with dichloromethane, aqueous sodium bicarbonate, and water, and dried to obtain 1-(4-(trifiuoroacetamido)phenyl)-4-trifiuoroacetylpiperazine (4.09 g, 46%, mp 193°-194° C.). To a mixture of this material (0.37 g, 1 mmol) and anhydrous potassium carbonate (1.1 g, 8.0 mmol) in acetonitrile (50 mL) was added 3,3,3-triphenylpropionyl chloride (0.54 g) and the mixture stirred at 80° C. for two days. With tlc monitoring, four additional lots of the acid chloride (4×0.54 g) and potassium carbonate (4×1.1 g) were added at 3 hr intervals, with continued reflux until complete disappearance of the starting piperazine by tlc. The solvent was removed in vacuo, the residue triturated with methanol, the solids removed by filtration and the flitrate evaporated to dryness in vacuo. The residue was stirred with 20% KOH in methanol (15 mL) for 3 hr and then evaporated to dryness in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer extracted with 2N HCl. The acid extract was basified with 2N NaOH to pH 9.5 and extracted with ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate and evaporated to dryness to give the title compound as a tan solid (0.40 g, 87%), mp 193°-195° C. 1H NMR (CDCl3) δ 7.33 (m,15H), 6.89 (d, J=8.9, 2H) 6.73 (d, J=8.9, 2H), 6.26 (s, 1H), 3.70 (s, 2H), 3.00 (d, J=10.0, 8H). IR 3056, 1665, 1598, 1515, 1447, 1239, 700 cm-1. MS 462 (MH+). Anal. calcd. for: C31H31N3O.0.5 H2O: C, 79.12; H, 6.85; N, 8.93. Found: C, 78.84; H, 6.66; N, 8.64.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:41]([C:43]1[C:47]([O:48][C:49]2[CH:50]=[C:51]([CH:54]=[C:55]([F:57])[CH:56]=2)[C:52]#[N:53])=[C:46]([CH2:58][CH2:59]O)[NH:45][N:44]=1)[CH3:42]>O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:42][CH2:41][C:43]2[NH:44][N:45]=[C:46]([CH2:58][CH3:59])[C:47]=2[O:48][C:49]2[CH:50]=[C:51]([CH:54]=[C:55]([F:57])[CH:56]=2)[C:52]#[N:53])=[CH:3][CH:4]=1)#[N:7]
Reactant: CCc1n[nH]c(CCO)c1Oc1cc(F)cc(C#N)c1
Reactant: N#Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1n[nH]c(CCOc2ccc(C#N)cc2)c1Oc1cc(F)cc(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
4-Hydroxy-benzonitrile (49 mg, 0.41 mmol), triphenylphosphine (106 mg, 0.41 mmol) and diethylazodicarboxylate (65 μl, 0.41 mmol) were added sequentially to a solution of the alcohol from Example 148 (74 mg, 0.27 mmol) in tetrahydrofuran (2 ml) under nitrogen at 0° C. The reaction was allowed to warm to room temperature and was stirred for 18 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with toluene:ethyl acetate (75:25, by volume) to provide the title compound (50 mg) as a yellow oil.
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[BH4-].[Na+].C(O)C.C(O)(=O)C>O>[OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=1
Reactant: CCCCCCCCCCC(=O)CCCCCNc1ccc(C(=O)OCC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCCCCCC(O)CCCCCNc1ccc(C(=O)OCC)cc1

Procedure:
A suspension of 10 g. of ethyl 4-(6-oxohexadecylamino)benzoate and 2.8 g. of sodium borohydride in 250 ml. of ethanol is stirred at ambient temperature for 3 hours, acidified with glacial acetic acid, and poured into water. The solid is collected by filtration, dried, and recrystallized from hexane to yield the product as a white solid. Alkaline hydrolysis of this ester by the method of Example 10 affords 4-(6-hydroxyhexadecylamino)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1F.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>CS(C)=O.CCOCC>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1ccccc1Cl
Reactant: CN1CCC2(CC1)CNc1cc(Cl)ccc12
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CN1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A mixture of 2.4 g of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine], Example 23b, 0.5 g of sodium hydride (99% ) and 6 g of 2-chlorofluorobenzene in 25 ml of dimethylsulfoxide is stirred at 45° C. under nitrogen for 1 hour. Thereafter, the mixture is quenched with ice-water before being extracted thrice with ether. The combined ether extracts are successively washed with water, dried and concentrated under vacuum leaving a reddish oil. The oil is passed through an alumina column, ether eluant, and the purified oil, in ether, is converted to its maleic acid salt. The salt is recrystallized from an acetone-ether mixture to provide off-white platelets, mp 172°-173° C. of 6-chloro-1-(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] maleate.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=1[F:18])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:19]C(OC(C)=O)=O.C(OCC)(OCC)OCC.[NH2:36][C:37]1([CH2:41][OH:42])[CH2:40][CH2:39][CH2:38]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:42][CH2:41][C:37]1([NH:36][CH:19]=[C:3]([C:2](=[O:1])[C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=2[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:40][CH2:39][CH2:38]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: NC1(CO)CCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CNC1(CO)CCC1)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.3 %

Procedure:
A stirred solution of ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (2.00 g, 7.57 mmol), Ac2O (4.29 mL, 45.4 mmol) and triethyl orthoformate (2.51 mL, 15.1 mmol) was heated at 120° C. for 3 hours. The mixture was concentrated in vacuo and dried under high vacuum. The crude product was dissolved in toluene (30 mL) and a suspension of (1-aminocyclobutyl)methanol (1.04 g, 7.57 mmol) in toluene (5 mL), triethylamine (1.06 mL, 7.57 mmol) were added under ice-cooling. The mixture was stirred for 18 h at room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by column chromatography (Hexane:EtOAc 10:1→1:1) to yield the title compound (1.57 g, 55%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 0.95-1.11 (3H, m), 1.85-1.90 (1H, m), 1.91-2.07 (2H, m), 2.17-2.26 (2H, m), 2.27-2.36 (2H, m), 3.80-3.83 (2H, m), 4.00-4.10 (2H, m), 6.95-7.13 (1H, m), 8.17-8.22 (1H, m), 9.87-11.36 (1H, m). ESIMS (+): 376 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][NH:8]C(=O)OC(C)(C)C)(=[O:4])=[O:3].[ClH:16].O1CCOCC1.C(OCC)(=O)C>C(OCC)C>[ClH:16].[ClH:16].[NH2:8][CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCCN
Yield: 100 %

Procedure:
tert-Butyl {2-[(methylsulfonyl)amino]ethyl}carbamate (21 g, 88 mmol) was stirred in a solution of 4 N hydrogen chloride in 1,4-dioxane (97 mL, 388 mmol) for 30 minutes. Trituration with ethyl acetate and hexanes followed by diethyl ether and hexanes gave the desired compound as a gum (19 g, 100%). LCMS calculated for C3H11N2O2S (M+H)+: m/z=139.0.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10](O)=[O:11])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10]([N:24]=[N+:25]=[N-:26])=[O:11])[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCOc1cc(C=CC(=O)O)ccc1OC(C)=O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C=CCOc1cc(C=CC(=O)N=[N+]=[N-])ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
26.2 g (0.1 mol) of 3-allyloxy-4-acetoxy-cinnamic acid are suspended in 90 ml of benzene and 14.6 ml (0.2 mol) of thionyl chloride are added. The reaction mixture is heated to the boil under reflux for 30 minutes. Thereafter the solvent and the excess thionyl chloride are removed by distillation under reduced pressure. The crude 3-allyloxy-4-acetoxycinnamic acid chloride which is left is dissolved in 100 ml of absolute dimethoxyethane, 19.5 g (0.3 mol) of sodium azide are added and the reaction mixture is subsequently stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30° C. Hereupon, colourless crystals separate out. The crystallisation is completed by addition of ether. 3-Allyloxy-4-acetoxy-cinnamic acid azide of melting point 83°-84° C. is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:9][NH:10]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:9][NH2:10])[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: CN(C)CCCc1cc(CNC(=O)OC(C)(C)C)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCc1cc(CN)ccc1F
Reaction time: 1 h

Procedure:
To [3-(3-Dimethylamino-propyl)-4-fluoro-benzyl]-Boc-amine (3.0 g, 10 mmol) in 100 mL of CH2Cl2 was slowly added TFA (10 mL). The resulting solution was stirred for 1 h, then concentrated. The residue was diluted with CH2Cl2 and aq. NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated to give the title compound. MS (ES+): 211 (M+H)+; (ES−): 209 (M−H). Calc'd C12H19FN2-210.29.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][NH:7]2.Cl.CN(C)CCCN=C=NCC.[N:26]1([C:32]2[N:33]=[C:34]([CH2:39][C:40]([O-])=[O:41])[NH:35][C:36](=[O:38])[CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[Na+].O>CN(C)C=O.N1C=CC=CC=1>[N:26]1([C:32]2[N:33]=[C:34]([CH2:39][C:40](=[O:41])[N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:11]=[CH:10][CH:9]=4)[CH2:5][CH2:6]3)[NH:35][C:36](=[O:38])[CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: FC(F)(F)c1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c1cccc2C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.4 %

Procedure:
700 mg of 4-trifluoromethyl-2,3-dihydro-1H-indole and 1.15 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 977 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2d of example 1d) in 25 ml of N,N-dimethylformamide and 25 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours, and then water is added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05: v/v), so as to give 220 mg of 6-(morpholin-4-yl)-2-{2-oxo-2-[4-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[CH:14][C:13]2=[O:26])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:28]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:59][C@@H:60]([CH2:90]O)[CH2:61][N:62]1[CH:66]=[CH:65][C:64]([NH:67]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:63]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[CH:14][C:13]2=[O:26])[C:9]([NH:67][C:64]2[CH:65]=[CH:66][N:62]([CH2:61][C:60]([OH:59])([CH3:90])[CH3:28])[N:63]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(Cl)cc2Cl)=CC1=O
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccc(Cl)cc3Cl)=CC2=O)n1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,4-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (210 mg, 0.5 mmol) in dichloromethane (10 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (300 mg, 1.6 mmol) and N,N-diisopropylethylamine (340 mg, 2.6 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (240 mg, 1.6 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 82 mg, 0.5 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-2-[4-(2,4-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (0.095 g, 34%) as a light brown solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.75-1.07 (m, 2H), 1.14 (br. s., 6H), 1.17-1.29 (m, 3H), 1.60-1.99 (m, 8H), 3.62 (br. s., 1H), 3.93 (s, 2H), 4.10 (d, J=18.1 Hz, 1H), 4.30 (d, J=18.1 Hz, 4.83-4.88 (m, 1H), 4.88 (s, 1H), 6.67 (d, J=2.0 Hz, 1H), 7.14-7.23 (m, 1H), 7.27-7.32 (m, 2H), 7.49 (d, J=2.0 Hz, 1H), 8.54 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.NC1C=C(C2N=C3N(C=2C2C=CN=C(NC4C=CC=C(OCCCN5CCOCC5)C=4)N=2)C=CS3)C=CC=1.[N:75]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)=[C:76]=[O:77].FC1C=CC=C(F)C=1C(Cl)=O>>[N:31]1([CH2:30][CH2:29][C:25]2[CH:24]=[C:23]([NH:22][C:18]3[N:17]=[C:16]([C:15]4[N:14]5[C:10]([S:11][CH:12]=[CH:13]5)=[N:9][C:8]=4[C:4]4[CH:3]=[C:2]([NH:1][C:76]([NH:75][C:78]5[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=5)=[O:77])[CH:7]=[CH:6][CH:5]=4)[CH:21]=[CH:20][N:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1
Agent: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Agent: O=C(Cl)c1c(F)cccc1F
Product: O=C(Nc1ccccc1)Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1

Procedure:
The title compound was prepared as described in EXAMPLE 297, with the following substitutions: 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(2-morpholinoethyl)phenyl)pyrimidin-2-amine for 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(3-morpholinopropoxy)phenyl)pyrimidin-2-amine and isocyanatobenzene for 2,6-difluorobenzoyl chloride. (ESI(+)) m/e 617 (M+H)+; (ESI(−)) m/e 615 (M−H)−; 1H-NMR (300 MHz, DMSO-d6) □9.65 (s, 1H), 8.84 (s, 2H), 8.70 (s, 1H), 8.29 (d, 1H), 7.74 (t, 1H), 7.49-7.63 (m, 4H), 7.43-7.48 (m, 2H), 7.39 (t, 1H), 7.16-7.31 (m, 4H), 6.92-7.01 (m, 1H), 6.87 (d, 1H), 6.63 (d, 1H), 3.52-3.60 (m, 4H), 2.66-2.77 (m, 2H), 2.52-2.57 (m, 2H), 2.36-2.44 (m, 4H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:15]([N:14]([CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNCc1ccccc1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCCCCN(C)Cc1ccccc1
Yield: 163.9 %

Procedure:
Ethyl 7-bromoheptanoate (6.00 g, 25.3 mmol) was dissolved in acetonitrile (30 mL), N-methyl-benzylamine (6.53 mL, 50.6 mmol) and potassium carbonate (13.99 g, 101 mmol) were added at room temperature, and the mixture was heated to reflux for 6 hours. The mixture was left to stand for cooling, and the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried with anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give crude ethyl 7-[benzyl(methyl)amino]heptanoate (11.5 g) as a light yellow oily substance. The resulting crude product was dissolved in 60 mL of ethanol, 10% palladium-carbon (0.72 g) was added, and the mixture was stirred at 60° C. under a hydrogen atmosphere for 16 hours. The mixture was left to stand for cooling, insoluble matter was removed by filtration, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by NH silica gel chromatography (ethyl acetate:methanol=10:0→10/1, v/v) to give the title compound (4.67 g; yield, 98%) as a colorless oily substance.
Reaction SMILES: [BrH:1].C(OC([N:12]([CH2:46][CH2:47][C:48]1[C:56]2[S:55][C:54](=[O:57])[NH:53][C:52]=2[C:51]([OH:58])=[CH:50][CH:49]=1)[CH2:13][CH2:14][N:15]([CH:39]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[C:16](=[O:38])[CH2:17][CH2:18][N:19]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)C(=O)OCC1C=CC=CC=1)=O)C1C=CC=CC=1.COC(C)(C)C>C(O)(=O)C>[BrH:1].[BrH:1].[CH:39]1([N:15]([CH2:14][CH2:13][NH:12][CH2:46][CH2:47][C:48]2[C:56]3[S:55][C:54](=[O:57])[NH:53][C:52]=3[C:51]([OH:58])=[CH:50][CH:49]=2)[C:16](=[O:38])[CH2:17][CH2:18][NH:19][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(OCc1ccccc1)N(CCC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCCC1)CCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: O=C(CCNCCc1ccccc1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C1CCCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen bromide (33% in acetic acid) (0.54 mL) was added to the product from step i) (0.238 g) in acetic acid (0.8 mL) at 0° C. The resulting solution was stirred at room temperature for 2 h then t-butyl methyl ether (3 mL) was added and the mixture stirred for 10 min. A gummy solid formed, which was filtered off and triturated with t-butyl methyl ether (4×3 mL) to form a pale orange solid (0.888 g). The solid was dried at 45° C. for 1 h then recrystallised from hot ethanol (˜3 mL) to afford the title product as a white solid (0.040 g).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.Br[C:9]1[CH:17]=[C:16]([CH3:18])[C:12]([N:13]([CH3:15])[CH3:14])=[C:11]([CH3:19])[CH:10]=1.[P:20]([O-:27])(OCC)OCC>O1CCCC1.C1(C)C=CC=CC=1.O>[CH3:14][N:13]([CH3:15])[C:12]1[C:11]([CH3:19])=[CH:10][C:9]([PH:20](=[O:27])[C:9]2[CH:17]=[C:16]([CH3:18])[C:12]([N:13]([CH3:15])[CH3:14])=[C:11]([CH3:19])[CH:10]=2)=[CH:17][C:5]=1[CH3:6]
Reactant: BrCCBr
Reactant: CCOP([O-])OCC
Reactant: Cc1cc(Br)cc(C)c1N(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc([PH](=O)c2cc(C)c(N(C)C)c(C)c2)cc(C)c1N(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Under an argon atmosphere, a solution of magnesium (2.4 g, 0.75 equivalent), a small amount of iodine and a small amount of 1,2-dibromoethane in tetrahydrofuran (15 mL) was stirred at room temperature for 1 hr. A solution of 4-bromo-N,N,2,6-tetramethylaniline (31.2 g, 0.137 moL) synthesized in Reference Example 2 in tetrahydrofuran (50 mL) was added to the mixture at 25° C. to 30° C. over 1 hr, and the mixture was stirred at 40° C. for 1 hr. Then, a solution of diethyl phosphite (4.69 g, 0.25 equivalent) in tetrahydrofuran (15 ml) was added at 25° C. to 30° C. over 1 hr. Water (60 mL) was added to the mixture at 0° C. to 5° C., and then toluene (100 mL) was added to the mixture, and the insoluble material was removed by filtration. The filtrate was partitioned, and the organic layer was washed with water (30 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane/ethyl acetate) to give the title compound (4.6 g, colorless liquid). yield 40%.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=O.[C:29]([O:35][CH2:36][CH2:37][CH3:38])(=[O:34])[CH2:30][C:31]([CH3:33])=O>C(O)(=O)C>[CH3:28][O:27][C:22]1[CH:21]=[C:8]2[C:7](=[CH:24][C:23]=1[O:25][CH3:26])[N:6]=[C:31]([CH3:33])[C:30]([C:29]([O:35][CH2:36][CH2:37][CH3:38])=[O:34])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 79 %

Procedure:
Conc. sulfuric acid was added to a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone, propyl acetoacetate and acetic acid. The resulting mixture was treated according to the same manner as that described in Reference example 1 to obtain propyl 6,7-dimethoxy-4-(3,4- dimethoxyphenyl)-2-methylquinoline-3-carboxylate (79%) which was recrystallized from ethyl acetate/isopropyl ether.