Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:33][C@H:11]([CH2:12][O:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:10]([I:34])[CH2:9]1)[CH3:2]>C(O)(=O)C.O>[CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:33][C@H:11]([CH2:12][OH:13])[C@@H:10]([I:34])[CH2:9]1)[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](I)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Solvent: O
Solvent: CC(=O)O
Product: CCc1cn([C@H]2C[C@H](I)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 41.5 %

Procedure:
A solution of 720 mg of 2',3'-dideoxy-5-ethyl-3'-iodo-5'-O-trityluridine in a mixture of 16 ml of acetic acid and 4 ml of water was stirred and heated under reflux for 1 hour. The solvent was removed by evaporation and the residue was crystallized from a mixture of ethyl acetate and hexane to give 180 mg of 2',3'-dideoxy-5-ethyl-3'-iodouridine in the form of a white solid of melting point 161.5°-163° C.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1.[C:24](Cl)(=[O:26])[CH3:25].[OH-].[Na+]>O1CCCC1>[C:24]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:12][CH2:13]1)(=[O:26])[CH3:25]
Reactant: c1cc2[nH]ncc2cc1NC1CCNCC1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Nc2ccc3[nH]ncc3c2)CC1
Yield: 60.2 %

Procedure:
Triethylamine (0.39 ml, 2.80 mmol) was added to a solution of the N-(4-piperidinyl)-1H-indazol-5-amine (0.301 g, 1.39 mmol) obtained in Example 15, (a) in tetrahydrofuran (5 ml) at room temperature, followed by adding thereto a solution of acetyl chloride (0.12 g, 1.53 mmol) in tetrahydrofuran (2 ml) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. Then, the reaction solution was poured into a 1N-aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was suspended in acetone and stirred. Thereafter, the solid was collected by filtration and dried under reduced pressure to obtain N-(1-acetyl-4-piperidinyl)-1H-indazol-5-amine (0.216 g, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N:14]2[C:18](=[O:19])[C:17]([CH2:27][CH:28]=[CH2:29])([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[NH:16][C:15]2=[S:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37](=[O:40])[CH2:38]Br)=[CH:35][CH:34]=1)#[N:32].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:12]([CH:11]2[N:14]2[C:18](=[O:19])[C:17]([CH2:27][CH:28]=[CH2:29])([CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[N:16]=[C:15]2[S:30][CH2:38][C:37]([C:36]2[CH:41]=[CH:42][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)=[O:40])[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC1(Cc2ccncc2)NC(=S)N(C2C3CN(C(=O)OC(C)(C)C)CC32)C1=O
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: C=CCC1(Cc2ccncc2)N=C(SCC(=O)c2ccc(C#N)cc2)N(C2C3CN(C(=O)OC(C)(C)C)CC32)C1=O

Procedure:
Using the same procedure as described in Example 2C, the reaction of the title compound of 30A (10.3 mmol) and 4-cyanophenacyl bromide (11.3 mmol) in the presence of potassium bis(trimethylsilyl)amide (11.3 mmol) generated the title compound of 30B, 4.82 g (8.4 mmol, 84% yield).
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:3]=1.[CH3:29][C:30]1([CH3:46])[C:42]2[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:4]2[C:5]3[C:16]4=[C:17]5[C:8](=[CH:7][CH:6]=3)[CH:9]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[C:12]5[CH:13]=[CH:14][C:15]4=[C:2]([C:40]3[CH:39]=[CH:38][C:37]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]([CH3:29])([CH3:46])[C:42]=4[CH:41]=3)[CH:3]=2)=[CH:27][CH:26]=1
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
Reactant: CC(C)(C)c1cc2ccc3c(Br)cc(-c4ccc(Cl)cc4)c4ccc(c1)c2c34
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1cc2ccc3c(-c4ccc(Cl)cc4)cc(-c4ccc5c(c4)C(C)(C)c4ccccc4-5)c4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
A mixed solution of 10.0 g of 1-bromo-7-t-butyl-3-(4-chlorophenyl)pyrene, 5.86 g of 9,9-dimethylfluoren-2-yl boronic acid, 0.016 g of bis(triphenylphosphine)palladium dichloride, 33 ml of an aqueous 1.5M sodium carbonate solution and 112 ml of 1,2-dimethoxyethane was heated and stirred for 3 hours under a nitrogen stream and under refluxing. After the mixture was cooled to room temperature, 223 ml of water was added, and this was extracted with 236 ml of toluene. The organic layer was washed with 640 ml of an aqueous sodium chloride solution two times, dried with magnesium sulfate, and evaporated, 50 ml of 2-propanol was added, and the mixture was stirred for 2 hours, and filtered. After the mixture was vacuum dried, 9.5 g of 1-(4-chlorophenyl)-3-(9,9-dimethylfluoren-2-yl)-7-t-butylpyrene was obtained.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:25]([CH3:26])[C:40]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:41])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:14][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2cccc3[nH]ccc23)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)C1CCCCC1)[C@H](CC1CCCCC1)CN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.6 g (1.69 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.25 g (1.69 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexanes) and converted to the hydrochloride.0.3 hydrate salt of the title compound with ethereal HCl yield 0.68 g (87%) as a white solid; mp=>260° C.; MS (+) ESI m/z=465 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)cc(C)n1
Yield: 48.5 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (143 mg, 0.5 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino -pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (106 mg, 48%). MS (ISP) 437.1 [(M+H)+]; mp 281° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:56](O)=[O:57])[CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:56](=[O:57])[C@H:40]([CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:47])[NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Product: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O)OCc1ccccc1
Yield: 53.8 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-(Nα,Nε -dibenzyloxycarbonyl-L-lysylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (420 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 with N-hydroxysuccinimide ester of Nα,Nε -dibenzyloxycarbonyl-L-lysine (608 mg) according to a similar manner to that of Example 5, mp. 150°-157° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7]CC1C=CC=CC=1>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[OH:7]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
To 4.5 g of ([2-(2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy)phenoxy]methyl)benzene were added 230 ml of ethyl acetate and 0.46 g of 10% palladium-on-carbon, and the mixture was stirred under hydrogen atmosphere at room temperature for 5 hours. After replacing the reaction system by nitrogen, the reaction solution was filtered over celite and the filtrate was concentrated to give 3.57 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:27]2[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=2)[O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22][CH:21]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:35][CH2:36][CH2:37]Br>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:27]2[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=2)[O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:35][CH2:36][CH3:37])[CH:21]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCBr
Reactant: Cn1cncc1C(OCc1ccc(C#N)cc1-c1ccc(=O)[nH]c1)c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cc(-c2cc(C#N)ccc2COC(c2ccc(C#N)cc2)c2cncn2C)ccc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A solution of Example 91F (27.3 mg, 0.0648 mmol) in DMF (2 mL) at 0° C. was treated with NaH (60%, 3.1 mg, 0.0777 mmol), stirred for 15 minutes, and treated with n-propyl bromide (11.8 μL, 0. 130 mmol). The mixture was slowly warmed to room temperature and stirred for about 18 hours. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography with 10:0.2:0.02 to 10:1:0.1 ethyl acetate/methanol/NH4OH to provide 10.5 mg (35%) of the desired product. MS.(HR-FAB) m/z calculated: 464.2087 (M+H)+; observed: 464.2078 (M+H)+; 1H NMR (CDCl3) δ 7.67 (d, 1H), 7.59 (d, 1H), 7.53 (d, 1H), 7.47-7.44 (m, 3H), 7.26-7.24 (m, 3H), 6.96 (s, 1H), 6.60-6.58 (m, 1H), 5.58 (s, 1H), 4.50 (q, 2H), 3.86 (t, 2H), 3.33 (s, 3H), 1.80-1.74 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].[OH-].[Na+].Cl.[CH3:12][S:13]([N:16]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[C:17]1=[O:24])(=[O:15])=[O:14]>O.CC(C)=O>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:21]([N:18]1[CH2:19][CH2:20][N:16]([S:13]([CH3:12])(=[O:15])=[O:14])[C:17]1=[O:24])=[O:22])[C:6]([OH:8])=[O:7]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](O)[C@@H](NC(=O)N1CCN(S(C)(=O)=O)C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
D-Threonine (5.0 g) was suspended in water (50 ml) and treated with 2M aqueous sodium hydroxide solution to pH 10, forming a clear solution. The pH was then re-adjusted to 7.5 with concentrated hydrochloric acid and the still clear solution cooled to 15°. 3-Methanesulphonyl-2-oxoimidazolidine-1-carbonyl chloride (9.5 g) was then added portionwise over 2 minutes, with simultaneous addition of 2M aqueous sodium hydroxide to maintain the pH at 6.0-7.5. Following this, acetone (30 ml) was added to give a clear solution which was then stirred at room temperature for 1 hour whilst still maintaining the pH at 6.0-7.5. After evaporation of the acetone in vacuo the aqueous residue was extracted well with ethyl acetate and the organic extracts were discarded. The pH of the aqueous phase was then adjusted to 1.5 with concentrated hydrochloric acid and the mixture was extracted using 3×50 ml portions of ethyl acetate:tetrahydrofuran (1:1). The organic extracts were dried and the solvent was evaporated to give the title compound as a white solid, (7.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:6]([OH:16])[C:5]([NH:17][C:18]2[C:21](=O)[C:20](=[O:23])[C:19]=2[O:24]CC)=[CH:4][CH:3]=1.[NH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([N:11]([CH2:12][CH3:13])[O:14][CH3:15])(=[O:9])=[O:10])=[C:6]([OH:16])[C:5]([NH:17][C:18]2[C:19](=[O:24])[C:20](=[O:23])[C:21]=2[NH:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CCC(N)CC
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Solvent: C1CCOC1
Product: CCC(CC)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Temperature: 50 °C

Procedure:
To a stirred solution of 6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Intermediate FA) (100 mg, 0.25 mmol) in THF (2 ml) was added 3-aminopentane (29 mg, 0.25 mmol) The reaction mixture was heated at 50° C. overnight. Further 3-aminopentane (29 mg, 0.25 mmol) was added and the reaction was heated at 50° C. for 7 hours. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 10% citric acid (aq), brine, dried (sodium sulfate) and concentrated in vacuo to give a solid; [M+H]+ 446.1. 1H NMR (DMSO) 0.9 (6H, t, 2×CH3), 1.2 (3H, t, CH3), 1.5 (2H, m), 1.6 (2H, m), 3.3 (2H, m), 3.7 (3H, s, CH3) 3.9 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.3 (1H, d), 9.4 (1H, s), 10.2 (1H, s).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH:28]=4)[CH2:25][C:24](=[O:40])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
The title compound was prepared from {4-(4-fluoro-phenylethynyl)-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M147) (287 mg, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (197 mg, 88%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]([OH:21])[N:18]=[C:17]([NH:22][NH2:23])[N:16]=2)=[CH:11][CH:10]=1>C1COCC1>[C:5]([NH:23][NH:22][C:17]1[N:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[N:20]=[C:19]([OH:21])[N:18]=1)(=[O:7])[CH3:6]
Reactant: NNc1nc(O)nc(-c2ccc(Cl)cc2)n1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NNc1nc(O)nc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C

Procedure:
Acetic anhydride (6 ml) is added to a suspension of 6-(4-chlorophenyl)-4-hydrazino-2-hydroxy-1,3,5-triazine in THF (500 ml) and the mixture stirred under reflux for 21/2 hours. The mixture is cooled to RT overnight and the solid filtered, washed with ether and air dried, yielding 13.95 g of the solid. The solid is washed in 500 ml of boiling dioxane, filtered, washed with ether and air dried, leaving 13.8 g of the acetyl hydrazine triazine, m.p. 250° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH:42]1(N)CC[CH2:43]1.NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:36]1([NH:35][CH2:34][CH2:33][N:31]2[CH:32]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])[CH2:14][CH2:15]3)[CH:29]=[N:30]2)[CH2:37][CH2:43][CH2:42]1
Reactant: NC1CCC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNC5CCC5)c4)cc23)CC1
Yield: 38 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting cyclobutanamine (31 mg, 0.43 mmol) for the 2-aminoethanol to afford 10 mg of the title compound (38%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([Cl:33])[CH:20]=1)=[N:11][CH:12]=[N:13]2)[CH:2]=[CH2:3].[C:34](Cl)(=[O:36])[CH3:35]>>[CH2:1]([N:4]([CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([Cl:33])[CH:20]=1)=[N:11][CH:12]=[N:13]2)[C:34](=[O:36])[CH3:35])[CH:2]=[CH2:3]
Reactant: CC(=O)Cl
Reactant: C=CCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C=CCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(C)=O
Yield: 47 %

Procedure:
The procedure described in Example 5 was repeated using 5-[2-(allylamino)ethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine and acetyl chloride to give the title compound in 47% yield; NMR spectrum (DMSO-d6) 1.95 (s, 3H), 3.86 (t, 2H), 4.02-4.06 (m, 2H), 4.38 (t, 2H), 5.07-5.18 (m, 2H), 5.31 (s, 2H), 5.82-5.92 (m, 1H), 7.14 (d, 1H), 7.25 (d, 1H), 7.32-7.40 (m, 2H), 7.55-7.61 (m, 2H), 7.70-7.75 (m, 1H), 7.86-7.93 (m, 2H), 8.44 (s, 1H), 8.61 (d, 1H), 9.76 (s, 1H); Mass spectrum MH+ 504.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27](Cl)=[O:28])[CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:24]3[CH:23]=[C:22]([CH3:21])[O:26][N:25]=3)=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cc(C)on2)CC1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol from Example 47, Step 1) was combined with 5-methylisoxazole-3-carbonyl chloride (0.023 g, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (0 to 5% methanol in dichloromethane) to give the desired product (32 mg, 77%). LCMS calculated for C20H20ClN4O3 (M+H)+: m/z=399.1; Found: 399.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]([O:14][CH3:15])=[C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)[CH:7]=1.[N:17]1([CH:23]2[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]([O:14][CH3:15])=[C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([N:20]2[CH2:21][CH2:22][N:17]([CH:23]3[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]3)[CH2:18][CH2:19]2)=[O:12])[CH:7]=1
Reactant: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of (S)-2-(5-bromo-4-chloro-2-methoxyphenylamino)propanoic acid (1.6 g, 5.21 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (1.88 g, 7.82 mmol), EDCI.HCl (2.0 g, 10.42 mmol), HOBt (1.41 g, 10.42 mmol) in DMF (20 mL) at 0° C., Et3N (1.58 g, 15.63 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (methanol/dichloroethane=1:50) to afford the desired product (2.1 g, 76% yield). ESI-MS m/z: 531.3[M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]([C:5]1[C:20]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[CH:19][C:8]([C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4].[OH-].[Li+].O.Cl>O1CCCC1>[CH3:1][N:2]([CH3:35])[C:3]([C:5]1[C:20]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[CH:19][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1-c1cnn(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cc(OCc2ccccc2)c(C(=O)O)cc1-c1cnn(C)c1
Reaction time: 18 h

Procedure:
To a solution of phenylmethyl 4-[(dimethylamino)carbonyl]-5-(1-methyl-1H-pyrazol-4-yl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 40; 195 mg, 0.42 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (34 mg, 1.42 mmol) and water (1 ml). The mixture was for 18 hours then 2M hydrochloric acid (0.73 ml, 1.45 mmol) was added. The solvent removed in vacuo to give the title compound as a gum. 154 mg.