Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])[C:5]2=[CH:4][CH:3]=1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:37].[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4nc(Cl)ccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3nc(Cl)ccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.020 g, 0.039 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-2-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.015 g, 75%).
Reaction SMILES: [Br:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[CH3:20].FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[Br:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][NH2:9])=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(OCCNC(=O)OC(C)(C)C)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OCCN)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 2-(4-bromo-3,5-dimethylphenoxy)ethylcarbamate (310 mg) in dichloromethane (8 mL) is added trifluoroacetic acid (700 μL). The mixture is stirred for 12 hours at room temperature. Then saturated aqueous K2CO3 solution is added, the mixture is stirred for 30 minutes and the phases are separated. The organic phase is washed with saturated aqueous K2CO3 solution and dried (MgSO4). The solvent is evaporated to give the title compound. Yield: 200 mg; LC (method 7): tR=0.83 min; Mass spectrum (ESI+): m/z=244 [M+H]+.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[N:7]([CH3:19])[CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17]C)=[N:15][CH:16]=2)[N:10]=1.C(Cl)Cl.Cl.C(=O)(O)[O-].[Na+]>CC#N>[CH3:19][N:7]1[CH:8]=[C:9]([C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:10]=[C:6]1[CH:2]=[O:1]
Reactant: CCc1ccc(-c2cn(C)c(C3OCCO3)n2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(-c2cn(C)c(C=O)n2)cn1
Temperature: 45 °C
Yield: 78.3 %

Procedure:
A mixture of 5-(2-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazol-4-yl)-2-ethylpyridine (140 mg, 0.571 mmol), DCM (5 mL), and 4 N HCl (5 mL) was heated to 45° C. for 16 h. Then the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution at 0° C., and the mixture was concentrated to give a crude product. 30 mL of CH3CN was added and the mixture was filtered. The filtrate was then concentrated to afford a white solid (90 mg). MS (ESI): m/z 202.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[CH:7]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:6]1[C:5]([O:15][CH3:16])=[CH:4][C:3]([O:17][CH3:18])=[C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=2)(=[O:29])=[O:28])[CH:7]=1)=[O:14]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(OC)c(C(=O)CCCCCl)cc1N
Solvent: C1CCOC1
Product: COc1cc(OC)c(C(=O)CCCCCl)cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of 1-(5-amino-2,4-dimethoxyphenyl)-5-chloro-1-pentanone (0.54 g, 2 mmol), prepared as in Example 13, 4-trifluoromethylbenzenesulfonyl chloride (0.51 g, 2.1 mmol) triethylamine (0.25 g, 2.5 mmol) and THF (approximately 50 mL) was stirred 16 hours at approximately 25° C. The mixture was concentrated and the residue was partitioned between ethyl acetate and dilute ammonium hydroxide. The organic layer was washed with water (1×) and then brine (1×), dried (K2CO3), filtered and concentrated to give N-[5-(5-chloropentanoyl)-2,4-dimethoxyphenyl]-4-trifluoromethylbenzenesulfonamide (0.8 g, 1.7 mmol), m.p. 150°-153° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24](Cl)=[O:25])[C:18]=2[C:17]2[C:12]1=[C:13]([Cl:29])[CH:14]=[CH:15][C:16]=2[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>ClCCl>[CH2:30]([N:32]([CH2:33][CH3:34])[C:24]([CH:19]1[C:18]2[C:17]3[C:12](=[C:13]([Cl:29])[CH:14]=[CH:15][C:16]=3[O:27][CH3:28])[N:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:25])[CH3:31]
Reactant: COc1ccc(Cl)c2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)Cl
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CCCc2c1c1c(OC)ccc(Cl)c1n2CCOCc1ccccc1
Temperature: 0 °C
Yield: 69.2 %

Procedure:
9-(2-Benzyloxy-ethyl)-8-chloro-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carbonyl chloride (8) (1.6 g, 3.7 mmol) was then dissolved in dichloromethane (50 mL), cooled to 0° C., stirred and diethylamine (810 mg, 11.0 mmol, 1.1 mL) was added dropwise. The reaction was allowed to warm to room temperature over a period of 18 h. The reaction mixture was then washed with 10% aqueous potassium carbonate (50 mL), separated, dried over magnesium sulfate and concentrated in vacuo to a gum. The crude material was crystallized from diethyl ether to afford 1.2 g (71%) of 9-(2-Benzyloxy-ethyl)-8-chloro-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (9) as a white crystalline solid. The structure was confirmed by 13C NMR (75 MHz; CDCl3): δC 13.0, 14.5, 19.8, 22.2, 27.9, 36.4, 40.4, 41.9, 43.8, 55.0, 70.8, 73.3, 100.2, 108.5, 108.6, 119.9, 122.5, 127.4, 127.5, 128.3, 131.5, 137.8, 138.2, 152.4, and 174.5.
Reaction SMILES: O.[OH-].[Li+].[I-:4].[C:5]1([NH:11][C:12](=[O:40])[NH:13][CH2:14][CH2:15][CH2:16][NH+:17]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.CO>[I-:4].[C:5]1([NH:11][C:12](=[O:40])[NH:13][CH2:14][CH2:15][CH2:16][NH+:17]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(CCC[NH+](CCCNC(=O)Nc2ccccc2)CCc2ccc(Cl)cc2)cc1
Agent: [I-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCCC[NH+](CCCc1ccc(C(=O)O)cc1)CCc1ccc(Cl)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 69.4 %

Procedure:
Lithium hydroxide monohydrate (4 mg, 0.095 mmol) was added to a solution of [3-(phenylureido)propyl][2-(4 chlorophenyl)ethyl][4-(methoxycarbonyl)benzyl]ethylammonium iodide (28 mg, 0.044 mmol) in 10% water/methanol (1.3 ml). After stirring at RT for 26 h, the reaction mixture was concentrated under vacuum to dryness. The residue was adsorbed on a plate of silica gel and then developed with 33% methanol/chloroform to afford [3-(phenylureido)propyl][2-(4-chlorophenyl)ethyl][4-(carboxy)benzyl]ethylammonium iodide (19 mg, 70%): MS(ES+) m/e 496 [M-I]+; 1H NMR (400 MHz, CD3OD) δ 8.01 (d, J=8.3 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.38 (m, 2H), 7.30 (m, 4H), 7.24 (m, 2H), 6.97 (m, 1H), 4.59 (s, 2H), 3.31 (m, 8H), 3.15 (m, 2H), 2.15 (m, 2H), 1.48 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[CH:16]([NH2:18])=[O:17]>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:18][CH:16]=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: NC=O
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Solvent: O
Product: O=CNC(c1ccccc1)c1cccc(O)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 4525.6 %

Procedure:
3-Hydroxybenzophenone (25 g, 126.1 mmol) in formamide (130 mL, 3.3 mmol) was heated to 180° C. for 18 hours. The reaction was allowed to cool slightly then poured into ice-cooled water and stirred for 30 minutes, filtered, and washed with water. The solid was stirred in water (60 mL) and ethanol (60 mL) and heated to 50° C. for 1 hour, then allowed to cool. The solid was filtered and washed with water to give the title compound (33.94 g, 118%).
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1)[CH2:28][CH3:29]
Reactant: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-dipropylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 109, 51.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 32.0 mg (70%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([O:20][CH2:21][CH2:22][OH:23])=[N:16][CH:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:28]([C:27]1[CH:26]=[C:25]([CH:32]=[CH:31][CH:30]=1)[O:23][CH2:22][CH2:21][O:20][C:15]1[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[N:19][CH:18]=[CH:17][N:16]=1)=[O:29]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the compound obtained in step 2 above (1.5 g, 4.7 mmol) in dry tetrahydrofuran (THF; 10 mL) was treated with 3-hydroxybenzaldehyde (0.74 g, 6.06 mmol) and triphenylphosphine (1.59 g, 6.06 mmol). This solution was stirred at room temperature then treated with diethyl azodicarboxylate (0.96 mL, 6.06 mmol) in dry THF (5 mL). After 1 hr, TLC indicated some remaining 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol. The reaction was heated at reflux under nitrogen for 5 h, then left to cool to room temperature overnight. TLC again showed unreacted starter. The mixture was treated with further triphenylphosphine (0.80 g, 3.03 mmol), diethyl azodicarboxylate (0.5 mL, 3.03 mmol) and 3-hydroxybenzaldehyde (0.40 g, 3.03 mmol), then stirred at RT for a further 3 hrs (reaction complete by TLC). The volatiles were removed in vacuo and the residue was purified by flash column on silica gel, eluting with petroleum ether/ethyl acetate (2:1). This furnished 0.33 g (16%) of the title product as a colourless oil. 1H NMR (CDCl3) δ 1.5 (s, 9H); 3.5 (bs, 8H), 4.45 (m, 2H); 4.75 (m, 2H); 7.2 (d, 1H); 7.45 (s, 1H); 7.5 (m, 2H); 7.6 (s, 1H); 7.75 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH2:19][CH2:20][Cl:21])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C1(C)C=CC=CC=1>[Cl:21][CH2:20][CH2:19][O:18][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:2](/[N:1]=[CH:24]/[N:25]([CH3:27])[CH3:26])=[N:3]2)=[CH:8][C:7]=1[O:16][CH3:17]
Reactant: COC(=O)c1cc2cc(OC)c(OCCCl)cc2nc1N
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(OC)c(OCCCl)cc2nc1/N=C/N(C)C
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of methyl 2-amino-7-[2-chloroethoxy]-6-methoxy-3-quinolinecarboxylate (5.00 g, 16.09 mmol) and 5.10 g of dimethylformamide dimethylacetal in 75 mL of toluene containing 50 mg of p-toluenesulfonic acid is heated at reflux for 10 minutes then cooled to room temperature. Diethyl ether is added and the solids are collected by filtration to provide 3.81 g of methyl 7-(2-chloroethoxy)-2-{[(IE)-(dimethylamino)methylidene]amino}-6-methoxy-3-quinolinecarboxylate as a pale yellow solid, mp 108-110° C.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[O:18][C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]([CH2:24][C:25]([OH:27])=[O:26])[S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[O:18][C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:2]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(-c2ccccc2)c1)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCc2cc(S(=O)(=O)N(CC(=O)O)Cc3cccc(-c4ccccc4)c3)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (20 mg, 0.056 mmol) in acetonitrile (1 mL) was added 3-(bromomethyl)biphenyl (19.47 mg, 0.079 mmol) and resin-supportedBEMP (42.9 mg, 0.084 mmol). The mixture was heated in an oil bath at 90° C. overnight. The reaction mixture was filtered, and the filtrate was concentrated to give an orange residue, which was purified by preparative HPLC using MeCN—H2O-0.1% TFA as the solvent to obtain tert-butyl 2-(N-(biphenyl-3-ylmethyl)-2,2-dimethylchroman-6-sulfonamido)acetate as an oil (26 mg, 84% yield). 1H NMR (500 MHz, CDCl3) δ 7.64-7.60 (m, 2H), 7.54-7.49 (m, 3H), 7.44-7.40 (m, 3H), 7.38 (dd, J=9.4, 5.8 Hz, 1H), 7.33 (ddd, J=6.7, 4.0, 1.2 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 4.57 (s, 2H), 3.84 (s, 2H), 2.78 (t, J=6.7 Hz, 2H), 1.80 (t, J=6.7LRMS [ESI, MNa+] m/z calcd for C30H35NO5SNa 544.21. found 544.32. To the solution of tert-butyl 2-(N-(biphenyl-3-ylmethyl)-2,2-dimethylchroman-6-sulfonamido)acetate (23 mg, 0.044 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.102 mL, 1.323 mmol). The mixture was stirred at RT for 1 hour. The reaction mixture was concentrated to give a reddish residue, which was purified by preparative HPLC using MeCN—H2O-0.1% TFA as the solvent to obtain the product as a white powder (17 mg, 82% yield). 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J=6.3 Hz, 1H), 7.60 (s, 1H), 7.51 (d, 1H), 7.50 (d, J=7.4 Hz, 2H), 7.41 (dd, J=13.4, 5.5 Hz, 2H), 7.39 (s, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.34 (t, J=7.3 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.87-6.83 (m, 1H), 4.52 (s, 2H), 3.97 (s, 2H), 2.77 (t, J=6.7 Hz, 2H), 1.79 (t, J=6.7 Hz, 2H), 1.33 (s, 6H). LRMS [ESI, (M−H)−] m/z calcd for C26H26NO5S 464.15, found 464.32.
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:2]3[N:18]=[C:5]4[C:6]([NH:10][CH2:11][C:12]5[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:28][CH:27]=2)[CH2:24][CH2:25]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Clc1nc2c(NCc3cccnc3)cccn2n1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(NCc5cccnc5)cccn4n3)cc2)CC1

Procedure:
N(2)-[4-(4-Methyl-piperazin-1-yl)-phenyl]-N(8)-pyridin-3-ylmethyl-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-pyridin-3-ylmethyl-amine (75.0 mg, 0.289 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (61.0 mg, 0.319 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.075 g, 63%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.66 (s, 1H), 8.55 (d, J=4.1 Hz, 1H), 7.83 (d, J=6.5 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.31-7.25 (m, 1H), 6.95 (d, J=8.9 Hz, 2H), 6.66 (t, J=7.3 Hz, 1H), 6.57 (s, 1H), 6.30 (d, J=7.7 Hz, 1H), 5.08 (t, J=5.6 Hz, 1H), 4.50 (d, J=5.8 Hz, 2H), 3.17-3.13 (m, 4H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=415 (MH)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH2:37]C)[CH:31]=2)[CH:25]=1)=O)(C)(C)C.[C:41](O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([C:32]1[CH:31]=[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:39])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:17])([F:18])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:35]=[C:34]([CH3:36])[N:33]=1)[CH3:41]
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Product: CCc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M229) (292 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (188 mg, 81%).
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][C:7]2[C:8]3[CH:9]=[N:10][NH:11][C:12]=3[CH:13]=[CH:14][C:6]=2[CH2:5]1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][C:41]2=[O:50])[CH2:36][CH2:35]1>ClCCl>[CH2:19]([N:16]1[C:17](=[O:18])[C@H:4]([CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][CH:37]([N:40]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:42][C:41]3=[O:50])[CH2:38][CH2:39]2)[CH2:5][C:6]2[CH:14]=[CH:13][C:12]3[NH:11][N:10]=[CH:9][C:8]=3[C:7]=2[CH2:15]1)[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](CCO)C1=O
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](CCN2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
(S)-7-(2-hydroxyethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (15 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL). Thionyl chloride (100 μL) was added to the mixture. Reaction stirred at room temperature for 2 hours. Thionyl chloride (500 μL) was added to the mixture. Reaction stirred at room temperature for 2 hours and then was warmed to reflux for 2 hours. Reaction mixture was concentrated in vacuo. Residue was dissolved in acetonitrile (1 mL). Potassium carbonate (25 mg, 0.18 mmol) was added to the mixture followed by 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (16 mg, 0.07 mmol). Reaction was heated at reflux for 2 hours. Preparatory HPLC purification afforded the title compound as white solid in 25% yield. High resolution MS m/e (M+H)+=529.3282.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:9])[C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14].Cl>O>[CH3:1][O:2][C@H:3]([CH3:9])[C@H:4]([NH:5][C:13]([O:15][CH3:16])=[O:14])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)Cl
Reactant: CO[C@H](C)[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reaction time: 12 h
Yield: 97 %

Procedure:
To a mixture of O-methyl-L-threonine (3.0 g, 22.55 mmol), NaOH (0.902 g, 22.55 mmol) in H2O (15 mL) was added ClCO2Me (1.74 mL, 22.55 mmol) dropwise at 0° C. The mixture was allowed to stir for 12 h and acidified to pH 1 using 1N HCl. The aqueous phase was extracted with EtOAc and (2×250 mL) and 10% MeOH in CH2Cl2 (250 mL) and the combined organic phases were concentrated under in vacuo to afford a colorless oil (4.18 g, 97%) which was of sufficient purity for use in subsequent steps. 1H NMR (400 MHz, CDCl3) δ 4.19 (s, 1H), 3.92-3.97 (m, 1H), 3.66 (s, 3H), 1.17 (d, J=7.7 Hz, 3H). LCMS: Anal. Calcd. for C7H13NO5: 191. Found: 190 (M−H)−.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21](=O)[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21](=[N:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CCCC(=O)c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCC(=NC(C)(C)C)c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)butan-1-one (3.2 g, 9.0 mmol), prepared according to procedure described in Example 151 Step 5, in CH2Cl2 (40 mL), cooled to 0° C., was added tBuNH2 (3.0 mL, 27.0 mmol). To this mixture was added a solution of TiCl4 (5.4 mL, 1M, 5.4 mmol) in CH2Cl2 dropwise via an addition funnel. Upon completion of addition, the reaction was stirred at room temperature for 24 hrs before it was quenched with a saturated solution of NaHCO3. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4, filtered, and concentrated to give a crude product that was used immediately without further purification. LC-MS 413.5 [M+H]+, RT 0.98 min.
Reaction SMILES: O[CH:2]=[C:3]1[C:12]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[NH2:26][N:27]([CH2:35][CH2:36][O:37][CH3:38])C(=O)OC(C)(C)C.[ClH:39].O1CCOCC1>C(O)C>[ClH:39].[CH3:38][O:37][CH2:36][CH2:35][N:27]1[C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:3]=2[CH:2]=[N:26]1
Reactant: COCCN(N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1C(=O)C2=CO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COCCn1ncc2c1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A mixture of tert-butyl 3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (200 mg, 0.58 mmol) and tert-butyl N-amino-N-(2-methoxyethyl)carbamate (130 mg, 0.70 mmol) in ethanol (5 mL) was allowed to stir at rt for 2 h. A solution of hydrogen chloride in 1,4-dioxane (150 μL of 4.0 M, 0.60 mmol) was added and the mixture was stirred at 50° C. for 1.5 h before it was concentrated in vacuo to give 1-(2-methoxyethyl)-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride (85 mg, 44%). ESI-MS m/z calc. 299.2. found 300.3 (M+1)+; Retention time: 0.95 minutes (3 min run).