Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Br:17][CH2:18][CH2:19]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: BrCCBr
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCBr)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A suspension of 3-fluoro-4-hydroxybenzonitrile (1.2 g, 8.76 mmol), anhydrous K2CO3 (2.43 g, 17.6 mmol) and 1,2-dibromoethane (4.5 mL, 52.0 mmol) in DMF (6 mL) was stirred at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered and extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give 1.52 g (71%) of the subtitle compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=9.2 Hz, 1H), 7.40 (d, J=12.0 Hz, 1H), 7.03 (dd, J=8.0 Hz, 8.4 Hz, 1H), 4.42 (t, J=6.2 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H).
Reaction SMILES: Br.[NH2:2][C:3]1[N:7]2[C:8](SC)=[N:9][CH:10]=[C:11]([Cl:12])[C:6]2=[N:5][N:4]=1.[C:15](OCC)(=[O:18])C=C.C[O-].[Na+].C(O)(=O)C>CO>[NH2:2][C:3]1[N:7]=[C:6]2[N:5]([C:8]([O:18][CH3:15])=[N:9][CH:10]=[C:11]2[Cl:12])[N:4]=1
Reactant: CSc1ncc(Cl)c2nnc(N)n12
Reactant: C=CC(=O)OCC
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ncc(Cl)c2nc(N)nn12
Temperature: 25 °C

Procedure:
A mixture of 15.0 g (51 mmol) of 3-amino-8-chloro-5-methylthio[1,2,4]triazolo[4,3-c]pyrimidine hydrobromide, 8.2 mL (76 mmol) of ethyl acrylate, and 150 mL of methanol was prepared and cooled in an ice bath. A solution of 17 mL (76 mmol) of 4.5 molar sodium methoxide in methanol was added to this slowly with cooling and stirring. When the addition was complete, the mixture was allowed to warm to ambient temperature and was stirred for 18 hours. It was then neutralized with 2.0 mL of acetic acid. The solids that formed were recovered by filtration, washed with diethyl ether, and dried to obtain 7.7 g (75 percent of theory) of the title compound as a tan powder melting above 250° C. 1H NMR (DMSO-d6): δ 8.0(s, 1H); 6.6 (brs, 2H); 4.1 (s, 3H); 13C: δ 166.40, 151.65, 147.73, 140.95, 108.57, 56.12. Anal. Calc'd for C6H6N5ClO: C, 36.1; H, 3.03; N, 35.1. Found: C, 36.1; H, 3.19; N, 34.8.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1[CH:8]=[C:7]([C:13]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:12]([F:20])([F:19])[F:11])[CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Temperature: 100 °C
Yield: 77.9 %

Procedure:
A mixture of 2.42 g of 2,6-dimethylaniline, 7.35 g of hexafluoroacetone hydrate, and 0.04 g of p-toluenesulfonic acid monohydrate was stirred under heating at 100° C. for 5 hours. After the temperature was returned to room temperature, the mixture was diluted with ethyl acetate and washed with a 1N sodium hydroxide aqueous solution. Then, the solvent was distilled off under reduced pressure, and the precipitated crude crystals were washed with a n-hexane-ethyl acetate mixed solvent to obtain 4.47 g (yield 78%) of the title compound as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:18])=[CH:15][C:14]=2[Br:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[O:18])=[CH:15][C:14]=2[Br:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[O:34][C:35](=[O:37])[CH3:36])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)OCCCN(C)C)cc2Br)ccc(C(C)=O)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(OCCCOc2ccc(C(=O)OCCCN(C)C)cc2Br)ccc(C(C)=O)c1OC(C)=O
Reaction time: 18 h

Procedure:
In a mixture of pyridine (5 ml) and acetic anhydride (5 ml) was dissolved 3-(N,N-dimethylamino)propyl 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-bromobenzoate (1 g). The solution was stirred at 110° to 120° C. for about 18 hours, followed by concentration. The residue was chromatographed on a column of silica gel. The elution was conducted with ethyl acetate, and the eluate was evaporated. The resulting oily substance was dissolved in ether, to which was added an ether solution of anhydrous oxalic acid. The resultant crystals were collected by filtration, which were washed with ethanol and then with isopropyl ether, followed by drying to give 866 mg of 3-(N,N-dimethyl-amino)propyl 4-[3-(4-acetyl-3-acetoxy-2-propylphenoxy)propoxy]-3-bromobenzoate.mono-oxalate, m.p. 141°-142° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: CCc1cc(C(=O)O)n(C)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Yield: 66.7 %

Procedure:
In the same manner as in Example 259 and using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (120 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (190 mg, 68%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Br)c4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 608.0 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[C:29]([F:30])=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][C:33]1([CH3:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:35]([NH2:42])[CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[C:29]([F:30])=[C:28]([NH:42][C@@H:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]([CH3:43])([CH3:32])[CH2:34]3)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)C[C@H](N)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2ncnc(Cl)c2F)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)C[C@H](Nc2ncnc(N[C@@H]3C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C3)c2F)c2ccccc21
Temperature: 180 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
A mixture of N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-6-chloro-5-fluoropyrimidin-4-amine (205 mg, 0.38 mmol), (1S)-3,3-dimethylindan-1-amine (243 mg, 1.51 mmol), and sodium carbonate (160 mg, 1.51 mmol) was stirred at 180° C. for 3 h in an oil bath. The reaction mixture was diluted with DCM and the suspension was filtered. The filtrate was concentrated under vacuum and the residue was purified by flash chromatography (5 to 10% ethyl acetate/hexanes) to afford the title compound (213 mg, 70%) as a colorless amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1.O.[OH-].[Li+].Cl>CO.O>[C:25]([O:24][C:22]([NH:21][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:8]([P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1)[C:3]([OH:2])=[O:29])=[O:23])([CH3:26])([CH3:27])[CH3:28]
Reactant: CCOP(=O)(OCC)c1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)ccc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)c1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 152.4 %

Procedure:
To a cooled (0° C.) solution (S)-2-tert-butoxycarbonylamino-3-[3-(diethoxy-phosphoryl)-4-hydroxy-phenyl]-propionic acid methyl ester (423 mg, 0.98 mmol) in MeOH (4 mL) was added lithium hydroxide monohydrate (84 mg, 2.0 mmol) in H2O (4 mL). After 1 h, the reaction was allowed to warm to rt. After 2.5 h, the solution was carefully acidified to pH 2 using 0.5 N HCl and extracted twice with EtOAc. The organic extracts were pooled, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 379 mg (91%) of a yellow foam. The crude material was carried on without further purification. Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 416 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.017 mole), 1,1'-carbonyldiimidazole (3.0 g, 0.018 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and a solution of piperdine (1.6 g, 0.019 mole) in dry tetrahydrofuran (50 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction was concentrated in vacuo and the residue triturated in water (100 ml) and the mix was filtered. The filter cake was recrystallized from isopropyl alcohol-isopropyl ether to give 3.4 g (56%) of off-white flakes, mp 149°-150 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccc(Cl)cc1Cl)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1ccc(Cl)cc1Cl)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of 4-(2,4-dichlorobenzyl)-4-phenyl-5-oxohexanoic acid (5.48 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.03 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. Then the reaction solution is cooled to room temperature, diluted with water (200 ml.) and extracted with ether to remove the excess p-chlorobenzaldehyde. The aqueous phase is then acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which precipitates is filtered and air-dried, yield 5.5 g., m.p. 215°-226°C. Recrystallizations from ethanol gives material with m.p. 224.5°-227°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([CH3:19])[CH:13]=1.C(N(CC)CC)C.O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][C:14]=2[CH3:19])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1cc(Cl)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Cl)ccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
4-Chlorobenzoyl chloride (19.5 g, 111 mmol) was added over 10 min. to a stirred, cooled (0° C.) solution of 4-chloro-2-methylaniline (15 g, 106 mmol) and triethylamine (22.2 mL, 16.1 g, 159 mmol) in dichloromethane (300 mL) and the mixture was stirred at room temperature for 2 h. Water (100 mL) was added and the dichloromethane was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate (saturated, 200 mL), water (200 mL) and ethyl acetate (1000 mL) were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with ether and the solid was collected and dried in vacuo to give the title compound (27.3 g, 92%). 1H NMR (360 MHz, CDCl3) δ 7.82 (3H, m), 7.79 (1H, br s), 7.48 (2H, d, J 8.5 Hz), 7.23 (2H, m), and 2.30 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:25])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(C(F)(F)F)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 75.1 %

Procedure:
To a solution of 4-[hydroxy-(4-trifluoromethylphenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.07 g, 2.98 mmol) in CH2Cl2 (15 mL) were added PCC (1.93 g, 8.94 mmol) and SiO2 (3.86 g) and the mixture was stirred at room temperature for 75 minutes. The mixture was filtered through a silica gel plug (1:4, EtOAc/Hexanes) to afford 4-(4-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (800 mg, 75%) as a white solid. 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.68-1.75 (m, 2H), 1.85 (d, 2H, J=12.0 Hz), 2.91 (t, 2H, J=11.4 Hz), 3.36-3.43 (m, 1H), 4.13-4.19 (m, 2H), 7.75 (d, 2H, J=8.1 Hz), 8.03 (d, 2H, J=8.1 Hz).
Reaction SMILES: [C:1]([O:9]C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([OH:16])[CH2:12][CH2:13][CH2:14][OH:15].C(O)C[O:19]CCO>>[C:14]([O:15][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:19])[CH3:13].[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([OH:16])[CH2:12][CH2:13][CH2:14][OH:15]
Reactant: OCCOCCO
Reactant: COC(=O)c1ccccc1
Solvent: OCCCCO
Product: CC(=O)Oc1ccccc1
Product: O=C([O-])c1ccccc1

Procedure:
In the same manner as in Example 1-11 except for using 120 g of methyl phenyl acetate, 55 g of methyl benzoate and 36 g of 1,4-butandiol in place of 180 g of methyl phenyl acetate and 43 g of diethylene glycol, 80 g of a mixture of phenylacetic acid diester of 1,4-butandiol (48%), a phenyl acetate and benzoate of 1,4-butandiol (42 mass %), and benzoic acid diester of 1,4-butandiol (10 mass %) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH2:9][CH3:10].C(N(CC)CC)C.[H][H]>O1CCCC1.[C].[Pd]>[N:4]1[CH:5]=[CH:6][C:7]([CH:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:9][CH3:10])=[CH:2][N:3]=1
Reactant: [H][H]
Reactant: CCC(c1cc(Cl)nnc1Cl)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(c1ccnnc1)N1C(=O)c2ccccc2C1=O
Yield: 28 %

Procedure:
2-[1-(3,6-Dichloropyridazin-4-yl)propyl]isoindoline-1,3-dione, triethylamine (1.11 mL, 8 mmol) and 10% palladium-carbon (50 wt %, 100 mg) were stirred in tetrahydrofuran in a hydrogen atmosphere (1 atm) at room temperature for 4 days. The reaction solution was filtered through celite and concentrated under reduced pressure, and the resulting residue was dissolved in chloroform, and the resulting organic layer was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/3) to give the desired product (294 mg, 28% yield, two steps).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]3[N:9]([C:13]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)=[C:14]([C:16]4[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=4)[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:41](Br)[CH:42]=[CH2:43].CCOCC>CN(C)C=O.O>[CH2:43]([O:22][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:8]3[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:11]=[CH:10][N:9]3[C:13]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:24]=2)[CH:21]=[CH:20][CH:19]=1)[CH:42]=[CH2:41]
Reactant: Oc1cccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: C=CCOc1cccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
To a solution of 3-{8-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-α]pyridin-2-yl}phenol (12 mg, 0.03 mmol) in N,N-dimethylformamide was added cesium carbonate (11 mg, 0.04 mmol) followed by allyl bromide (0.1 mL, 1.15 mmol). The resulting mixture was stirred at room temperature for 5 hours. Ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes:ethyl acetate) provided 2-[3-(allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-α]pyridin-8-amine (10 mg, 77%) as an oil. 1H NMR (CDCl3): δ 8.87 (broad, 1H), 8.01 (d, 1H), 7.30 (t, 1H), 7.20–7.17 (m, 2H), 6.95 (m, 1H), 6.78 (t, 1H), 6.38 (d, 1H), 6.28 (d, 1H), 6.03 (m, 1H), 30 5.43–5.24 (m, 4H), 4.54 (d, 2H), 4.34 (m, 1H), 3.91 (m, 1H), 2.12–2.04 (m, 4H), 1.82–1.55 (m, 12H); MS m/z 495 (M+1). This material was treated with anhydrous hydrochloric acid in ether to provide the corresponding hydrochoride salt as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:33])([CH3:32])[C:29]([NH2:31])=O)[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.O1CCCC1.[AlH4-].[Li+]>>[CH3:33][C:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:1])([F:35])[F:34])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:24]=[N:25]1)([CH3:32])[CH2:29][NH2:31]
Reactant: CC(C)(C(N)=O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CN)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 7.2 %

Procedure:
To a solution of 2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-isobutyramide (0.182 g, 0.000361 mol) in tetrahydrofuran (5.864 mL, 0.07229 mol) under N2 at 0° C. was added lithium tetrahydroaluminate (1M in THF, 1.44 mL, 0.00145 mol) dropwise. The reaction was stirred at room temperature for 6 h. The reaction was quenched with saturated Na2SO4 until no more hydrogen evolution was observed. MgSO4 was added and the solution was filtered and rinsed with copious amounts of methylene chloride. The mixture was concentrated and purified by reverse-phase HPLC to give 412 (12.8 mg) as a colorless solid. MS (ESI+) 490.1. 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.29 (s, 1H), 8.26 (d, J=8.3, 1H), 7.98 (s, 1H), 7.49 (dd, J=8.3, 1.7, 1H), 7.37 (d, J=1.7, 1H), 5.86 (q, J=8.7, 2H), 4.39 (t, J=5.0, 2H), 3.47 (t, J=5.0, 2H), 2.86 (s, 2H), 1.50 (s, 6H)
Reaction SMILES: [N:1]1([C:7](=[O:9])[CH3:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][N:4]6[CH2:5][CH2:6][N:1]([C:7](=[O:9])[CH3:8])[CH2:2][CH2:3]6)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(Cc2ccc(-c3cc4ncnc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)CC1

Procedure:
The title compound was prepared from 1-piperazin-1-yl-ethanone and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 163-180° C.; LC-MS: 483 (MH+); HPLC RT: 4.24 minutes.
Reaction SMILES: [CH3:1][Li].[ClH:3].[C:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2)([OH:6])=O.O>CCOCC>[ClH:3].[C:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2)(=[O:6])[CH3:1]
Reactant: [Li]C
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)O)c2C1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)C1CCc2cccc(C(C)=O)c2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
A 5% solution of methyl lithium in ether (0.6 ml, 0.96 mmol) was added to a chilled slurry of (±)-8-Carboxy-2-(dipropylamino)tetralin hydrochloride (100 mg, 0, 32 mmol) in ether. The mixture was stirred at room temperature and under nitrogen for three days. Water was added carefully and the mixture was extracted with ether. The organic layer was dried (potassium carbonate) and concentrated. The residue was purified by chromatography on an alumina column eluted with ether/light petroleum 1:4. The pure fractions were pooled, concentrated and converted into the hydrochloride. Recrystallization from acetonitrile/ether gave 55 mg (56%) of pure 8-acetyl-2-(dipropylamino)tetralin hydrochloride.