Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4].[CH2:12]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:12]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]([O:2][CH3:1])[CH3:4])=[CH:6][CH:7]=2)=[O:26])=[CH:28][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: COC(C)c1ccc(O)cc1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(C(C)OC)cc2)cc1

Procedure:
The procedure of Example 26 was followed except for use of (-)-4-(1-methoxyethyl)phenol in place of (+)-4-(1-methoxyethyl)phenol and 4-octyloxybenzoic acid chloride in place of 4'-octyloxy-4-biphenylcarboxylic acid chloride to obtain (-)-4-(1-methoxyethyl)phenyl 4-octyloxybenzoate. [α]D20 =-57.5° (c=1, CHCl3).
Reaction SMILES: CO.[Br:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.O.OS(O)(=O)=O.[I:17]Cl>C(Cl)Cl>[I:17][C:9]1[CH:10]=[C:4]([Br:3])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: ClI
Reactant: Nc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(Br)cc1I
Reaction time: 8 h

Procedure:
To a mixture of 900 mL of MeOH and 100 mL water 4-bromoaniline (40.0 g, 0.232 mol) was added and the resulting solution was cooled in an ice bath. To this 35 mL of concentrated H2SO4 was added followed by a 1 M solution of ICl (255 mL 0.232 mol) in CH2Cl2. The bath was then removed and the reaction was stirred overnight. The volatiles were then removed by rotary evaporation, 200 mL of ice water was added to the product along with 500 mL CH2Cl2. The mixture was made strongly basic with 1 M NaOH and then extracted (3×CH2Cl2). The combined extracts were dried with Na2SO4 and then concentrated and dried in vacuo to give 2-iodo-4-bromoaniline. 1H-NMR (400 MHz, CDCl3): δ 4.1 (s, 2H, NH), 6.60 (m, 1H, NCH), 7.22 (m, 1H, CHCH), 7.77 (s, 1H, ICCHCBr). The crude product was then added to a mixture of acetyl chloride (36.0 g, 0.472 mol) and pyridine (56.0 g, 0.708 mol) in 1 L of dry THF cooled in an ice bath. The bath was then removed and the resulting mixture was stirred at room temperature overnight. THF was removed by rotary evaporation and then 400 mL of ice water was added. The product was extracted with CH2Cl2 (3×300 mL) and then the layers were combined and dried with Na2SO4. Silica column chromatography using mixtures of EtOAc and hexanes gave 12 g of 2-Iodo-4-bromoacetanilide. 1H-NMR (400 MHz, CDCl3): δ=2.24 (s, 3H, CH3), 7.39 (s, 1H, NH), 7.46 (d, 8.4 Hz, 1H, BrCCH), 7.90 (s, 1H, ICCHCBr), 8.13 (d, 8.0 Hz, 1H, NCCH).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:35][C@H:36]1[NH:40][C:39](=[O:41])[CH2:38][CH2:37]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH2:35][C@H:36]2[NH:40][C:39](=[O:41])[CH2:38][CH2:37]2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OC[C@@H]4CCC(=O)N4)c3)cc2)cccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
The product from Example 61F (88 mg, 0.2 mmole), (S)-5-(hydroxymethyl)-2-pyrrolidinone (58 mg, 0.5 mmole), di-tert-butyl azodicarboxylate (69 mg, 0.3 mmole), and triphenylphosphine (77 mg, 0.3 mmole) were dissolved in tetrahydrofuran (1.5 mL) in a capped test-tube and shaked at room temperature overnight. Ethyl acetate (2 mL) was added to dilute the reaction mixture. Then, the diluted organic solution was washed with water (2 mL) and saturated sodium chloride solution (2 mL), dried in vaccuo, and purified by HPLC to give the pure intermediate.
Reaction SMILES: [I-].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N+:10]=1C)=[O:8].C(C1C=C(C)C=CN=1)#N.O1C=CC=C1[Li]>>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: Cc1cc[n+](C)c(C(=O)c2ccco2)c1
Agent: Cc1ccnc(C#N)c1
Agent: [I-]
Agent: [Li]c1ccco1
Product: Cc1ccnc(C(=O)c2ccco2)c1

Procedure:
A process for preparing 2-(2-furoyl)-1,4-dimethylpyridinium iodide comprising the steps of reacting 2-cyano-4-methylpyridine under a nitrogen atmosphere with an ethereal solution of freshly prepared 2-furyl-lithium, hydrolyzing the reaction mixture under acid conditions to form 2-(2-furoyl)-4-methylpyridine, and heating the 2-(2-furoyl)-4--methylpyridine in the presence of methyl iodide to form 2-(2-furoyl)-1,4-dimethylpyridinium iodide.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:26])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:9])(C)(C)C.Cl>C(Cl)(Cl)Cl>[CH3:9][CH:8]1[C:10](=[O:26])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:7]1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a stirred solution of the benzophenone 109 (10.65 g 29.38 mmol) in CHCl3 (400 mL) at rt, hydrogen chloride gas was added in slowly. After 20 min, the addition was stopped and the solution was stirred overnight at rt. The reaction mixture was washed with a saturated solution of sodium bicarbonate (2×50 mL) and water (2×50 mL). The organic layer was concentrated under reduced pressure. The residual oil was dissolved in methanol-water (2:1, 500 mL) and the pH was adjusted to 8.5 by the addition of aqueous sodium hydroxide (1 N). The reaction mixture was stirred for 10 h at rt. The solution was concentrated under reduced pressure and water (100 mL) was added. The solution was extracted with CH2Cl2 (3×100 mL) and concentrated under reduced pressure. The crude solid 110 was purified by recrystallization from methanol/water to provide 110 (6.10 g, 83%). mp 160-162° C.; IR (KBr, cm−1) 3215, 3059, 2974, 2932, 1681, 1574, 1478, 1445, 1372, 1321, 1242, 1160, 1131; 1H NMR (CDCl3) δ 9.65 (s, 1 H), 7.54-7.13 (m, 9 H), 3.78 (q, J=6.5 Hz, 1 H), 1.78 (d, J=7.1 Hz 3H); MS (EI) m/e (relative intensity) 250 (M+, 40), 249 (83), 234 (15), 209 (75), 208 (76), 207 (100), 180 (17), 152 (19) 103 (23), 77 (40); [α]26D=290.2 (c 0.78, EtOAc).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19]1(=O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1.Cl>C(OCC)C>[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:20]1
Reactant: c1ccc(Cc2ccccn2)cc1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C1=C(c2ccccc2Cc2ccccn2)c2ccccc2C1
Temperature: -20 °C
Yield: 33.5 %

Procedure:
A mixture of 3.23 ml (0.02 mol) of 2-benzylpyridine in 15 ml of diethyl ether was cooled to −20° C. and 13 ml of n-butyllithium (1.6M in hexane, 0.02 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature, stirred for another one hour and subsequently cooled to −60° C. A solution of 2.8 g (0.021 mol) of 1-indanone in 10 ml of diethyl ether was subsequently added while maintaining the temperature. The mixture was allowed to warm to room temperature, stirred for a further 3.5 hours and hydrolyzed with 40 ml of dilute hydrochloric acid. The solid which had precipitated was filtered off, the organic phase was separated off and the aqueous phase was extracted twice with ethyl acetate. The aqueous phase was then neutralized with aqueous ammonia solution and extracted three times with 30 ml each time of methylene chloride. The organic phases were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. Recrystallization of the residue obtained in this way from hexane gave 1.9 g (34%) of [2-(1H-inden-3-yl)(phenyl)-methyl]pyridine.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:20])[NH:12][C@H:13]([CH2:18][OH:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[N:10]=2)[CH2:3]1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O>[Si:21]([O:19][CH2:18][C@@H:13]([NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:20])[CH2:14][CH:15]([CH3:17])[CH3:16])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)C[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 64.5 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(1S)-1-(hydroxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (820 mg, 2.74 mmol) (obtained as described in Reference Example 37(3)) in dimethylformamide (41 ml) were added t-butyldimethylsilyl chloride (495 mg, 3.29 mmol) and imidazole (224 mg, 3.29 mmol) in an ice bath, and then the reaction mixture was stirred in the ice bath overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (731 mg, yield 65%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([C:10]([OH:12])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH:20][CH2:21]/[C:22](/[CH3:25])=[CH:23]/[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[O-]P1(OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)O1)=O.[Na+].[Na+].[Na+].[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:13]([N:20]([CH2:21]/[C:22](/[CH3:25])=[CH:23]/[CH3:24])[C:10]([CH:9]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=2[CH2:8]1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1Cc2c(Cl)cccc21
Reactant: C/C=C(\C)CNCc1ccccc1
Agent: O=P1([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])O1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C/C=C(\C)CN(Cc1ccccc1)C(=O)C1Cc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
3-Chloro-1,2-dihydrocyclobutabenzene-1-carboxylic acid (3.78 mmol, 690 mg) was dissolved in DCM (10 ml). (E)-N-benzyl-2-methylbut-2-en-1-amine (5.67 mmol, 993 mg) and triethylamine (7.56 mmol, 1.050 ml, 765 mg) were added, followed by cyclophos 50% in ethyl acetate (4.53 mmol, 2.70 ml, 2886 mg). The reaction mixture was stirred overnight at room temperature and then diluted with DCM (5 ml) and washed in turn with 2 N HCl (10 ml), 2 N NaOH (10 ml) and brine (10 ml). The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a crude residue that was purified by silica column chromatography (eluting with heptane—50% ethyl acetate:heptane) to give (E)-N-benzyl-3-chloro-N-(2-methylbut-2-enyl)-1,2-dihydrocyclobutabenzene-1-carboxamide (430 mg). m/z: 340.5 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9](=[O:24])[N:10]([CH2:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]2[C:9](=[O:24])[N:10]([CH2:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=[C:3]2[C:2]=1[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(Cl)ccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(Cl)ccn2c1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 63.5 %

Procedure:
To a suspension of 8-bromo-7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (506 mg, 1.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (984 mg, 4.8 mmol), and 2.0 M aqueous sodium carbonate (2.6 mL) in toluene (10 mL) was added (Ph3P)4Pd (208 mg, 0.18 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon at 100° C. Analysis by HPLC/MS after 2.5 h indicated about 70% of starting 8-bromo-7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one remained. Additional (Ph3P)4Pd (60 mg, 0.05 mmol) was added. After stirring for 3 h more, the same amount of catalyst was again added, and the reaction mixture was stirred at 100° C. under argon for 5 h more. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (40 mL×3). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product, which was purified using a silica gel cartridge (80 g) eluted with a gradient of EtOAc (0-100%) in hexanes to afford the title compound as a white foam (320 mg, 62%). HPLC/MS: retention time=2.14 min, [M+H]+=420.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])#[N:2].[OH:18]O>C1COCC1>[OH:18][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC[C@H](C)COc1ccc(B(O)O)cc1C#N
Reactant: OO
Solvent: C1CCOC1
Product: CC[C@H](C)COc1ccc(O)cc1C#N

Procedure:
A mixture of compound 47 (3.00 g, 0.014 mol), hydrogen peroxide (30% w/v, 150 ml) and THF (200 ml) was heated under reflux for 3 h. The water/THF mixture was removed in vacuo and the oily residue was dissolved in diethyl ether and washed with water. The ether was dried (MgSO4) and evaporated in vacuo to give a viscous, fawn oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][OH:32])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:34](O)(=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].Cl.CN(C)CCCN=C=NCC.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][O:32][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution (20 ml) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (640 mg, 2.066 mmol) synthesized in the same manner as in Example 1, stearic acid (587 mg, 2.062 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (395 mg, 2.062 mmol) in methylene chloride was added 4-dimethylaminopyridine (33.6 mg, 0.275 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. This was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) and further by basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) and concentrated under reduced pressure to give the title compound (yield 649 mg, 64.5%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26]([N:17]2[C:14]3=[N:15][CH:16]=[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:12]=[C:13]3[CH:19]=[CH:18]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(-c2cnc3[nH]ccc3c2)cc1OC
Product: COc1ccc(-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)cc1OC

Procedure:
1-Benzenesulfonyl-5-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine 132 was prepared using the same protocol as described in Example 9, substituting 3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo-[2,3-b]pyridine and quioline-8-sulfonyl chloride with 5-(3,4-Dimethoxy-phenyl)-1H-pyrrolo-[2,3-b]pyridine and benzene sulfonyl chloride respectively. MS(ESI) [M+H+]+=395.20
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[NH2:11][N:12]1[C:21]([OH:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:29])[CH:19]=2)[N:14]=[CH:13]1>C(O)(=O)C>[Cl:29][C:18]1[CH:17]=[CH:16][C:15]([N:14]2[CH:1]=[N:11][N:12]=[CH:13]2)=[C:20]([CH:19]=1)[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:28]
Reactant: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O=CO
Product: O=C(c1ccccc1)c1cc(Cl)ccc1-n1cnnc1
Reaction time: 18 h

Procedure:
A stirred solution of acetic anhydride (25.3 ml) and 97% formic acid (10.6 ml) is kep at ambient temperature (25°) for 30 minutes, cooled in an ice bath and treated with 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline (12.24 g, 0.0447 mole). The solution is kept at ambient temperature for 18 hours, diluted with acetic acid (25 ml), warmed to the reflux temperature during 1 hour and refluxed for 1.5 hours. The solution is concentrated in vacuo, and the residue is mixed with cold water, made alkaline with sodium hydroxide and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized from ethylacetate to give 7.76 g of 5-chloro-2-(4H-1,2,4-triazol-4-yl)-benzophenone of melting point 184°-186° C., 0.971 g of melting point 182.5°-184° C., and 0.144 of melting point 181°-182° C.
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[CH:15][C:10]3[CH2:9][NH:8][CH2:30][CH2:29][C:11]=3[N:12]=2)[CH:22]=[C:21]([O:23][CH3:24])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc(OC)c1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of tert-Butyl-2-[(3,4,5-trimethoxyphenyl)amino]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carboxylate, Intermediate 2 (870 mg, 2.09 mmol) in 4.0 N HCl solution in 1,4-dioxane (15 mL) was stirred at room temperature for 20 hours (orange colored solution with precipitate). The solvent was removed in vacuo and the salt was mostly taken up in water (20 mL). The pH of the aqueous mixture was made basic by addition of 1.0 N NaOH(aq) and the white, amorphous precipitate was collected, washed with water, ethyl acetate, and dried (616 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=C(Cl)C=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[O:25]1[CH2:30][CH2:29][CH:28]([N:31]2[C:35]([NH2:36])=[CH:34][N:33]=[CH:32]2)[CH2:27][CH2:26]1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:11]([C:12]([NH:36][C:35]2[N:31]([CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH:32]=[N:33][CH:34]=2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccc(Cl)cc21
Reactant: Nc1cncn1C1CCOCC1
Solvent: CN1CCCC1=O
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncn1C1CCOCC1
Temperature: 100 °C
Reaction time: 19 h
Yield: 19.5 %

Procedure:
(6-chlorobenzotriazol-1-yl) 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate (120.1 mg, 0.3454 mmol) and 3-tetrahydropyran-4-ylimidazol-4-amine (75 mg, 0.314 mmol) (prepared according to a procedure similar to Preparation 10) were suspended in NMP (1 mL) and stirred at 100° C. for 19 hours. The reaction was cooled to ambient temperature and purified by passing the crude reaction mixture through a 10 g SCX-2 cartridge (pre-washed with MeOH). The cartridge was washed with DCM/MeOH mixtures then the product eluted with 2M NH3 in MeOH/DCM mixtures. The solvent was removed in vacuo and the material was purified by fractionlynx. The clean fractions were freeze-dried to give title compound 2-amino-6-fluoro-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a beige solid (21.1 mg, 19% Yield). MS (ES+) 346.1.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:23])[CH:19]=[C:20](Cl)[CH3:21])[CH3:16]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:23])/[CH:19]=[C:20](/[O:14][C:10]1[CH:9]=[C:8]([CH3:7])[CH:13]=[CH:12][CH:11]=1)\[CH3:21])[CH3:16]
Reactant: Cc1cccc(O)c1
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(C)c1
Temperature: 23 °C
Yield: 63.3 %

Procedure:
Potassium t-butoxide (10.4 g, 0.092 mol) was added to a stirred solution of 3-methyl-phenol (5.00 g, 0.046 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 6.85 g, 0.046 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-m-tolyloxy-but-2-enoic acid ethyl ester (6.41 g, 63%) as a yellow oil.