Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:18]COCC)(C)[CH3:16])=[CH:11][C:10]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)([CH3:8])[CH3:7])[CH3:2].Cl>C1COCC1>[CH2:1]([O:3][CH2:4][O:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH3:16])=[CH:11][C:10]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:30])([CH3:31])[O:24]1)([CH3:7])[CH3:8])[CH3:2]
Reactant: CCOCOC(C)(C)c1ccc(C(C)(C)OCOCC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCOCOC(C)(C)c1ccc(C(C)=O)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.5 %

Procedure:
To a solution of 2-(2,5-bis(2-(ethoxymethoxy)propan-2-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (510 mg) in THF (15 mL) was added 6 N HCl (3.8 mL). The reaction mixture was stirred at rt for 5 h, and extracted with DCM (200 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combiflash to give 6-(2-hydroxypropan-2-yl)-3,3-dimethylbenzo-[c][1,2]oxaborol-1(3H)-ol [112 mg, yield 45% (2 steps, step 5 and 6)] as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.77 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 4.98 (s, 1H), 1.43 (s, 12H) ppm; HPLC purity: 94.6% at 220 nm and 100% at 254 nm; MS: m/z=203.1 (M−17, ESI+).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].[CH2:19]([O:21][C:22]([C:24]1[O:25][C:26]2[C:32]([CH:33]=[O:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=2[CH:28]=1)=[O:23])[CH3:20]>C1COCC1.CCCCCCC>[CH2:19]([O:21][C:22]([C:24]1[O:25][C:26]2[C:32]([CH:33]([C:9]3[N:8]=[C:7]([Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])[N:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:18])[CH3:1])[CH:10]=3)[OH:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=2[CH:28]=1)=[O:23])[CH3:20]
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)c1cc2cc(C)cc(C=O)c2o1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(C)cc(C(O)c3cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n3)c2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethylamide (1.0 g) in THF (10 ml) was cooled under an Argon atmosphere to −78° C. n-Buthyllithium solution (1.6 M in heptane, 2.37 ml) were added dropwise. After stirring for 1 hr at −78° C. a solution of 7-formyl-5-methyl-benzofuran-2-carboxylic acid ethyl ester (963 mg) in THF (10 ml) was added dropwise. Stirring was continued for 15 min at −78° C., then the reaction mixture was warmed up to r.t. overnight. After quenching with water, the mixture was extracted with EtOAc. The organics were dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give rac-7-{[2-(tert-butyl-dimethyl-silanyl)-1-dimethylsulfamoyl-1H-imidazol-4-yl]-hydroxy-methyl}-5-methyl-benzofuran-2-carboxylic acid ethyl ester as light yellow amorphous solid; MS (ISP): 522.3 ((M+H)+.).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[NH:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3C(O)=O)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:20].[C:21](=O)=O>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:20]
Reactant: O=C=O
Reactant: O=C(O)c1ncn2c1CNC(=O)c1c-2ccc(F)c1Cl
Solvent: CCO
Product: CN1Cc2cncn2-c2ccc(F)c(Cl)c2C1=O

Procedure:
11.64 g (37.5 mmol) of 7-chloro-8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid was heated to 285° in a metal bath until the CO2 cleavage has finished. The melt was poured into 50 ml of ethanol and the precipitated product was filtered off under suction and washed with ethanol. After drying there was obtained 7-chloro-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 234°-235°.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8]([F:11])([F:10])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[OH-].[Li+]>C(#N)C.O>[C:15]([O:14][C:12]([N:6]1[CH2:7][C:8]([F:10])([F:11])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.6 %

Procedure:
4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (Example 14a, 7.53 g, 28.403 mmol) was dissolved in acetonitrile (330 mL) and a solution of lithium hydroxide (1.36 g, 56.807 mmol) in water (110 mL) was added. After stirring for 16 h at 25° C., the acetonitrile was removed in vacuo and the aqueous phase was slowly acidified with 1.0 M aqueous hydrochloric acid solution until a precipitate formed. The product was extracted into ethyl acetate (3×50 mL) and the combined organic layers were dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford the desired product, 4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.54 g, 6.13 mmol, 95.6% yield) as a brittle, tan solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 1.51 (9H, s), 2.50-2.84 (2H, m), 3.71-3.90 (2H, m), 6.73 (1H, bs).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([OH:16])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.Cl.[NH2:47][CH:48]1[CH:55]2[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:57][CH:49]1[CH2:50]3)[CH2:54]2>ClCCl.CN(C=O)C.O>[CH:49]12[CH2:57][CH:53]3[CH2:52][CH:51]([CH2:56][CH:55]([CH2:54]3)[CH:48]1[NH:47][C:14]([C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:16])[CH2:50]2
Reactant: CC(C)(C)n1ncc(C(=O)O)c1C(F)(F)F
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1C(F)(F)F
Reaction time: 1 h
Yield: 64.5 %

Procedure:
tert-Butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (Intermediate 7, 61 mg, 0.26 mmol) was dissolved in a mixture of dry dichloromethane (3.2 mL) and dry DMF (0.8 mL). DIPEA (0.23 mL, 1.3 mmol) and TSTU (93 mg, 0.28 mmol) were added to the above mixture. After the mixture was stirred for 1 h, the appearance of active ester was detected by LC-MS. Then 2-aminoadamantane hydrochloride (58 mg, 0.31 mmol) was added. After another 2 hours water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried under vacuum and purified by C-18 reversed phase HPLC with a gradient of 10-100% acetonitrile/water to give 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (62 mg, 65%). Mass spectrum: m/z: 370.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH3:16])[C:14]([C:17]([OH:20])([CH3:19])[CH3:18])=[N:13][CH:12]=3)[S:10][C:3]=12.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH2:31])=[CH:26][CH:25]=2.ClC(Cl)C>C(O)(C)(C)C>[CH3:16][N:15]1[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:31][C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22]([CH3:21])=[CH:30]4)[CH:8]=2)=[CH:12][N:13]=[C:14]1[C:17]([OH:20])([CH3:19])[CH3:18]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Cn1c(-c2cc3nccc(Cl)c3s2)cnc1C(C)(C)O
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cnc(C(C)(C)O)n5C)sc34)ccc2[nH]1
Yield: 64.1 %

Procedure:
2-[5-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-2-yl]-propan-2-ol (190 mg, 0.62 mmol) and 2-methyl-5-aminoindole (108 mg, 0.714 mmol) were dissolved in 3 mL of t-butyl alcohol and 3 mL of dichloroethane and the solution was heated to 85° C. After allowing the reaction to go dry overnight solvent was added along with an additional 45 mg of the indole an the solution was heated an additional 18 hours. Chromatography of the residue with 20% methanol:methylene chloride afforded 166 mg (66%) of 2-{1-methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol. 1H NMR (400 MHz, CD3OD) δ8.17 (d, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.40 (d, 1H), 7.02 (d, 1H), 6.84 (s, 1H), 6.20 (s, 1H), 3.33 (s, 3H), 2.44 (s, 3H), 1.64 (s, 6H). LC-MS: 418, 419 (MH+); HPLC RT: 3.98 min.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].[CH2:17](O)[CH2:18][OH:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([C:14]2([CH3:15])[O:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1
Reactant: OCCO
Reactant: CC(=O)c1cccc(-c2ccncc2)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2cccc(-c3ccncc3)c2F)OCCO1
Yield: 64.8 %

Procedure:
A mixture of 1-(2-fluoro-3-pyridin-4-ylphenyl)ethanone (1.28 g, 5.95 mmol), ethylene glycol (1.66 ml, 29.75 mmol), molecular sieves (5 g, 3 Å) and p-toluenesulfonic acid monohydrate (0.11 g, 0.59 mmol) in toluene (20 ml) was heated at reflux for 2 h. The molecular sieves was filtered off and the residue was evaporated to dryness. Purification by flash column chromatography (ethyl acetate) gave the title compound (1.0 g). MS m/z (rel. intensity, 70 eV) 259 (M+, 1), 245 (15), 244 (bp), 200 (56), 87 (17).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[CH:7][C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[CH:3]=1.[C:22]1(=[O:28])[NH:26][C:25](=[O:27])[CH:24]=[CH:23]1.[Sn](Cl)Cl>>[Br:1][C:2]1[C:10]2[O:9][C:8]3[CH2:11][CH:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[Cl:19])[CH:23]4[CH:24]([C:25](=[O:27])[NH:26][C:22]4=[O:28])[C:7]=3[C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(Br)c2oc(/C=C/c3ccccc3Cl)cc2c1
Reactant: O=C1C=CC(=O)N1
Agent: Cl[Sn]Cl
Product: COc1cc(Br)c2oc3c(c2c1)C1C(=O)NC(=O)C1C(c1ccccc1Cl)C3
Temperature: 150 °C

Procedure:
A solution of (859) (4.89 g, 0.0185 mol) prepared as described in example 441, maleimide (1.44 g, 0.02 mol) and tin(II) chloride (2.8 g, 0.02 mol) in xylenes (40 mL) was heated to 150° C. overnight. After the addition of more maleimide (1.44 g, 0.02 mol) and tin(II) chloride (1.44 g, 0.01 mol) the reaction was again heated to 150° C. overnight. The solid which formed was collected and washed with xylenes (20 mL) before dissolving in ethyl acetate (200 mL). Water (50 mL) was added and the mixture was filtered through a pad of Celite. The resulting layers were separated, the organic phase was washed with brine (50 mL) dried over magnesium sulphate, filtered and concentrated to dryness. The product (860) (6.1 g, 71%) was used without further purification. 1H NMR δ (CDCl3) 7.60 (d, J=6.5 Hz, 1H), 7.40 (m, 2H), 7.25 (m, 1H), 7.1 (m, 2H), 4.36 (dd, J=7.3, 1 Hz, 1H), 4.0 (m, 1H), 3.86 (s, 3H), 3.81 (m, 1H), 3.45 (m, 1H), 3.10 (dd, J=4.7, 17 Hz, 1H); MH+:462,460.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)CC(NC3C=CC(F)=CC=3)=O)=[CH:11][C:10]=2[F:29])[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].ClC1C=CN=C([C:43]([NH2:45])=[O:44])C=1>CN(C=O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:43]([NH2:45])=[O:44])[CH:7]=2)=[C:10]([F:29])[CH:11]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1)Nc1ccc(F)cc1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A solution of 4-amino-2-fluorophenol (Compound A of Example 20, 0.81 g, 6.4 mmol, 1.0 eq) in DMF (6.5 mL) was treated with potassium tert-butoxide (0.79 g, 7.1 mmol, 1.1 eq) at room temperature and the reaction mixture was stirred for 1 h. 4-Chloropicolinamide (1.0 g, 6.4 mmol, 1.0 eq) was added and the reaction mixture was heated to 110° C. for 8 h. The reaction was cooled to room temperature and the reaction mixture quenched with water. The resulting heterogeneous solution was filtered and the solid material was washed with water. The solid was triturated with a small amount of MeOH followed by Et2O. The solid was filtered and dried in vacuo to afford the product (1.3 g, 82%) as a solid. 1H NMR (DMSO-d6) δ 8.49-8.50 (m, 1H), 8.12 (br s, 1H), 7.71 (br s, 1H), 7.35-7.36 (m, 1H), 7.14-7.16 (m, 1H), 7.01-7.06 (m, 1H), 6.44-6.47 (m, 2H), 5.53 (s, 2H); MS(ESI+) m/z 248 (M+H)+.
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[N:13]([CH3:16])[CH2:12][CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24]>O1CCOCC1>[ClH:24].[CH2:1]([CH:8]1[NH:9][CH2:10][CH2:11][CH2:12][N:13]([CH3:16])[C:14]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCCN(C(=O)OC(C)(C)C)C(Cc2ccccc2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCNC(Cc2ccccc2)C1=O

Procedure:
tert-Butyl 2-benzylhexahydro-4-methyl-3-oxo-1H-1,4-diazepine-1-carboxylate obtained in Step A was dissolved in 4M hydrochoride in dioxane and evaporated after 2.5 h to yield the hydrochloride salt of the desired compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:16][C:15]2[C:14]3[CH:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:9]=3[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[C:6]=1[O:25][CH3:26])=[O:4].[OH-].[Na+].O.N1C2C(=CC=C3OC=CC3=2)C=C1>C(O)C.ClCCl>[CH3:26][O:25][C:6]1[C:7]2[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[CH:13][C:14]=3[C:15]=2[O:16][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1oc2c3cc(OC)ccc3n(-c3ccccc3)c2c1OC
Agent: [Na+]
Agent: [OH-]
Agent: c1cc2ccc3occc3c2[nH]1
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)c1oc(C(=O)O)c(OC)c1n2-c1ccccc1

Procedure:
A suspension of 11.5 g (0.033 mole) of 3,7-dimethoxy-4-phenyl-4H-furo[3,2-b]indole-2-carboxylic acid methyl ester in 200 ml of 50% aqueous ethanol was treated with 25 ml of 10% aqueous sodium hydroxide solution. After stirring at reflux for 90 minutes, the reaction mixture was cooled and distributed between 750 ml of water and 250 ml of dichloromethane. The insoluble material (primarily the sodium salt of the product) was removed by filtration. The filtrate layers were separated, and the organic layer was discarded. The aqueous layer was washed several times with fresh dichloromethane, cooled in ice, and acidified with 4N hydrochloric acid. The precipitate crude product was filtered and washed with water. The original insoluble sodium salt was stirred for several hours in 400 ml of cold 1N hydrochloric acid, and the product acid was filtered, washed with water, and combined with the material obtained from acidification of the original aqueous layer. The crude yield of the furoindole acid was 9.4 g (85%) yield). A sample recrystallized from acetone/water was analytically pure, mp 148° C. (dec).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]2[N:14]([C:15]=1[C:16]([O:18]CC)=[S:17])[CH:13]=[CH:12][S:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([C:8]1[N:9]=[C:10]2[N:14]([C:15]=1[C:16]([OH:18])=[S:17])[CH:13]=[CH:12][S:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=S)c1c(Cc2ccccc2)nc2sccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC(=S)c1c(Cc2ccccc2)nc2sccn12
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 3.5 g of ethyl 6-benzylthioimidazo [2,1-b]thiazole-5-carboxylate in 25 ml of ethanol is added sodium hydroxide solution (prepared by dissolving 1.5 g of sodium hydroxide in 7 ml of water) and the mixture is stirred for 30 minutes at 50°-60° C. and then under reflux for 20 minutes. The reaction solution is concentrated, added with 70 ml of water and adjusted to pH 3 by addition of hydrochloric acid. The precipitate is collected by filtration and dried to obtain 3.0 g of the title compound, mp. 147°-150° C. (decomp.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH3:17])=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([O:35]C(N(C)C)N(C)C)(C)(C)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][C:19](=[O:28])[C:20]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[CH:31][OH:35])[CH3:17])=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CC(C)NC(=O)Cc2ccc(C)cc2)ccc1OCc1ccccc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CC(C)NC(=O)C(=CO)c2ccc(C)cc2)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2.40 g (5.95 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)-1-methylethyl]-2-(4-methylphenyl)acetamide and 3.10 g (17.8 mmol) of t-butoxybis(dimethylamino) methane were mixed and stirred at 80° C. for 2 hours. The reaction mixture was cooled and tetrahydrofuran was added thereto. The reaction mixture was acidified with hydrochloric acid and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the residue was extracted with chloroform washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=3:2) and dried to give 1.90 g of N-[2-(4-benzyloxy-3-methoxyphenyl)-1-methylethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide.
Reaction SMILES: [CH:1]([CH:9]([CH2:13][C:14]([OH:16])=[O:15])[C:10]([OH:12])=[O:11])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(C1CC(=O)OC1=O)=CCCCCCC.[OH-].[Na+:33]>>[CH:1]([CH:9]([CH2:13][C:14]([O-:16])=[O:15])[C:10]([O-:12])=[O:11])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Na+:33].[Na+:33]
Reactant: CCCCCCC=CC(CC(=O)O)C(=O)O
Agent: CCCCCCC=CC1CC(=O)OC1=O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCC=CC(CC(=O)[O-])C(=O)[O-]
Yield: 35 %

Procedure:
This example illustrates the use in an anionic surfactant composition of an octenylsuccinic acid liquid-stabilizing agent. An aqueous disodium octenylsuccinate (about 35%) was prepared from octenyl succinic anhydride (OSA from Dixie Chemical, Houston, Tex.) and aqueous sodium hydroxide. According to the manufacturer of the OSA, this material is reportedly predominantly 1-OSA, but some 2-OSA is also present.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:44][CH2:45][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:47][CH2:48]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: OCC(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 100 °C
Yield: 72.2 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(methyloxy)-4-[4-(methylsulfonyl)-1-piperazinyl]aniline (Example 232, step B) (51 mg, 0.18 mmol), and p-toluenesulfonicacid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (92 mg, 0.13 mmol, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 9.40 (s, 1H), 8.49 (s, 1H), 8.33 (s, 1H), 8.21 (d, J=5.13 Hz, 1H), 8.05 (d, J=7.70 Hz, 1H), 7.82 (d, J=7.70 Hz, 1H), 7.73 (d, J=8.80 Hz, 1H), 7.61 (t, J=7.70 Hz, 1H), 7.43-7.49 (m, 2H), 7.35-7.43 (m, 1H), 7.16-7.24 (m, 2H), 6.99 (t, J=6.78 Hz, 1H), 6.73 (d, J=2.20 Hz, 1H), 6.52 (dd, J=8.62, 2.38 Hz, 1H), 6.48 (d, J=5.13 Hz, 1H), 3.81 (s, 3H), 3.25 (br. s., 8H), 2.92 (s, 3H); MS (ESI): 711 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:12][CH2:13][CH2:14][NH:15]C(OCC1C=CC=CC=1)=O)[CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH:9]1[CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCNC(=O)OCc1ccccc1)CC1CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCCN)CC1CC1

Procedure:
A solution of (3-benzyloxycarbonylamino-propyl)-cyclopropylmethyl-carbamic acid tert-butyl ester (4.2 g, 0.012 mol) in ethanol (60 ml) was stirred in the presence of palladium on carbon (10%, 0.42 g) under a hydrogen atmosphere for 2 h. Filtration through celite and concentration gave (3-amino-propyl)-cyclopropylmethyl-carbamic acid tert-butyl ester; 1H NMR (CDCl3, 400 MHz) δ 3.35 (m, 2H), 3.08 (m, 2H), 2.70 (t, 2H, J=6.8 Hz), 1.67 (m, 2H), 1.46 (s, 9H), 1.30 (bs, 2H), 0.97 (m, 1H), 0.48 (m, 2H), 0.20 (q, 2H, J=5 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(O)=O.[CH2:24]([NH2:27])[CH2:25][CH3:26].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][CH:16]([NH:27][CH2:24][CH2:25][CH3:26])[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCNC1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A solution of compound 119 (0.75 g, 2.926 mmol) in 1,2-dichloroethane (20 mL) was treated with AcOH (0.16 mL, 2.926 mmol), n-propylamine (0.24 g, 2.926 mmol), NaBH(OAc)3 (0.93 g, 4.390 mmol) at room temperature and stirred for over night (16 h). The reaction was basified with 2 N NaOH (25 mL) and product was extracted into ethyl acetate (3×50 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 133 (0.58 g, 66%) as a brown semi-solid. 1H NMR (DMSO-d6) δ 0.89 (t, 3H, J=7.2 Hz), 1.37-1.51 (m, 4H), 1.91-2.00 (m, 2H), 2.44-2.57 (m, 4H), 2.68-2.76 (m, 1H), 6.14 (s, 1H), 7.80 (s, 1H), 7.86-7.97 (m, 2H), 8.30 (d, 1H, J=2.1 Hz), 11.82 (brs, 1H); ESI-MS (m/z, %) 300 (MH+, 100).
Reaction SMILES: [CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccc(C(=O)C2CCCCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)C1CCCCCC1

Procedure:
The title compound is prepared in analogy to the procedure of Example II from 53.2 g (0.229 mol) of the compound from Example XI and 458 ml of a 1M solution of boron tribromide (0.458 mol) in dichloromethane.