Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[O:12]=[C:13]1[N:17]([CH2:18][C@@H:19]2[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[C:16](=O)[CH2:15][NH:14]1>O1CCCC1>[OH:24][C@H:22]1[CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])[C@H:19]([CH2:18][N:17]2[CH:16]=[CH:15][NH:14][C:13]2=[O:12])[CH2:23]1
Reactant: O=C1CNC(=O)N1C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1Cn1cc[nH]c1=O
Reaction time: 12 h
Yield: 4.2 %

Procedure:
To a suspension of sodium borohydr-ide (6.03 g) in tetrahydrofuran (270 ml) was added boron trifluoride etherate (72 ml) at 0° C. under stirring. After stirring for 10 minutes, to the suspension was added a solution of (2S,4R)-2-(2,4-dioxoimidazolidin-3-yl)methyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (27.3 g) obtained in Preparation 10 in tetrahydrofuran (140 ml) and the mixture was stirred for 14 hours at ambient temperature. This reaction mixture was evaporated in vacuo and to the residue was added a solution of conc. hydrochloric acid (31 ml) in methanol (400 ml). After standing for 12 hours at ambient temperature, the solution was evaporated in vacuo and the resulting residue was poured into saturated aqueous sodium hydrogen carbonate (450 ml). The aqueous layer was extracted three times with a mixture of ethyl acetate (200 ml) and tetrahydrofuran (200 ml) and evaporated in vacuo. The resulting residue was chromatographed on silica gel (600 ml) eluting with a mixture of methanol and dichloromethane (5:95, V/V) to give (2 S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxo-4-imidazolin-1-yl)methyl pyrrolidine (1.11 g).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([CH3:19])(=[O:18])=[O:17])([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+].O>CO>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([CH3:19])(=[O:18])=[O:17])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccccc1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(Oc1ccccc1S(C)(=O)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
The product of Example 46B (1.22 g) was dissolved in MeOH (8 mL) and treated with 50% NaOH (1.75 g, 21.27 mmol) and water (6 mL). The mixture was heated until all was soluble and stirred at 25° C. for 1 hr. The solvents were removed in vacuo, water (6 mL) was added and the solution acidified with HCl. The mixture was extracted with CHCl3, dried (Na2SO4), filtered and concentrated in vacuo. The residue was crystallized from ether and heptane (1:4) to yield the title compound (0.953 g), m.p. 114-116° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3.[N:18]#[C:19]Br>O1CCCC1>[C:19]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3)#[N:18]
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(CN)C2
Reactant: N#CBr
Solvent: C1CCOC1
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNC#N)C2
Yield: 43.8 %

Procedure:
Using 2-aminomethyl-5-methyl-2,3,6,7,8,9-hexahydrofuro[2,3-f]quinoline-7-one (1.30 g, 5.6 mmol), cyanogen bromide (3.56 g, 33.6 mmol), and tetrahydrofuran (150 ml), the procedure of Example 342 was followed. 0.631 g of the title compound was obtained as yellow crystals (43.8%). Recrystallization from chloroform-methanol yielded the title compound as colorless needles (mp.: 209°-210° C.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(Cl)nc32)cc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)nc32)cc1
Yield: 87.5 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(4-methoxyphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example W-2, 0.17 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.17 g of the title compound as a solid, mp 186-188° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][N:9]2[C:13](=[O:14])/[C:12](=[CH:15]/[C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=3[C:36]([F:39])([F:38])[F:37])[N:20]=[CH:19]4)/[S:11][C:10]2=[O:40])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:41]1([C:44](Cl)=[O:45])[CH2:43][CH2:42]1>>[F:37][C:36]([F:38])([F:39])[C:27]1[CH:28]=[C:29]([C:32]([F:33])([F:34])[F:35])[CH:30]=[CH:31][C:26]=1[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16](/[CH:15]=[C:12]3/[C:13](=[O:14])[N:9]([CH2:8][C:2]4([NH:1][C:44]([CH:41]5[CH2:43][CH2:42]5)=[O:45])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)[C:10](=[O:40])[S:11]/3)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: NC1(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)CCOCC1
Reactant: O=C(Cl)C1CC1
Product: O=C(NC1(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)CCOCC1)C1CC1

Procedure:
N-(4-{[(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}tetrahydro-2H-pyran-4-yl)cyclopropane carboxamide was prepared from (5Z)-3-[(4-aminotetrahydro-2H-pyran-4-yl)methyl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (Example 310) and cyclopropanecarbonyl chloride following General Procedure R3.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.N1C=CC=CC=1.[F:29][C:30]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:31]=1[CH2:32][O:33][C:34]1[C:35]2[N:36]([C:40]([C:44]([NH:46][C@H:47]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:48][OH:49])=[O:45])=[C:41]([CH3:43])[N:42]=2)[CH:37]=[CH:38][CH:39]=1.[OH-].[Na+]>ClCCl>[F:29][C:30]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:31]=1[CH2:32][O:33][C:34]1[C:35]2[N:36]([C:40]([C:44]([NH:46][C@H:47]([CH2:50][CH2:51][CH2:52][CH3:53])[CH:48]=[O:49])=[O:45])=[C:41]([CH3:43])[N:42]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC[C@H](C=O)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Reaction time: 2 h

Procedure:
1.14 g of Dess-Martin periodinane (2.7 mmol, 1.5 equivalents) were initially charged in 25 ml of dichloromethane, and 0.145 ml of pyridine (1.8 mmol, 1 equivalent) and 750 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (Example 3A, 1.8 mmol) were added at −20° C. The reaction mixture was stirred at this temperature for 2 h. 1 N aqueous sodium hydroxide solution was added with ice cooling, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. This gave 899 mg (about 70% pure; 90% of theory) of the target compound which were not purified any further.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][NH:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].C(N(CC)CC)C>C(OCC)C>[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][N:14]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(CNc1c(C)cccc1C)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(CN(C(=O)c1ccccc1)c1c(C)cccc1C)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
2.81 g (0.02 mol) of benzoyl chloride were added in drops in 20 minutes and at a temperature of 0°-5° C. to a solution of N-(2',2'-dimethoxy-ethyl)-2,6-dimethyl aniline (4.45 g; 0.02 mol) in ethyl ether (20 ml) containing triethylamine (2.76 ml; 0.02 mol). The reaction mixture was stirred at room temperature for 15 minutes. The resulting salt was filtered and the solution was washed with 8 ml of an aqueous solution of hydrochloric acid at 5% and then with water up to neutral pH. The organic phase was anhydrified with anhydrous NaSO4 and the solvent was evaporated, so obtaining 5.2 g of a white solid which, recrystallized from petroleum ether (25 ml) provided 4.5 g of product (purity=91% by GLC) with a yield of 65.5% (white solid, melting point=58°-59° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[S:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH3:18])[CH:12]=2)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35].O>C1(C)C=CC=CC=1>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH3:18])[CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:34]=[O:35])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(SC(c2cnc(Br)cc2C)c2cc(F)ccc2F)ccc1F
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(SC(c2cnc(C=O)cc2C)c2cc(F)ccc2F)ccc1F
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
A solution of 2-bromo-5-[(2,5-difluorophenyl)[(4-fluoro-3-methylphenyl)thio]methyl]-4-methylpyridine (2.0 g, 4.6 mmol) in toluene (50 ml) was cooled to −78° C., and in an argon atmosphere, n-butyllithium (1.54 M hexane solution, 3.6 ml, 5.5 mmol) was added thereto. After stirring for 10 minutes at the same temperature, the mixture was allowed to warm to −40° C., stirred for 30 minutes, and cooled again to −78° C., and then N,N-dimethylformamide (424 μl, 5.5 mmol) was added. After stirring for 30 minutes at the same temperature, water was added thereto, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=95:5 was concentrated under reduced pressure to obtain the title compound (1.1 g, 2.8 mmol, 63%) as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([O:1][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1nc(C)cc(C)n1
Yield: 26.8 %

Procedure:
2-Hydroxy-4,6-dimethyl pyrimidine (10g, 0.08 mol) was dissolved in 150ml of dimethylformamide. Ethyl bromoacetate (13.5g, 0.08 mol) was added and also, subsequently, 11.lg of potassium carbonate. The reaction mixture was refluxed overnight. A precipitate had formed which was filtered off and the solvent was then evaporated off from the filtrate to form a crude oily product. Following purification by flash chromatography, 4.5g of the title product were obtained in the form of a red oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]1[C:6]2[C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1coc2cccc(O)c12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc2occ(C)c12

Procedure:
A solution of 3-methyl-4-hydroxybenzofuran (5.0 gm, 34.7 mmoles), acetic anhydride (50 mL) and triethylamine (25 mL) in tetrahydrofuran (150 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by chromatography on silica gel. Elution with 15% ethylacetate in hexane yielded 3-methyl-4-acetoxybenzofuran.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.CO[C:22]1[CH:23]=[C:24]([CH:26]=[C:27](OC)[C:28]=1OC)[NH2:25].CCOC(C)=O>C(O)(C)C>[C:24]1([NH:25][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)[CH:26]=[CH:27][CH:28]=[CH:22][CH:23]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C(c1cccnc1)N1CCc2nc(Nc3ccccc3)ncc2C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 3,4,5-trimethoxyaniline (0.021 g, 0.0498 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 54.8% yield (0.021 g, 0.049 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].Cl.CN.[C:15]([BH3-])#[N:16].[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:16][CH3:15])=[O:5])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)C1CCCC1=O
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(NC)CCC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with methylamine hydrochloride (1.296 g, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the crude product, 2-methylamino-cyclopent-1-enecarboxylic acid ethyl ester, as a light yellow oil. LC-MS (ESI) calcd for C9H15NO2 169.11, found 170.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6].N1C2C(=CC=CN=2)C=C1.[Cl-:23].[Cl-].[Cl-].[Al+3]>S(Cl)(Cl)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([Cl:23])=[O:6]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Reactant: [Cl-]
Agent: [Al+3]
Agent: c1cnc2[nH]ccc2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-fluoro-5-nitrobenzoic acid (2.00 g, 10.8 mmol) was dissolved in thionyl chloride (20.0 mL) and the reaction was heated to reflux overnight. The reaction was cooled and was concentrated to provide a white solid which was dried under vacuum overnight. Compound 2 (512 mg, 4.33 mmol) was dissolved in methylene chloride (10.0 mL), under an atmosphere of argon and aluminum trichloride (2.85 g, 21.4 mmol) was added. The reaction was stirred at room temperature for 1 hour. The 3-fluoro-5-nitrobenzoyl chloride formed above was dissolved in methylene chloride (10.0 mL) and was added to the reaction. The reaction was stirred at room temperature overnight. The reaction was quenched with methanol and concentrated under reduced pressure. The resulting solid was extracted with ethyl acetate and saturated sodium bicarbonate. The organic portion was dried with anhydrous magnesium sulfate, adsorbed onto silica and purified by silica gel flash chromatography with 40%-50% ethyl acetate:hexanes. The appropriate fractions were combined and concentrated to provide compound 295 as a white solid characterized by MS and 1H-NMR (139 mg, LRMS (ESI) [M+H+]+=286.1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8](O)([CH3:10])[CH3:9]>>[CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([CH3:10])[CH3:9]
Reactant: CC(C)O
Reactant: Oc1ccccc1
Product: CC(C)c1ccccc1O

Procedure:
In a manner similar to the procedure of Example I, phenol is alkylated with an isopropanol alkylating agent in the presence of an amorphous aluminosilicate alkylation catalyst. Using reaction conditions approximately identical to those of the Example I alklation procedure, an alkylation product containing phenol and isopropylphenol is produced.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)=[CH:6][CH:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:16][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([O:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: Oc1ccccc1
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(Oc3ccccc3)nn2)cc1F
Temperature: 150 °C

Procedure:
A mixture of 3-chloro-6-(3-fluoro-4-methoxy-phenyl)-pyridazine (1.0 g, 4019 mmol), phenol (0.26 g, 5.03 mmol) and Cs2CO3 (1.64 g, 5.03 mmol) in 15 mL of DMF (in microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 150° C. for 15 min. The mixture was cooled to RT and diluted with 60 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The solid was washed with 50% EtOAc/hexanes to provide the title compound as an off-white solid. MS (ESI pos. ion) m/z: 297.3 (M+H). Calc'd Exact Mass for C17H13FN2O2: 296.30.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](=N)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[C:7]1([C:6](=[N:1][CH2:2][CH2:3][CH2:4][OH:5])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: NCCCO
Solvent: ClCCl
Product: OCCCN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
A solution of 3-amino-1-propanol [Aldrich product # A76400] (2.0 mL, 26 mmol) in dichloromethane (79 mL) was treated with benzophenone imine (4.4 mL, 26 mmol) and stirred at 25° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (6.3 g, quantitative) as an oil. This material was used without further purification. LCMS for C16H18NO (M+H)+: m/z=240.2.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[N+:18]([O-:20])=[O:19])[CH:11]=1)[CH2:6][CH2:7][CH3:8].[BH4-].[Na+]>CS(C)=O>[CH2:5]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])[CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOc1cccc(/C=C/[N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCCCOc1cccc(CC[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To an acetic acid (3.9 mL) and dimethyl sulfoxide (67 mL) solution of 1-butoxy-3-((E)-2-nitro-vinyl)-benzene (3.92 g, 17.7 mmol) described in Manufacturing Example 65-1-2 was added sodium borohydride (1.07 g, 28.3 mmol) at room temperature while cooling appropriately. This mixture was stirred for 4 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (2.29 g, 58%).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:35])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:15]=2[CH3:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>ClCCl>[C:45]([CH:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:9][CH2:10][NH:11][C:12](=[O:35])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[C:15]=1[CH3:34])(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)c(CC(=O)NCCCNC1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)NCCC(NC1CCCCC1)C(C)=O)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.100 g (0.2 mmol) of N-(3-cyclohexylaminoprop-1-yl)-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide in 1 mL of anhydrous dichloromethane was added 0.04 mL (0.24 mmol) of diisopropylethyl amine followed by 0.015 mL (0.2 mmol) of acetyl chloride. The reaction was stirred at room temperature for 20 hr then diluted with more dichloromethane (2 mL). The solution was washed with dilute aqueous citric acid (1 mL) before drying (Na2SO4), filtering and evaporating. The residue was purified by preparative HPLC to give the title compound. 1H NMR (CDCl3) δ 7.68 (2H, d), 7.39 (2H, d), 7.16 (1H, bt), 6.86 (1H, d), 6.79 (1H, d), 6.61 (1H, dd), 3.75 (3H, s), 3.57 (2H, s), 3.36 (1H, bt), 3.06 (4H, m), 2.33 (3H, s), 1.96 (3H, s), 0.9-1.8 (12H, m).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][CH:8]([O:12][CH3:13])[CH2:9][NH:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CC1CCCO1>[Cl:1][CH2:2][C:3]([N:10]([CH2:9][CH:8]([O:12][CH3:13])[O:7][CH3:6])[CH3:11])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNCC(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC1CCCO1
Product: COC(CN(C)C(=O)CCl)OC

Procedure:
195 ml chloroacetyl chloride in 200 ml 2-methyltetrahydrofuran are added dropwise at 2° C. within one hour to a mixture of 300 ml (methylamino)-acetaldehyde dimethylacetal, 1200 ml 2-methyltetrahydrofuran and 1200 ml saturated potassium carbonate solution. After 40 min 1450 ml of water are added and the phases are separated. The aqueous phase is extracted with 600 ml 2-methyltetrahydrofuran. The combined organic phases are dried on sodium sulphate and evaporated down. 451 g product remain.