Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([O:19][CH3:20])[C:13](N(OC)C)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:30]2[N:31]=[CH:32][O:33][CH:34]=2)=[CH:24][C:23]=1[O:35][CH3:36]>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([O:19][CH3:20])[C:13]([C:32]3[O:33][CH:34]=[C:30]([C:25]4[CH:24]=[C:23]([O:35][CH3:36])[C:22]([Br:21])=[C:27]([O:28][CH3:29])[CH:26]=4)[N:31]=3)=[O:14])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(C(=O)N(C)OC)c1ccc(-n2cccn2)cc1
Reactant: COc1cc(-c2cocn2)cc(OC)c1Br
Product: COc1cc(-c2coc(C(=O)C(OC)c3ccc(-n4cccn4)cc3)n2)cc(OC)c1Br

Procedure:
2-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-(4-bromo-3,5-dimethoxyphenyl) oxazol-2-yl)-2-methoxyethanone was synthesized from 2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole by a method similar to that used for Example 2 except that the amide was added to the reaction mixture at −50° C. MS: m/z 498.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1.Cl.N1C=CC=CC=1.O>CCOC(C)=O>[OH:19][C:16]1[CH:17]=[CH:18][C:12]2[O:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=3)=[CH:14][C:13]=2[CH:15]=1
Reactant: COC(=O)c1ccc(-c2cc3cc(OC)ccc3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2cc3cc(O)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture of 4-(5-Methoxy-benzofuran-2-yl)-benzoic acid methyl ester (0.5 g, 1.8 mmol) and Pyridine HCl (5 g) was heated to 200° C. After 2 hr, the reaction was cooled and poured into water and exracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated and the product was purified by column chrmatography on silica gel (75% EtOAc/hex) to give a solid (0.21 g, 47%): 1H NMR (DMSO-d6) δ 13.07 (br s, 1 H), 9.29 (br s, 1 H), 8.02 (d, 2 H, J=8.1 Hz), 7.97 (d, 2 H, J=8.7 Hz), 7.46 (m, 2 H), 6.97 (d, 1H, J=2.9 Hz), 6.79 (dd, 1 H, J=9.3 Hz, 2.9 Hz); MS 253 (M−H)−
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:24][C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=3[C:35]([O:37][CH3:38])=[O:36])[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)[nH]4)ccc3c2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
A mixture of 6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthol (200 mg, 0.701 mmol), prepared in step 5 of Example 1, dimethyl 4-(bromomethyl)isophthalate (241 mg, 0.841 mmol) and cesium carbonate (1.14 g, 3.50 mmol) in 50 mL of acetone was stirred at room temperature for 1.5 h. The reaction was concentrated under reduced pressure to remove the acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted two times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give a yellow solid. Purification of the solid on a Biotage Horizon™ system with a KP-SIL Flash 40+M column using a gradient of 85% methylene chloride in hexane to 100% methylene chloride as the eluent gave dimethyl 4-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalate (280 mg, 81%) as a yellow solid, mp 203–205° C. Elemental Analysis for C31H25NO5.0.10 CH2Cl2 Calc'd: C, 74.70; H, 5.08; N, 2.80. Found: C, 74.24; H, 4.80; N, 2.76.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]12[CH2:15][CH2:14][C:11]([C:16]3[NH:17][C:18]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=4)=[C:19]([C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[N:20]=3)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)=[O:7]>C1COCC1.CO.O>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([C:19]3[N:20]=[C:16]([C:11]45[CH2:14][CH2:15][C:8]([C:6]([OH:7])=[O:5])([CH2:9][CH2:10]4)[CH2:13][CH2:12]5)[NH:17][C:18]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: COC(=O)C12CCC(c3nc(-c4ccc5c(c4)OCO5)c(-c4cccc(C)n4)[nH]3)(CC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cccc(-c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2-c2ccc3c(c2)OCO3)n1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Lithium hydroxide monohydrate (0.020 g, 0.487 mmol) was added to a solution of 4-[4-benzo[1,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (see Example 21; 0.150 g, 0.325 mmol) in a mixture of THF/MeOH/H2O (2/1/1, 4 mL). The mixture was stirred for 3 hours. Solvent was removed. Residue was diluted with water (30 mL). Citric acid was added to the solution to make the pH lower than 7. The aqueous solution was extracted with ethyl acetate. Ethyl acetate extract was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.140 g (99%) of the title compound as a yellow solid. MS (ESP+) m/z 432.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.72 (m, 1H), 7.33 (d, 1H, J=7.7 Hz), 7.22 (d, 1H, J=7.7 Hz), 6.98 (m, 3H), 6.05 (s, 2H), 2.64 (s, 3H), 2.11 (m, 6H), 1.99 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])=[N:6][CH:7]=1.[F:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24](F)[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:24]3[CH:23]=[N:22][CH:21]=[C:20]([F:19])[CH:25]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Fc1cncc(F)c1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(F)cn2)n1
Product: Cc1ccc(Nc2cncc(F)c2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, light yellow solid, MS (ISP): m/e=342.1 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide and 3,5-Difluoropyridine in accordance with the general method of example 7.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C1C=C(C)C=CC=1S([O-])(=O)=O>O1CCCC1>[CH3:1][NH:2][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([F:26])([F:3])[C:22]([F:25])([F:24])[F:23]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCCCCCC(F)(F)C(F)(F)F)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
4.0 g of methylamine is condensed in a solution of 2.9 g of 7,7,8,8,8-pentafluor-octyltosylate in 10 ml of absolute tetrahydrofuran at −20° C., and it is stirred overnight in a pressure vessel at room temperature. After the pressure vessel was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. The reaction solution is taken up in dichloromethane, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 1.58 g of methyl-(7,7,8,8,8-pentafluor-octyl)-amine is obtained as a crude product.
Reaction SMILES: CN([C:4]1[C-:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)C.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].[C-]#N.[K+].[CH3:19][N:20](C)C>O>[C:19]([CH2:9][C-:5]1[CH:4]=[CH:8][CH:7]=[CH:6]1)#[N:20].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: CN(C)C
Reactant: C[c-]1cccc1N(C)C
Agent: [Fe+2]
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CC[c-]1cccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
58 g (0.15 mol) of N,N-dimethylamino-methylferrocene methoiodide were added to a solution of 57 g (0.88 mol) of potassium cyanide in 570 ml of water and the mixture was heated to the boil, the solid material dissolving. Within a few minutes, the evolution of trimethylamine started, while at the same time a volatile oil separated out. After stirring for two hours under reflux, the mixture was cooled to room temperature, whereupon the oily product solidified. The solid material was separated off and the solution which remained was extracted with ether. The combined organic phases were washed with water and, after drying over sodium sulphate, were concentrated under reduced pressure. The residue was recrystallized from 200 ml of hexane. 26 g (76.9% of theory) of cyanomethylferrocene of melting point 82° to 83° C. were obtained in this manner.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15].[CH:19]1([CH2:24][C:25](OC)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.C(O)(=O)C.O>[CH:19]1([CH2:24][C:25](=[O:26])[CH2:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CC1CCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)CC1CCCC1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To an ice-cooled and stirred solution of cyclopentylacetic acid (7.9 g, 0.062 mol) in 30 ml of ether was added an excess solution of diazomethane in ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent liquid of methyl cyclopentylacetate (yielded amount 5.5g, 0.039 mol, yield 62.5%, b.p. 64°-65° C./15 mmHg). Then, a solution of n-butyl lithium in hexane (1.58N, 55.7 ml, 0.088 mol) was added dropwise to a stirred solution of dimethyl methylphosphonate (10.9 g, 0.088 mol) in 100 ml of anhydrous THF under argon atmosphere at -78° C. After 30 minutes, the above-mentioned methyl cyclopentylacetate (5.0 g, 0.035 mol) in 10 ml of anhydrous THF was further added dropwise, and the mixture was stirred in situ for 30 minutes. This reaction mixture was allowed to warm to 0° C., diluted with 5.3 ml of acetic acid and 20 ml of water, and concentrated. 30 ml of water was added to the residue. The mixture was extracted with ethyl acetate (50 ml×2), and the combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 3-cyclopentyl-2-oxo-propylphosphonate (7.8 g, 0.033 mol, yield 94.7%, b.p. 110°-112° C./0.13 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30]([NH:9][CH2:8][C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)cn1
Yield: 42 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (5-methylpyrazin-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 42% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.83 (t, J=5.7 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 8.44 (s, 2H), 7.48-7.31 (m, 5H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.48 (d, J=5.7 Hz, 2H), 2.54 (m, 3H), 2.43 (s, 3H); MS (ES+) m/z 448.2 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH3:29])[C:17]([NH:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](OC)=[O:26])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C[Al](C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[O:18]=[C:17]([NH:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](=[O:26])[NH:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C@@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:29]
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: NC1CCOCC1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)NC1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Tetrahydro-2H-pyran-4-amine (900 microl, 8.69 mmols) was added to a solution of (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (900 mg, 2.89 mmols, preparation 109) in toluene (36 ml). A 2M solution of Trimethyl aluminium in toluene (7 ml, 14.00 mmols) was added and it was stirred at 80° C. overnight. Water (50 ml) and a 0.5M solution of sodium tartrate (25 ml) were added. It was extracted with ethylacetate. The combined organic layers were washed with water and brine. It was dried, filtered and concentrated in vacuum. The title compound was obtained (617 mg, 56%).
Reaction SMILES: C([O:5][C:6](=[O:33])/[CH:7]=[CH:8]/[C:9]1[C:10]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[C:11]([C:19]([O:21][CH3:22])=[O:20])[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=2[CH:18]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][O:21][C:19]([C:11]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=2[CH:18]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:33])=[O:5])[C:10]=1[NH:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:25])=[O:26])=[O:20]
Reactant: COC(=O)c1c2c(cc(/C=C/C(=O)OC(C)(C)C)c1NS(=O)(=O)c1ccccc1)CCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c2c(cc(/C=C/C(=O)O)c1NS(=O)(=O)c1ccccc1)CCCC2
Reaction time: 2 h
Yield: 105.9 %

Procedure:
A mixture of Example 476C (0.12 g, 0.25 mmol) in CH2Cl2 (3 mL) was treated with TFA (6 mL), stirred for 2 hours, and diluted with CH2Cl2. The organic layer was washed with 1M NaOH and brine (200 mL), dried (MgSO4), filtered, and concentrated to provide the desired product (0.11 g). MS (DCI) m/e 416 (M+H)+.
Reaction SMILES: Br[C:2]1[C:8]([I:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:10].C1(O)C=CC=CC=1.I.[H][H]>>[Cl:10][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([I:9])[CH:2]=1)[NH2:6]
Reactant: [H][H]
Reactant: Nc1cc(Cl)c(Br)c(I)c1
Agent: I
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(I)c1
Yield: 90 %

Procedure:
55.5 parts of 4-bromo-3-chloro-5-iodoaniline, 250 parts of phenol, 8 parts of hydroiodic acid (57% strength) and 15 parts of ruthenium-on-charcoal catalyst (5% strength) are reacted with hydrogen under a pressure of 23 to 47 bars and at 145° C., during the course of 2 hours, whilst stirring. After the usual working up, 38 parts of 3-chloro-5-iodo-aniline are obtained. Yield: 90% of theory.
Reaction SMILES: Cl.CC([N:6]([CH2:10][CH:11]([NH:19][C:20]([C:22]1[N:23]([CH3:33])[CH:24]=[C:25]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)[CH:26]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C(=O)[O-])(C)C>O1CCOCC1.C(Cl)(Cl)Cl.CO>[NH2:6][CH2:10][CH:11]([NH:19][C:20]([C:22]1[N:23]([CH3:33])[CH:24]=[C:25]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)[CH:26]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1cc(-c2ccnn2C)cc1C(=O)NC(Cc1ccccc1)CN(C(=O)[O-])C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2ccnn2C)cc1C(=O)NC(CN)Cc1ccccc1
Yield: 32.3 %

Procedure:
HCl in Dioxane (4M, 2 mL) was added to a solution of 1,1-dimethylethyl[2-({[1-methyl-4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate (285 mg, 0.65 mmol) in CHCl3/MeOH (10:1, 10 mL) affording the title compound as a white solid (71 mg, 0.21 mmol, 32%): LC-MS (ES) m/z 338 (M+H)+, 1H NMR (400 MHz, MeOD) δ ppm 2.77-2.93 (m, 4H) 3.86 (s, 3H) 3.92 (s, 3H) 4.29 (ddd, J=8.15, 4.74, 2.02 Hz, 1H) 6.30 (d, J=2.02 Hz, 1H) 6.94 (d, J=1.77 Hz, 1H) 7.14 (d, J=1.77 Hz, 1H) 7.19 (td, J=5.56, 3.03 Hz, 1H) 7.25-7.30 (m, 4H) 7.41 (d, J=1.77 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:3]1.[CH:18](Br)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:18]([N:16]1[NH:15][N:14]=[C:13]([C:4]2[C:5](=[O:12])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:2]([CH3:1])[CH:3]=2)[NH:17]1)([CH3:20])[CH3:19]
Reactant: CC(C)Br
Reactant: Cn1cc(-c2nnn[nH]2)c(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)N1NN=C(c2cn(C)c3ccccc3c2=O)N1
Reaction time: 7 h

Procedure:
A mixture of 1-methyl-3-(1H-tetrazol-5-yl)-4-quinolone (0.74 g), isopropyl bromide (0.31 ml), anhydrous potassium carbonate (0.45 g) and butanone (30 ml) was boiled under reflux for 16 hours. More isopropyl bromide (0.5 ml) was added and boiling under reflux was continued for 7 hours. More isopropyl bromide (0.5 ml) was added and boiling under reflux was continued for a further 24 hours. The mixture was evaporated to dryness and the residue treated with water (30 ml). The solid product was collected by filtration and partially purified by high pressure liquid chromatography over silica gel using dichloromethane:methanol 95:5 as the eluent. The solid product was recrystallised from ethyl acetate:diethyl ether 3:2 to give the novel compound 3-(2-isopropyl-1H-tetrazol-5-yl)-1-methyl-4-quinolone, m.p. 134°-137°.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:27]([NH:34][CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC#N>[CH2:27]([N:34]([C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)[NH:10][C:4]=12)[CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCCNCc1ccccc1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Solvent: CC#N
Product: OCCN(Cc1ccccc1)c1c(Cl)cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c12

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.10 g, 0.25 mmol) and N-benzylethanolamine (0.3 g) were heated to 180° C. for 15 h. The reaction mixture was diluted with CH3CN and purified by HPLC-C18 to deliver the title product as the bis(trifluoroacetate) (44%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>ClCCl>[CH3:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11][C:6]=2[N:7]=1
Reactant: COc1ccc2nc(C)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a cooled (−78° C.) solution of 6-methoxy-2-methylbenzo[d]thiazole (0.861 g, 4.80 mmol) in dichloromethane (10 mL) was added BBr3 (5 mL of 1.0 M solution in dichloromethane). After slowly warming to room temperature and stirring for 16 hours, the mixture was cooled to 0° C. and slowly quenched with methanol (20 mL). The reaction mixture was warmed to room temperature and concentrated under reduced pressure. The residue was partitioned between saturated NaHCO3 and dichloromethane/isopropyl alcohol (85/15). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the crude product (0.351 g, 44%) that was used without further purification.
Reaction SMILES: OC(CCCC)[C:3]([O:5][CH2:6][C:7](=[O:15])[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11]C=1)=[O:4]>O1CCCC1>[CH2:14]([CH:9]1[O:8][C:7](=[O:15])[CH2:6][O:5][C:3]1=[O:4])[CH2:13][CH2:12][CH3:11]
Reactant: CCCCC(O)C(=O)OCC(=O)Oc1ccccc1
Solvent: C1CCOC1
Product: CCCCC1OC(=O)COC1=O
Temperature: 300 °C
Reaction time: 0 h

Procedure:
Experiment 4. 2-Oxo-2-phenoxyethyl 2-hydroxycaproate (240 mL of a 10% w/v solution in tetrahydrofuran at 10 mL/hr) and nitrogen (300 mL/min) were passed through a 23-mm I.D. quartz tube containing 5 mL of coarsely crushed quartz on top of 15 mL of Catalyst A heated to 300° C. Contact time and WWH were 1.83 s and 0 28 hr-1 respectively. Conversion and selectivity, determined by integration of NMR spectra, were 100% and 80%, respectively. The column effluent was rotovaped, phenol was removed by distillation under reduced pressure, and a fraction which was predominantly product was obtained by distillation (13.2 g, 98°-110° C./0.1 mm Hg). Crystallization from 30 mL of dry isopropanol gave 8.28 g (48.1 mmol) 3-butyl-1, 4-dioxane-2,5-dione. mp 37°-39° C. 1H NMR (300 MHz, CDCl3): δ0.94 (t, 3H, J=7.2 Hz), δ1.4-1.6 (m, 4H), δ1.9-2.15 (m, 2H), δ4.89 (d, 1H, J=16.5 Hz), ca δ4.92 (m, 1H), and δ4.91 (d, 1H, J=16.5 Hz). 13C NMR: (75 MHz, CDCl3): 13.6, 22.0, 26.4, 30.5, 65.3, 75.6, 164.4, and 165.7. HRMS: calcd for C8H12O 4 =172. 0735, found 172. 0757.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[CH2:32][CH2:31][C:11]3([N:15]([CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:14](=[O:23])[N:13]=[C:12]3[NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[Li+].[OH-].Cl>CO.C1COCC1>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][C:11]3([N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:14](=[O:23])[N:13]=[C:12]3[NH:24][CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:31][CH2:32]2)=[CH:33][CH:34]=1
Reactant: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1ccc(CN)cc1)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3CCCC(=O)O)cc1
Reaction time: 3 h

Procedure:
Methyl 4-[8-[4-(aminomethyl)benzyl]-4-(cyclohexylamino)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-1-yl]butanoate (265 mg, 0.56 mmol) was dissolved in a 1:1 solution of methanol and THF, and 1N LiOH (1.7 mL, 1.7 mmol) was added to the resulting solution at room temperature. After 3 h, the reaction reached complete conversion, and the resulting solution was neutralized with 1N HCl (1.7 mL, 1.7 mmol) and concentrated in vacuo to give a white solid. LRMS (M+1)=455.3.
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH:22]([CH3:24])[CH3:23])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])[OH:4].C(Cl)(Cl)Cl.[CH:36](=O)[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]>C1C=CC=CC=1>[CH:36](=[N:1][C@H:2]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH:22]([CH3:23])[CH3:24])[OH:4])[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]
Reactant: CC(C)Oc1ccccc1C(O)(c1ccccc1OC(C)C)[C@H](N)Cc1ccccc1
Reactant: O=Cc1ccccc1O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)Oc1ccccc1C(O)(c1ccccc1OC(C)C)[C@@H](Cc1ccccc1)N=Cc1ccccc1O

Procedure:
A mixture of 2.5 g. (5.9 millimols) of (R)-2-amino-1,1-di(2-isopropoxyphenyl)-3-phenyl-1-propanol {[α]D +65.0° (c 1.0, chloroform)} and 0.66 g. (5.4 millimols) of salicylaldehyde in 50 ml benzene was heated under reflux for 2.5 hours. After the distillation of the solvent from the reaction mixture, the residue was recrystallized from ethanol to give (R)-N-salicylidene-2-amino-1,1-di(2-isopropoxyphenyl)-3-phenyl-1-propanol as yellow crystals. Yield, 2.43 g. (85%); melting point, 152° - 153° C.; [α]D, +65.25° (c 1.00, chloroform).