Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)([CH3:4])([CH3:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:43]>CO>[ClH:43].[C:1]([C:5]1[CH:6]=[C:7]([C:14]2[N:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][N:15]=2)[C:8]([OH:13])=[C:9]([CH2:10][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:12]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2nccc(C(F)(F)F)n2)c1
Reactant: CC(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2nccc(C(F)(F)F)n2)c1O
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 5-(tert-butyl)-2-hydroxy-3-(4-(trifluoromethyl)pyrimidin-2-yl)benzaldehyde (324 mg, 1.00 mmol) and tert-butylamine (0.21 mL, 2.00 mmol) in methanol (10 mL) was added sodium triacetoxyborohydride (254 mg, 1.20 mmol). The solution was stirred at 25° C. for one hour at which time a second portion of sodium triacetoxyborohydride (254 mg, 1.20 mmol) was added. After one hour a third portion of sodium triacetoxyborohydride (254 mg, 1.20 mmol) was added and the mixture was stirred for one hour. The solution was brought to pH 1 by the addition of 1N solution of hydrochloric acid and then partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was separated, concentrated under reduced pressure and purified using flash chromatography on silica eluting with a solvent gradient of 100:0 to 0:100 v/v 100% dichloromethane to a solution of 10% methanol, 1% ammonium hydroxide, 89% dichloromethane. The product was further purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% acetone in hexanes. The residue was dissolved in an excess of a 1N solution of hydrochloric acid in ethanol, the solvent was removed under reduced pressure and the solid was triturated with ether to give 4-(tert-butyl)-2-((tert-butylamino)methyl)-6-(4-(trifluoromethyl)pyrimidin-2-yl)phenol hydrochloride (156 mg, 38% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[O:17])[CH:25]=1)[CH3:19]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (131)(50 mg, 0.19 mmol) was coupled to aniline (60)(40 mg, 0.21 mmol) using Method D. The residue was triturated with TBME (3 ml) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:16])=[O:15])=[CH:11][CH:12]=2)[C:7]2([O:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:6]1=O.N>CCO>[O:23]([CH2:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][N:17]1[S:14]([C:10]1[CH:11]=[CH:12][C:13]2[N:5]3[CH2:4][CH2:3][CH2:2][N:1]=[C:6]3[C:7]3([O:34][CH2:33][CH2:32][CH2:31][O:30]3)[C:8]=2[CH:9]=1)(=[O:16])=[O:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCCN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Agent: N
Solvent: CCO
Product: O=S(=O)(c1ccc2c(c1)C1(OCCCO1)C1=NCCCN12)N1CCC[C@H]1COc1ccccc1
Temperature: 135 °C
Yield: 77.4 %

Procedure:
1′-(3 -Aminopropyl)-5′-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (0.98 g, 1.95 mmol) was taken up in 2M EtOH.NH3 (100 mL) poured into a steel pressure bottle and heated at 135° C. for 20.5 hr. The mixture was cooled to room temperature and concentrated. The residue was washed with H2O (3×), brine (2×), dried over MgSO4, and filtered. The filtrate was flash chromatographed (Biotage KP silica gel, CH2Cl2/CH3OH/NH4OH (98.5/1.0/0.5)) to give the title compound as a white solid (0.73 g, 77% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (APCI+) m/z 483 [M+H]. Opt. Rotation: −169.0 (calculated) at 25° C. in CHCl3 (1% concentration) at 589 nM.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:31][CH:32]([OH:35])[CH2:33][OH:34])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:38]>CS(C)=O>[C:1]([C:5]1[N:6]([CH2:31][C:32](=[O:35])[C:33]([OH:38])=[O:34])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:18][CH2:19]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(O)CO
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(2-tert-butyl-1-(2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamide (97 mg, 0.20 mmol) in DMSO (1 mL) was added Dess-Martin periodinane (130 mg, 0.30 mmol). The mixture was stirred at room temperature for 3 h. The solid was filtered off and washed with EtOAc. The filtrate was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by preparative TLC to yield 3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-yl)-2-oxopropanoic acid that was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH2:19]([S:23](Cl)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:23]([CH2:19][CH2:20][CH2:21][CH3:22])(=[O:25])=[O:24])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: CCCCS(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Yield: 55 %

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with n-butylsulfonyl chloride to obtain the desired product. Yield: 55%. 1H-NMR (500 MHz, CDCl3): δ=7.50-7.43 (m, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H), 7.15-7.09 (q, 1H, J=1.6 Hz), 6.62 (s, 1H, br), 6.22-6.18 (q, 1H, J=1.5 Hz)5 5.65(s, 1H, br), 3.06-3.031 (t, 2H, J=1.4 Hz), 1.75-1.71 (m, 2H), 1.38-1.36 (m, 2H), 0.87-0.86 (t, 3H, J=1.3 Hz); m/z=483 [M−1]−.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C(#N)C>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH:21][CH:18]2[CH2:20][CH2:19]2)=[C:3]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:4]2=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: NC1CC1
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (950 mg, 0.0037 mole) in acetonitrile, cyclopropyl amine (0.525 ml, 0.0074 mole) was added. After stirring for about 2 hours at 110° C., acetonitrile was removed under reduced pressure. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give light yellow solid compound. Yield: 1 g. m/z: (M++1) 275.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18].[CH2:35]([O:37][C:38]1[C:39](=O)[C:40](=[O:45])[C:41]=1[O:42]CC)[CH3:36]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:39]3[C:40](=[O:45])[C:41](=[O:42])[C:38]=3[O:37][CH2:35][CH3:36])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: COc1cc(OC2CCNCC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Solvent: CCO
Product: CCOc1c(N2CCC(Oc3ccc(CC(=O)N4CCN(c5ccccc5C)CC4C(N)=O)c(OC)c3)CC2)c(=O)c1=O

Procedure:
1-(2-Methoxy-4-(4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl) piperazine-2-carboxamide (128 mg, 0.274 mmole) was dissolved in 4 ml of absolute ethanol. 3,4-Diethoxy-3-cyclobutene-1,2-dione (62 mg, 0.364 mmole), prepared according to the procedure in Angew. Chem. Int. Ed. 1966, 5(10), 890, was then added to the solution and the resulting reaction mixture was heated to reflux for 72 hr. The reaction mixture was cooled and filtered. The filter cake was washed with cold ethanol and dried to give the title compound as a white solid: m.p. 155°-157° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45](F)[CH:44]=2)[CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:22]=2[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:54][C:55](=[O:72])C1C=C(O)C=C(C2C=CC3OCOC=3C=2)C=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:7])[C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:22]=2[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:11]=[C:10]([C:43]2[CH:48]=[CH:47][C:46]3[O:54][CH2:55][O:72][C:45]=3[CH:44]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Reactant: CC(C)(C)OC(=O)c1cc(O)cc(-c2ccc3c(c2)OCO3)c1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC

Procedure:
The title compound was prepared in the same way as 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid tert-butyl ester starting from 3-benzo[1,3]dioxol-5-yl-5-hydroxy-benzoic acid tert-butyl ester.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]2[O:5][CH2:4]1.[C:12]([O-:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].CS(C)=O>O>[C:12]([O:20][CH2:2][CH:3]1[CH2:4][O:5][C:6]2=[CH:11][S:10][CH:9]=[C:7]2[O:8]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCC1COc2cscc2O1
Reactant: O=C([O-])c1ccccc1
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCC1COc2cscc2O1)c1ccccc1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
In a 100 mL round bottom flask 9.00 g (0.0382 mol) 2-(bromomethyl)-2,3-dihydrothieno[3,4-b][1,4]dioxine, 6.39 g (0.0459 mol) ammonium benzoate, and 55 g DMSO were combined. A reflux condenser was equipped and the reaction was heated to 100 C overnight. After cooling to room temperature, the reaction mixture was poured into water and the product was extracted with methylene chloride. The organic fractions were combined and the solvent removed under reduced pressure. Purification by column chromatography provided 7.5 g (71% yield) of a white solid whose structure was confirmed by 1H/13C NMR and LC-MS.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:15]OS(OC)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([C:5]1[C:6]([O:12][CH3:15])=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cccc1C(C)(C)C
Temperature: 95 °C
Reaction time: 15 h

Procedure:
A mixture of 0.12 mole of 2-t-butyl-6-methylphenol and 12.0 ml. of 10.0 N sodium hydroxide solution is stirred and heated on the steam bath for 1 hour. The water is evaporated in vacuo. The residue is added portion-wise with stirring to 0.24 mole of dimethylsulfate and the mixture is stirred at 95° C. for 6 hours and at room temperature for 15 hours. Sodium carbonate (0.25 mole) in 100 ml. of water is added and stirring is continued for 5 hours. The mixture is extracted with 3 × 100 ml. of ether and the extract is dried and concentrated to dryness to give 3-t-butyl-2-methoxytoluene.
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:51])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]4[CH:37]=[C:38]([NH:42][C:43]([C:45]5[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=5)=[O:44])[CH:39]=[CH:40][CH:41]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>C(O)(=O)C.O>[OH:51][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]2[CH:37]=[C:38]([NH:42][C:43]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)=[O:44])[CH:39]=[CH:40][CH:41]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)Nc4cccc(NC(=O)c5cccnc5)c4)c3)ccc2O1
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1cccc(COCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1)Nc1cccc(NC(=O)c2cccnc2)c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A solution of N-(3-{[({3-[(2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy)methyl]phenyl}amino)carbonyl]amino}-phenyl)pyridine-3-carboxamide (0.109 g) in acetic acid (4 ml) and water (2 ml) was heated to 68° for 30 min. The mixture was cooled to room temperature before concentrating in vacuo to leave a residue that was purified by Biotage. Elution with dichloromethane-EtOH-ammonia (25:8:1) followed by solvent evaporation in vacuo gave the title compound (0.089 g). LCMS RT=2.02 min, ES+ve 672 (MH)+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.N1C=CC=CC=1.[CH:19]([O:22][C:23](Cl)=[O:24])([CH3:21])[CH3:20]>ClCCl>[CH:19]([O:22][C:23]([N:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2)=[O:24])([CH3:21])[CH3:20]
Reactant: O=C1CCCNc2ccccc21
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)N1CCCC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled (0° C.) solution of 1,2,3,4-Tetrahydro-benzo[b]azepin-5-one (1.5 g, 9.3 mmol) and pyridine (2.26 ml, 27.9 mmol) in dichloromethane (30 ml) was added 1M isopropylchloroformate (solution in toluene) dropwise over 10 minutes. After addition was completed, the mixture was removed from the cold bath and stirred for 18 hours at room temperature. The mixture was cooled to 0° C., then treated with aqueous 1N NaOH and stirred for 30 minutes. After layer separation, the aqueous layer was extracted with dichloromethane. The combined organic phases were washed with 1N HCl, saturated aqueous NaHCO3, brine, then dried (Na2SO4) and concentrated to an oil. Purification by silica gel chromatography (eluent, 3:1 n-hexanes:ethyl acetate) provided 5-Oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (1.91 g).
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].BrN1C(=[O:24])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClC1C=CC=CC=1>[C:1]([N:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]([OH:24])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CN1c2ccccc2CCc2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Solvent: O
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 50 °C
Yield: 51.9 %

Procedure:
6.60 g (0.030 mols) of (I) are dissolved in 45 ml of chlorobenzene, the mixture is heated to 50° C. under stirring. The resulting solution is added under stirring with 5.6 g (0.0315 mols) of N-bromosuccinimide then with 0.49 g (0.003 mols) of azobisisobutyronitrile, stirring for 1 hour while heating at 75-80° C. The mixture is then is cooled to 40° C., added with 30 ml of water and stirred at 40° C. for 30 minutes, then heated to 80° C. for 3 hours. After decanting for 30 minutes, the aqueous phase is separated and re-extracted with 8 ml of chlorobenzene. The combined organic phases are washed with water (10 ml) and dried, then concentrated at 60° C. to 20 ml, adding 15 ml of hexane at this temperature. The mixture is cooled to 0-5° C. for 30 minutes and the separated solid is filtered, to obtain 3.68 g (52%) of 5-cyano-10-hydroxy-10,11-dihydro-5H-dibenz[b,f]azepine (VI), m.p. 117-8° C., purity>98% (HPLC).
Reaction SMILES: [CH3:1][C:2](C)=CCBr.[CH2:7]1[O:15][C:14]2[CH:13]=[CH:12][C:11](O)=[CH:10][C:9]=2O1.CCCCC>[Cl-].[Cl-].[Zn+2].C1C=CC=CC=1>[O:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:1][CH2:7]1
Reactant: CC(C)=CCBr
Reactant: Oc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCC
Solvent: c1ccccc1
Product: c1ccc2c(c1)CCCO2
Yield: 190.4 %

Procedure:
5.1 gm of 3-methyl-1-bromo-2-butene was combined with 4 gm of 3,4-methylenedioxyphenol and dissolved in 50 ml. of pentane and 50 ml. benzene. 2 gm of anhydrous ZnCl2 was added and the reaction mixture refluxed for 1 hour and cooled. The mixture was extracted with ether and washed successively with 100 ml. of water, 100 ml. 5% sodium carbonate and 100 ml. of saturated salt solution. After drying the extract over anhydrous sodium sulfate, the solvent was removed in vacuo leaving 7.4 g of crude chromane. The crude material was fractionated on a column of Florisil and eluted with increasing concentrations of ether in petroleum ether to yield 4.5 g of pure chromane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=3)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:39][C:40]1[C:41]([OH:51])=[C:42]([S:47](Cl)(=[O:49])=[O:48])[CH:43]=[C:44]([Cl:46])[CH:45]=1>ClCCl>[Cl:39][C:40]1[C:41]([OH:51])=[C:42]([S:47]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=2)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)(=[O:49])=[O:48])[CH:43]=[C:44]([Cl:46])[CH:45]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(-c3ccc(F)cc3)cc2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
tert-Butyl 3-(((4′-fluorobiphenyl-4-yl)methylamino)methyl)benzylcarbamate (1.8 g, 4.28 mmol, 1.0 eq) was dissolved in dichloromethane and cooled 0° C. Triethylamine (1.85 mL, 12.8 mmol, 3.0 eq) was added slowly over 5-10 minutes and the mixture was stirred for 10 minutes at 0° C. 3,5-Dichloro-2-hydroxybenzene-1-sulfonyl chloride (1.2 g, 4.7 mmol, 1.1 eq) was dissolved in DCM and added slowly to the above mixture at 0° C. After 2 h, the reaction mixture was concentrated under vacuum at low temperature and the white precipitate that formed was removed. The solution was purified by silica gel (60-120) column chromatography using 15-20% ethyl acetate/hexane as the eluent to afford the desired product (2.3 g, 85%). 1H NMR (400 MHz, CD3OD) δ 1.45 (d, 9H), 4.11-4.15 (d, 2H) 4.49-4.52 (d, 4H), 7.07-7.19 (m, 8H), 7.42-7.44 (d, 2H), 7.56-7.59 (m, 3H), 7.65-7.66 (d, 1H). MS (ESI): 644.0 (M−H)−.
Reaction SMILES: [N+]([C:4]([CH3:15])=[CH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[CH:13][N:14]=2)[CH:11]=1)([O-])=O.Cl.[OH2:17]>CCO>[N:14]1[CH:13]=[CH:12][N:10]2[CH:11]=[C:6]([CH2:5][C:4](=[O:17])[CH3:15])[CH:7]=[CH:8][C:9]=12
Reactant: O
Reactant: CC(=Cc1ccc2nccn2c1)[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: CC(=O)Cc1ccc2nccn2c1

Procedure:
In 25 ml of water and 25 ml of EtOH, 1.14 g of 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine was heated to 80° C. together with 100 mg of ferrous chloride. With stirring, 2.5 ml of conc. hydrochloric acid was added at a refluxing rate and the mixture was stirred for 1 hour. Upon heating, insoluble matter was removed by filtration. After the insoluble matter was thoroughly washed with ethanol, the solvent was removed by distillation under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue and the mixture was extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure. The residue was purified by column chromatography to obtain 500 mg of 1-(imidazo[1,2-a]pyridin-6-yl)-2-propanone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:11]=[C:10]([C:12](O)=[O:13])[O:9][N:8]=1)[CH3:2].C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>ClCCl>[Cl:19][C:12]([C:10]1[O:9][N:8]=[C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:11]=1)=[O:13]
Reactant: CCOC(=O)COc1cc(C(=O)O)on1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)COc1cc(C(=O)Cl)on1

Procedure:
Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was prepared following the procedure for N-(4-chlorophenyl)-N-{(2S,4R)-1-[(1-isopropyl-1H-pyrazol-4-yl)carbonyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}acetamide substituting ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate for 1-isopropyl-1H-pyrazole-4-carbonyl chloride. (Ethyl {[15-chlorocarbonyl)isoxazol-3-yl]oxy}acetate was prepared in 4 steps from methyl 3-hydroxy 5-isoxazole carboxylate. Methyl 3-hydroxy 5-isoxazole carboxylate (1.00 g, 6.95 mmol) was alkylated using ethyl bromoacetate (0.850 mL, 7.64 mmol) in presence of potassium carbonate (1.05 g, 7.64 mmol) and catalytic potassium iodide in DMF (3.00 mL) at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate (60%). (Ref: WO 03/063800 PCT/US03/03224). Methyl 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylate was further treated with aqueous 5% sodium hydroxide in methanol to yield 3-(carboxymethoxy)isoxazole-5-carboxylic acid (86%). This diacid (0.700 g, 3.76 mmol) was selectively esterified in the presence of catalytic p-toluenesulfonic acid monohydrate (100 mg) in ethanol at room temperature. Water was added to the reaction and the mixture was extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired 3-(2-ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid (90%). 3-(2-Ethoxy-2-oxoethoxy)isoxazole-5-carboxylic acid was treated with oxalyl chloride and catalytic DMF in dichloromethane to yield the desired ethyl {[5-(chlorocarbonyl)isoxazol-3-yl]oxy}acetate). Ethyl [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetate was treated with a solution of lithium hydroxide monohydrate (aq) in methanol at room temperature overnight to afford [(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid in 60% yield.