Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH2:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[Cl:28][C:29]1[CH:30]=[C:31]([CH:44]=[CH:45][CH:46]=1)[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=1[O:42][CH3:43].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:44]=[CH:45][CH:46]=1)[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:3]([CH2:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[N:5]3[C:10]=2[C:9]([NH2:11])=[N:8][CH:7]=[N:6]3)=[CH:35][C:34]=1[O:42][CH3:43]
Reactant: COc1cc(B(O)O)ccc1Oc1cccc(Cl)c1
Reactant: COc1cccc(-c2c(CCCN3CCCC3)c(Br)c3c(N)ncnn23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(CCCN3CCCC3)c(-c3ccc(Oc4cccc(Cl)c4)c(OC)c3)c3c(N)ncnn23)c1
Temperature: 90 °C
Yield: 41.1 %

Procedure:
To a solution of the compound (43 mg, 0.01 mmol) prepared in Example 15, the compound (29.4 mg, 0.15 mmol) prepared in Example 10, potassium phosphate (2N, 0.1 mL, 0.2 mmol), Pd(PPh3)4 (3 mg, 0.003 mmol) in DMF (3 mL) was deoxygenated by nitrogen gas for 5 minutes, and the reactor was sealed, heated at 90° C. for 6 hours. The mixture was concentrated, purified by prep TLC using 5% methanol in DCM (with 3% ammonium hydroxide solution) to give crude product which was further purified by prep HPLC to obtain the title compound (2.4 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:27])([CH2:23][CH2:24][CH2:25][CH3:26])[C:3](=[O:22])[CH:4]=[CH:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2>[Pd].C(OCC)(=O)C>[F:27][C:2]([F:1])([CH2:23][CH2:24][CH2:25][CH3:26])[C:3](=[O:22])[CH2:4][CH2:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2
Reactant: CCCCC(F)(F)C(=O)C=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC(F)(F)C(=O)CC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1

Procedure:
The compound (50) (12.7 g) was catalytically hydrogenated over 5% palladium on carbon (catalytic amount) in ethyl acetate (300 ml) under hydrogen atmosphere to give the titled compound (51). Yield: 12.5 g (99%).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(Cl)Cl.N1C=CC=CC=1.[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O>[N:20]1([C:26]([O:10][C:3]2[C:4]([CH:5]=[O:6])=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=Cc1cccc(F)c1O
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1cccc(F)c1OC(=O)N1CCOCC1
Yield: 94.1 %

Procedure:
To a 250 mL dry round bottom flask were added 3-fluoro-2-hydroxybenzaldehyde (4.90 g, 35.0 mmol), anhydrous CH2Cl2 (50 mL) and pyridine (3.40 mL, 42.0 mmol). The mixture was stirred in an ice-water bath, then 4-morpholinecarbonyl chloride (4.50 mL, 38.5 mmol) was added. The mixture was stirred at room temperature for 24 hours. Water (80 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (100 mL×2). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 2-fluoro-6-formylphenyl morpholine-4-carboxylate (8.34 g) as white solid. Yield: 94%. 1H NMR (CDCl3, 300 MHz): δ=10.06 (s, 1H), 7.58 (dt, J=7.8, 1.5 Hz, 1H), 7.39-7.22 (m, 2H), 3.69 (br, 6H), 3.50 (br, 2H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): δ=187.6, 187.5, 170.5, 156.4, 152.4 (d, J=100.7 Hz), 139.9 (d, J=12.8 Hz), 130.5, 126.5 (d, J=7.3 Hz), 125.2 (d, J=3.1 Hz), 121.7 (d, J=17.4 Hz), 66.1, 45.0, 44.3.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][C:18]2[C@:13]([CH2:21][OH:22])([CH2:14][CH2:15][C@H:16]([OH:20])[CH:17]=2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C@@H:7]([OH:23])[CH2:6][CH2:5]1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:23][C@H:7]1[CH2:6][CH2:5][C@H:4]2[C@H:3]3[C@H:12]([CH2:11][CH2:10][C@:8]12[CH3:9])[C@:13]1([CH2:21][OH:22])[C:18](=[CH:17][C:16](=[O:20])[CH2:15][CH2:14]1)[CH2:19][C@H:2]3[CH3:1]
Reactant: C[C@@H]1CC2=C[C@@H](O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CC2=CC(=O)CC[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 15 °C
Reaction time: 1 h

Procedure:
7α-Methyl-4-androstene-3β,17β,19-triol is dissolved in hot chloroform and cooled to 15° C. Activated manganese dioxide is added at a rate such that the temperature does not rise above 25° C. Stirring is continued at room temperature for about 1 hour, the manganese dioxide is removed by filtration through a bed of diatomaceous earth and the chloroform distilled under vacuum. The residue which remains is crystallized from acetonitrile to yield 17β,19-dihydroxy-7α-methyl-4-androsten-3-one.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Br)cccc21
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Product: CCOC(=O)CC1CC2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MS Method 1 tR=2.27, min, m/z=554, 552
Reaction SMILES: [CH:1]([N:3]1[CH2:12][CH2:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2/[C:4]/1=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:2]>P.[Ru]>[CH:1]([N:3]1[CH2:12][CH2:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]1=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:2]
Reactant: COc1ccc(/C=C2/C3=C(CCCC3)CCN2C=O)cc1
Agent: [Ru]
Agent: P
Product: COc1ccc(C=C2C3=C(CCCC3)CCN2C=O)cc1

Procedure:
Using each of the ruthenium-phosphine complexes obtained in Examples 2 to 16, the asymmetric hydrogenation reaction of (Z)-N-formyl-1-(4-methoxyphenylmethylene)- 3,4,5,6,7,8-hexahydroisoquinoline was carried out in the same reaction procedures as in Use Example 1 to produce (+)-N-formyl-1-(4-methoxyphenylmethylene)-1,2,3,4,5,6,7,8-octahydroisoquinoline. The results are shown in table 2.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O:25][CH:26]=C(O[Si](C)(C)C)O[Si](C)(C)C.Cl.[Cl-].[Na+]>O1CCOCC1>[CH2:7]([C@H:8]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:9](=[O:10])[CH2:26][OH:25])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)OC=C(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: O=C(Cl)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(CO)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 95 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
A mixture of 134 g of 3-phenyl-2(S)-phthalimidopropionyl chloride and 269.7 g of tris(trimethylsilyloxy)ethylene was stirred at 95° C. for 5 hours. A further 54 g of tris(trimethylsilyloxy)ethylene were added and the mixture was stirred at 95° C. for a further 1.5 hours. The cooled reaction mixture was then treated with 435 ml of dioxan and 174 ml of 0.6N hydrochloric acid and the resulting mixture was heated to 85° C. for 30 minutes. The cooled mixture was saturated with sodium chloride and then extracted with diethyl ether. The ethereal solution was washed with aqueous sodium bicarbonate solution and evaporated. The resulting pale yellow solid was crystallized from ethyl acetate/n-hexane to give 103 g of N-[1(S)-benzyl-3-hydroxy-2-oxopropyl]phthalimide as a white solid, MS: m/e 310 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[CH3:39][N:40]1[CH2:43][CH:42]([C:44](O)=[O:45])[CH2:41]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:44]([CH:42]3[CH2:43][N:40]([CH3:39])[CH2:41]3)=[O:45])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: CN1CC(C(=O)O)C1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CN(C)C4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to which Et3N (3 equiv.) and 1-methylazetidine-3-carboxylic acid (2 equiv.) was added. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([OH:20])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]1(O)[CH2:25][CH2:24][CH2:23][CH2:22]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OC1CCCC1
Reactant: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 460 mg of ethyl 4-(t-butoxycarbonylamino)-2-hydroxybenzoate, 300 mg of cyclopentanol, 1.5 g of diethyl azodicarboxylate (40% solution in toluene), 900 mg of triphenylphosphine and 10 ml of tetrahydrofuran was stirred at room temperature for 3 days. The solvent was evaporated and the residue was purified by the silica gel chromatography (ethyl acetate/hexane) to obtain crude ethyl 4-(t-butoxycarbonylamino)-2-cyclopentyloxybenzoate. A mixture of this crude product, 20 ml of ethanol and 5 ml of 1 M aqueous sodium hydroxide solution was stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent in an ordinary manner, the title compound was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([Br:15])[C:9]=1[CH:16]=[N:17][NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([Br:15])[C:9]=1[CH:16]=[N:17][NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([O:24][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:23]
Reactant: BrCc1ccccc1
Reactant: Cc1cc(Br)c(C=NNc2cccc(C(=O)O)c2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)c(C=NNc2cccc(C(=O)OCc3ccccc3)c2)c(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 103.5 %

Procedure:
Potassium carbonate (7.41 g, 53.61 mmol) was added to a solution of 3-{2-[(2,6-dibromo-4-methylphenyl)methylidene]hydrazino}benzoic acid (19.4 g, 44.65 mmol) in dry DMF (200 mL). Benzyl bromide (5.42 mL, 45.6 mmol) was then added and the mixture stirred at room temperature for 15 hours and then partitioned between ethyl acetate (500 mL) and water (500 mL). The organic phase was separated, combined with a second ethyl acetate extract (300 mL), washed successively with water (4×500 mL) and brine (300 mL), dried over anhydrous sodium sulphate, evaporated and further dried under vacuum to give the title compound (23.2 g).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH2:18][O:19]CC2C=CC=CC=2)[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:27]([CH3:29])[CH3:28])[S:14]2)[C@H:10]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CC(OC(C)=O)=O.CC(O)=O.CO.[Cl-].[Cl-].[Zn+2]>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH2:18][OH:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:27]([CH3:29])[CH3:28])[S:14]2)[C@H:10]1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)O[C@@H]2S1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 92 (166 g, 0.3 mol) in Ac2O (1 L) and AcOH (100 mL) was added anhydrous ZnCl2 (353 g, 2.6 mol) at 0° C. After kept additional 2 hours at room temperature, the reaction was poured into ice-cold H2O (1.5 kg) slowly and extracted with dichloromethane (3×500 mL). The organic layers combined, washed with brine (3×200 mL) and dried over anhydrous sodium sulfate. After filtration, volatiles were distilled out by high vacuum to give crude 93 (160 g, (ES, m/z) [M+H]+ 471.0) as a brown oil. A solution of the above crude 93 in methanol (1 L) was treated with K2CO3 (18 g, 0.13 mol) at 30° C. for 8 hours, after filtration, the solvent was distilled out under vacuum to give a residue, which was purified by a silica gel column with 20%-30% ethyl acetate in petroleum ether to afford the title compound (94) (108 g, 79% 2 steps) as a yellow syrup; (ES, m/z) [M+H]+ 429.0; 1H NMR (300 MHz, CDCl3) δ 7.26-7.43 (m, 10H), 6.29 (d, J=6.6 Hz, 1H), 4.54-4.81 (m, 4H), 4.41 (d, J=4.8 Hz, 1H), 4.17-4.18 (m, 1H), 3.57-3.79 (m, 4H), 3.02 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[NH:11]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: Clc1ccnc2[nH]cnc12
Solvent: c1ccccc1
Product: c1ccc(Nc2ccnc3[nH]cnc23)cc1
Temperature: 130 °C
Yield: 35.3 %

Procedure:
To 7-chloro-3H-imidazo(4,5-b)pyridine (16 g, 97 mmol) was added aniline (200 mL, 2.1 mol). The resulting mixture was heated under a nitrogen atmosphere at 130° C. for 24 hours. Benzene was added to the cooled mixture and the precipitate was filtered. The solid was dissolved in water and 1N NaOH was added to give a pH reading of 9. The precipitate was filtered and recrystallized from EtOH (decolorized by charcoal) to give 7.2 g (35%) of the 7-anilino-3H-imidazo[4,5-b]pyridine, m.p. 251°-252° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:12][C:11](=[O:13])[CH2:10][CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: O=C(O)CC1Cc2ccccc2C1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A solution of indan-2-yl-acetic acid (Lancaster, 20 g, 0.11 mol) in methanol (200 mL) was stirred and cooled to 0–10° C. in an ice bath and treated drop-wise with thionyl chloride (14.8 g, 0.125 mol). The mixture was stirred at RT for 16 h, concentrated in vacuo, and the oily residue was dissolved in ethyl acetate, washed with 2.5 N sodium hydroxide, water, and brine, dried (MgSO4), and concentrated in vacuo to give the title compound (21 g, 97%) which solidified.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>ClCCl>[C:1]1([CH:7]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[CH:8]2[CH2:12][CH2:11][N:10]([CH2:30][C:29]([O:28][CH3:27])=[O:32])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: Cc1cccc(C(c2ccccc2)C2CCNC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN1CCC(C(c2ccccc2)c2cccc(C)c2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
A solution of 3-(phenyl(m-tolyl)methyl)pyrrolidine (3.0 g, 12 mmol) and triethylamine (1.8 mL, 12.9 mmol) in dichloromethane (30 mL) was stirred at 0° C. for 10 min, and then methylbromoacetate (1.5 mL, 15.8 mmol) was added dropwise. After stirring the reaction mixture at 0° C. for 3 h, reaction mixture was warmed to room temperature and concentrated under reduced pressure. To the residue was added water and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was dissolved in dichloromethane and precipitated with diethyl ether to afford 1.6 g of methyl 2-(3-(phenyl(m-tolyl)methyl)pyrrolidin-1-yl)acetate.
Reaction SMILES: C([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[Cl:21][C:20]1[C:13]2[CH2:12][CH2:11][C@@:10]3([CH3:22])[C@H:15]([CH2:16][N:8]([C:23]([O:24][CH2:25][CH3:26])=[O:27])[CH2:9]3)[C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cl
Reactant: C[C@]12CCc3c(Cl)cccc3[C@H]1CN(Cc1ccccc1)C2
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C[C@@H]2c3cccc(Cl)c3CC[C@]2(C)C1
Yield: 89.5 %

Procedure:
cis-2-Benzyl-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (18.60 mmol, 5.8 g) was dissolved in toluene and heated to reflux. Ethyl carbonochloridate (55.8 mmol, 5.33 ml, 6.06 g) was added dropwise and the reaction mixture left to stir at reflux for 2 hours. TLC and mass spec showed no starting material. Solvent removed in vacuo and crude material purified by silica column chromatography (eluting with 0-30% ethyl acetate:heptane) to give cis-ethyl 6-chloro-3a-methyl-3,3a,4,5-tetrahydro-1H-benzo[e]isoindole-2(9bH)-carboxylate (4.89 g), m/z=294.3 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:44]1[CH:52]=[CH:51][C:47]([C:48]([NH2:50])=[O:49])=[CH:46][CH:45]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][C:44]3[CH:52]=[CH:51][C:47]([C:48](=[O:49])[NH2:50])=[CH:46][CH:45]=3)=[O:16])[CH:12]=2)[CH:7]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(C)C(=O)Oc3ccc(C(N)=O)cc3)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To the solution of 1 (naproxen, 4 g, 17.4 mmol) in 80 mL of dimethylformamide, hydroxybenzotriazole (2.59 g, 19.14 mmol) and DCC (2.59 g, 19.14 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 3.58 g, 26.1 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, with NaHCO3 5%, with citric acid 10% and than dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9.5/0.5), from which 4-carbamoylphenyl 2-(2-methoxynaphthalen-6-yl)-propanoate (5) was obtained (1.91 g, 32% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:4][C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:38])[O:34][CH:35]([CH3:37])[CH3:36]>ClCCl>[CH3:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:33]([O:34][CH:35]([CH3:37])[CH3:36])=[O:38])[CH2:22][CH2:21]2)=[CH:4][C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1cn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1OC1CCN(C(=O)OC(C)C)CC1

Procedure:
The compound obtained in Example 160, Step A (25 mg, 0.069 mmol) was dissolved in dichloromethane (0.5 mL) to which was then added triethylamine (0.029 mL, 0.207 mmol) and isopropyl carbonochloridate (10.1 mg, 0.083 mmol). After 45 minutes the solvent was removed in vacuo and the residue purified by passing through a UCT (United Chemical Technologies) 2.5 g C-18 cartridge (#CEC181(2500)6) and eluting as follows:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[C:35]([CH3:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[C:39]([N:42](CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)[CH:43]1CCCN(C(OC(C)C)=O)C2C=C(Cl)C(N(C)C)=CC1=2)(=O)C>>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34]([N:42]([CH3:43])[CH3:39])[C:35]([CH3:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(N(C)C)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(Br)cc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(N(C)C)cc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 50 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate the procedure of Example 50 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-chloro-7-dimethylamino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. ESI MS m/z 574 (M+H).