Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:26]=3[OH:27])[O:23][CH2:22][CH2:21][CH2:20]4)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][C:26]=4[O:27][CH2:35]3)[O:23][CH2:22][CH2:21][CH2:20]5)[C:9]2=[O:28])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCCC3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one was obtained (70%) as an off-white solid: mp 208-211° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ7.41-7.29 (m, 10H), 7.16 (dd, J=6.6, 1.8 Hz, 1H), 7.08 (s, 1H), 7.05-6.94 (m, 2H), 6.52 (d, J=7.8 Hz, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.11 (dd, J=5.1, 5.1 Hz, 2H), 2.56 (t, J=6.3 Hz, 2H), 1.94-1.86 (m, 2H); 13C NMR (75 MHz, CDCl3) δ δ178.1, 160.1, 156.3, 141.8, 137.9, 137.5, 132.9, 128.75, 128.73, 128.53, 128.52, 128.2, 128.00, 127.96, 132.9, 132.8, 123.2, 121.3, 115.2, 112.3, 98.9, 80.3, 66.6, 58.8, 57.5, 24.8, 22.3; MS (ES+) m/z 460.1 (M+1).
Reaction SMILES: COC1C=CC(C[N:10](CC2C=CC(OC)=CC=2)[S:11]([CH2:14][CH2:15][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[F:30])[C:17]([O:19][CH3:20])=[O:18])(=[O:13])=[O:12])=CC=1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:10][S:11]([CH2:14][CH2:15][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[F:30])[C:17]([O:19][CH3:20])=[O:18])(=[O:12])=[O:13]
Reactant: COC(=O)C(CCS(=O)(=O)N(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1)c1ccc([N+](=O)[O-])cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CCS(N)(=O)=O)c1ccc([N+](=O)[O-])cc1F
Reaction time: 48 h
Yield: 86.1 %

Procedure:
Methyl .alpha.-[2-[[bis[(4-methoxyphenyl)methyl]amino]sulfonyl]ethyl]-2-fluoro-4-nitrobenzeneacetate (41.6 g, 74.3 mmol) is dissolved in methylene chloride (200 ml) and trifluoroacetic acid (50 ml). The solution is stirred for 2 days then the solvents evaporated. The residue is dissolved in ethyl acetate (750 ml) and washed with sodium bicarbonate solution (200 ml) and brine (100 ml). After drying (MgSO4), filtration and evaporation the title compound is obtained as a solid (20.5 g, 86%) mp 99-101°.
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][CH:7]=[C:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[N:9]=1)([CH3:3])[CH3:2].S(Cl)([Cl:18])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:1]([S:4][C:5]1[S:6][C:7]([Cl:18])=[C:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Sc1nc(OS(C)(=O)=O)cs1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Sc1nc(OS(C)(=O)=O)c(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
3.5 g of 2-isopropylthio-4-methylsulfonyloxy-1,3-thiazole (No. 171) was dissolved in 50 ml of methylene chloride. 2 g of sulfuryl chloride was added dropwise to the solution keeping the temperature below 0° C., followed by stirring at room temperature for 2 hours. Then, 20% aqueous solution of sodium carbonate was added to the reaction mixture to cease the reaction, and the methylene chloride layer was separated and washed with water, followed by drying over anhydrous sodium sulfate. The oil obtained by concentration was purified by silica-gel column chromatography to 2 g of the objective compound as a pale yellow oil (yield: 50.4%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[S:17][CH:18]1[CH2:23][CH2:22][N:21]([O:24][CH3:25])[CH2:20][CH2:19]1.[C:26](=[O:28])=[O:27].[Cl-].[NH4+]>O1CCCC1>[CH3:25][O:24][N:21]1[CH2:22][CH2:23][CH:18]([S:17][C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:26]([OH:28])=[O:27])[CH:8]=3)[N:12]([CH3:16])[CH:11]=2)[CH2:19][CH2:20]1
Reactant: O=C=O
Reactant: CON1CCC(Sc2cn(C)c3ccc(Br)cc23)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CON1CCC(Sc2cn(C)c3ccc(C(=O)O)cc23)CC1
Reaction time: 1 h

Procedure:
A solution of butyllithium (7.1 ml, 2.5M in hexane) is added dropwise to 5-bromo-3-[(1-methoxypiperidin-4-yl)thio]-1-methyl-1H-indole (4.5 g, prepared in Example 59) in tetrahydrofuran (45 ml) at -78° C. After 1 hour at this temperature, a stream of CO2 is passed into the solution. After the temperature has risen to 0° C., a solution of ammonium chloride is added. The reaction mixture is concentrated, taken up with ether and washed with water. The organic phase is dried over sodium sulfate and concentrated. The 3-[(1-methoxypiperidin-4-yl)thio]-1-methyl-1H-indole-5-carboxylic acid obtained (1.4 g) is crystallized from a small volume of isopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][S:18][C:12]3=[N:11][C:10]=2[CH3:19])=[CH:5][CH:4]=1.[CH:20]1([CH2:23][O:24][C:25]2[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)[CH2:22][CH2:21]1.[O-]CC.[Na+]>C(O)C>[CH:20]1([CH2:23][O:24][C:25]2[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:26]=2/[CH:27]=[CH:19]/[C:10]2[N:11]=[C:12]3[S:18][CH:17]=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:21][CH2:22]1
Reactant: COc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2c(/C=C/c3cccc(OC)c3OCC3CC3)nc3sccn3c2=O)cc1
Yield: 43.2 %

Procedure:
The title compound was prepared by condensation of Intermediate 9 (350 mg, 1.283 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde (371 mg, 1.799 mmol) in presence of sodium ethoxide (174 mg, 2.570 mmol) in ethanol (10 ml) according to the procedure of Example 24 afforded 255 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.25-0.27 (m, 2H), 0.49-0.51 (m, 2H), 1.03-1.05 (m, 1H), 3.67-3.70 (m, 2H), 3.77-3.81 (m, 3H), 6.89-6.91 (m, 2H), 6.98-7.02 (m, 4H), 7.23-7.26 (m, 2H), 7.47-7.49 (m, 1H), 7.96-8.10 (m, 1H), 8.10-8.15 (m, 1H); ESI-MS (m/z) 461.39 (M+H)+.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[OH-].[Na+].[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([Br:23])=[C:19]([CH:22]=1)[CH:20]=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C.C(Cl)Cl>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([Br:23])=[C:19]([CH:20]([OH:21])[CH2:4][N+:1]([O-:3])=[O:2])[CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1Br
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=[N+]([O-])CC(O)c1cc(OCc2ccccc2)ccc1Br
Reaction time: 18 h

Procedure:
A solution of nitromethane (2.02 mL, 37.3 mmol) in ethanol (10 mL) was treated with 10N NaOH (3.0 mL) at ambient temperature. A white solid precipitated immediately, and a solution of 5-benzyloxy-2-bromo-benzaldehyde (8.67 g, 29.8 mmol) in CH2Cl2 (50 mL) was added. The reaction mixture was stirred for 18 h and quenched with water (100 mL). The mixture was extracted with CH2Cl2 (2×50 mL), dried (Na2SO4), and concentrated to a residue, which was then purified by silica gel chromatography (hexanes/EtOAc 8/2) to afford 1-(5-benzyloxy-2-bromo-phenyl)-2-nitro-ethanol as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4]C=1C.OS(O)(=O)=O.[OH-].[Na+].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:20]=1[C:19]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAC was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 hour to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The pH of the solution was adjusted to 4 with aqueous NaOH. The mixture was extracted with more ethyl acetate. The combined organic layers were washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 hour. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. Ethyl 2fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.
Reaction SMILES: [H-].[K+].[CH3:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[CH2:10](Br)[C:11]#[CH:12]>C1COCC1.C1(C)C=CC=CC=1>[CH3:3][N:4]1[CH2:8][CH2:7][N:6]([CH2:12][C:11]#[CH:10])[C:5]1=[O:9]
Reactant: CN1CCNC1=O
Reactant: C#CCBr
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCN1CCN(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of potassium hydride (10.44 g of a 35% by wt suspension in mineral oil, washed with ether to remove oil, 0.09 mol) in dry THF (50 mL) was added dropwise, with cooling, to a stirred solution of 1-methyl-2-imidazolidinone (7.6 g, 0.076 mol) in dry THF (150 mL). After warming to room temperature and stirring for 20 min, the reaction was cooled again and propargyl bromide (13.54 g of an 80% solution in toluene, 0.09 mol) was added dropwise. The reaction was then allowed to slowly warm to room temperature and was stirred for 0.5 hr. The reaction was quenched with methanol and water and the solvents were removed under reduced pressure. The residual oil was partitioned between ethyl acetate and water; evaporation of the organic phase gave 10.65 g crude product. The compound was purified by chromatography on silica gel in chloroform to get 4.51 g of crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[CH:26]=O)([CH3:17])[CH3:16].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1/[CH:26]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:17])[CH3:16]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 72 %

Procedure:
To the mixture of 6-chloro-1,3-dihydro-indol-2-one (43 g, 0.26 mol) and 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid methyl ester (66 g, 0.26 mol) in methanol (700 mL) was added pyrrolidine (22 g, 0.31 mol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered and resulting precipitate was collected, dried to give the title compound as a yellow solid (76 g).
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.COCCOC>O>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]21[C:17]1[C:5](=[CH:4][CH:3]=[C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)[CH:18]=1)[CH2:6][CH2:7]2
Reactant: OB(O)c1cncnc1
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Solvent: COCCOC
Solvent: O
Product: NC1=N[C@@]2(CCc3ccc(-c4cncnc4)cc32)C(F)(F)CO1
Yield: 19 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with pyrimidin-5-ylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound (19% yield) as an off-white solid. MS (ISP): m/z=317.0 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][C:7]=1[F:14]>>[N:1]([CH2:10][C:9]1[CH:12]=[CH:13][C:6]([Br:5])=[C:7]([F:14])[CH:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cc(CBr)ccc1Br
Agent: [Na+]
Product: [N-]=[N+]=NCc1ccc(Br)c(F)c1
Temperature: 90 °C
Yield: 95.5 %

Procedure:
Add sodium azide (2.912 g, 44.8 mmol) to a solution of 4-bromo-3-fluorobenzyl bromide (6 g, 22.4 mmol) in anhydrous DM (127 mL) at room temperature under nitrogen. Heat the mixture at 90° C. for 1 h. Concentrate in vacuo and partition the residue between water and EtOAc. Extract the aqueous phase twice with EtOAc. Wash the combined organics extracts with iced-water. Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a solid (4.92 g, 96%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:37])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[CH:20]([C:29]([OH:31])=O)[NH:19][CH:18]3[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:62][C:63]1[CH:72]=[CH:71][C:66]([C:67]([O:69][CH3:70])=[O:68])=[CH:65][C:64]=1[O:73][CH3:74]>>[CH3:70][O:69][C:67](=[O:68])[C:66]1[CH:71]=[CH:72][C:63]([NH:62][C:29]([C@@H:20]2[NH:19][C@@H:18]([CH2:32][C:33]([CH3:36])([CH3:34])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:37])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:31])=[C:64]([O:73][CH3:74])[CH:65]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 63 (0.28 g, 0.5 mmol), was reacted with diisopropylethylamine (0.38 mL, 2.25 mmol), diphenylphosphinic chloride (0.36 mL, 1.9 mmol), then reacted with methyl 4-amino-3-methoxy-benzoate (Ark Pharm) (0.09 g, 0.5 mmol) to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 102 mg, 33%). MS (H+), 610.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1ccccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1ccccc1C(=O)OC
Yield: 96 %

Procedure:
2-Ethyl-benzoic acid (3.0 g, 17.6 mmol) was dissolved in MeOH (20 mL) and sulfuric acid (1 mL) was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated Na2CO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the product (3.1 g, yield 96%) was used without further purification.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[O:5][C:6]([C:9]23[CH2:16][N:13]([CH2:14][CH2:15]2)[CH2:12][CH2:11][CH2:10]3)=[CH:7][N:8]=1.[CH3:17][O-:18].[Na+]>CO>[CH3:17][O:18][CH2:3][C:4]1[O:5][C:6]([C:9]23[CH2:16][N:13]([CH2:14][CH2:15]2)[CH2:12][CH2:11][CH2:10]3)=[CH:7][N:8]=1
Reactant: ClCc1ncc(C23CCCN(CC2)C3)o1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ncc(C23CCCN(CC2)C3)o1
Yield: 79 %

Procedure:
A solution of (±)5-(2-chloromethyl-1,3-oxazol-5-yl)-1-azabicyclo[3.2.1]octane hydrochloride (D25) (75 mg, 0.28 mmole) in dry methanol (2 ml) was added dropwise over 2h to a solution of sodium methoxide in methanol (15 ml of a 25 wt % solution, 66 mmole), under nitrogen, cooled in ice. After evaporation of the solvent in vacuo the residue was treated with saturated aqueous potassium carbonate solution (10 ml) and extracted with chloroform. The combined extracts were dried over sodium sulphate then concentrated in vacuo. The residue was chromatographed on neutral alumina in a gradient of 0-0.5% methanol in chloroform. This afforded the title compound (E11) as an oil (50 mg, 79%) which was converted into the hydrochloride salt m.p. 129°-131° C. (from acetone-ether).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[S:18][C:19]([CH:22]=[CH2:23])=[CH:20][CH:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:23][CH2:22][C:19]3[S:18][C:17]([CH3:16])=[CH:21][CH:20]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C)s1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)s2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylthiophene and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:33]([C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43](=O)[O:44]C2C=CC=CC=2)=[CH:38][CH:37]=1)(=[O:35])[NH2:34]>>[CH3:32][NH:31][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:10]2[N:11]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:43]([NH:42][C:39]4[CH:40]=[CH:41][C:36]([C:33]([NH2:34])=[O:35])=[CH:37][CH:38]=4)=[O:44])=[CH:7][CH:6]=3)[N:9]=2)=[CH:23][CH:24]=1)=[O:30]
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Reactant: NC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Yield: 13 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 4-carbamoylphenylcarbamate. Yield 90 mg, 13% yield.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26](C(OCC)=O)[C:27]([O:29]CC)=[O:28].CC(C)=O>CN(C)C=O>[Br:18][C:16]1[CH:17]=[C:9]2[C:10](=[CH:14][CH:15]=1)[CH2:11][O:13][C:26]([C:27]([OH:29])=[O:28])=[C:1]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=C(O)C1=C(c2ccccc2)c2cc(Br)ccc2CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.6 %

Procedure:
A mixture of 2-benzoyl-4-bromobenzoic acid (25 g, 82 mmol), potassium carbonate (12 g, 87 mmol), diethyl bromomalonate (22 g, 92 mmol), acetone (450 mL) and N,N-dimethylformamide (8 mL) was stirred at room temperature for 15 h. The solvent was evaporated under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The residue was crystallized from hexane and the crystals were collected by filtration. The obtained crystals were added to a mixture of acetic acid (235 mL) and concentrated hydrochloric acid (360 mL) and the mixture was stirred at 120° C. for 8 h. The reaction mixture was cooled and concentrated. The residue was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with diisopropyl ether and dried to give 6-bromo-4-phenyl-1H-isochromene-3-carboxylic acid (17 g, 60%) as crystals.
Reaction SMILES: O.[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10].[H][H]>[C].[Pd].C1(C)C=CC=CC=1>[F:2][C:3]([F:15])([F:16])[C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CCc1cccc(C(F)(F)F)c1
Yield: 97.8 %

Procedure:
Palladium carbon (10%, 6 gm) was added to water (20 ml) and then added 3-(trifluoromethyl)cinnamic acid (100 gm) and toluene (1000 ml). The resulting contents were hydrogenated with hydrogen gas at a pressure of 4 kg at 45 to 50° C. for 2 hour 30 minutes. The reaction mass was then filtered through celite bed and the layers were separated. The organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain 98.7 gm of 3-[3-(trifluoromethyl)phenyl]propionic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[N:13]1([C:18]2[C:19]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N=C=NCCCN(C)C)C>>[CH2:15]1[CH2:14][N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][C:19]=2[N:24]2[CH2:25][CH2:26][N:27]([C:10]([C:2]3[NH:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=3)=[O:12])[CH2:28][CH2:29]2)[CH2:17][CH2:16]1
Reactant: c1cnc(N2CCNCC2)c(N2CCCC2)c1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Product: O=C(c1cc2ccccc2[nH]1)N1CCN(c2ncccc2N2CCCC2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with indole-2-carboxylic acid (0.12 g), 1-[3-(1-pyrrolidinyl)-2pyridinyl]piperazine (PREPARATION 48, 0.17 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.17 g), the title compound is obtained, mp 181°-182°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Oc1ccccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccccc1OC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Triphenylphosphine (1.91 g, 7.31 mmol) was added to an ice-cooled solution of di-isopropylazodicarboxylate (1.48 g, 7.31 mmol) in dichloromethane (15 mL) and the mixture was stirred for 10 minutes. A solution of 2-chlorophenol (806 mg, 6.27 mmol) and 1-benzyl-4-hydroxypiperidine (1 g, 5.22 mmol) in dichloromethane (5 mL) was then added dropwise to the ice-cooled reaction mixture and stirring continued for a further 72 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in diethyl ether and extracted with saturated citric acid solution (5×10 mL). The combined aqueous solution was then basified with sodium hydroxide and extracted with dichloromethane (2×20 mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a clear oil in 89% yield, 1.4 g. 1H NMR (CDCl3, 400 MHz) □: 1.85-1.95 (m, 2H), 1.97-2.08 (m, 2H), 2.32-2.47 (m, 2H), 3.58 (s, 2H), 4.46-4.34 (m, 1H), 6.87-6.95 (m, 2H), 7.16-7.22 (m, 1H), 7.20 (dd, 1H), 7.26-7.37 (m, 6H)