Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:7]=[CH:6]2)[CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[CH:30]=O.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:8]2[N:7]=[CH:6][N:5]([CH:3]3[CH2:2][N:1]([CH2:30][C:25]4[N:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH2:4]3)[C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=2)=[CH:18][CH:19]=1
Reactant: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CNC2)n1
Reactant: O=Cc1ncccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CN(Cc3ncccn3)C2)n1
Reaction time: 0.5 h

Procedure:
A mixture of 4-[1-azetidin-3-yl-4-(4-fluorophenyl)-1H-imidazol-5-yl]pyrimidin-2-amine (C5) (11.2 mg, 0.0361 mmol), pyrimidine-2-carbaldehyde (5.9 mg, 0.055 mmol), triethylamine (0.010 mL, 0.072 mmol) and acetic acid (0.010 mL, 0.17 mmol) in 1,2-dichloroethane (1.0 mL) was stirred for 30 minutes. Sodium triacetoxyborohydride (22.9 mg, 0.11 mmol) was added and stirring was continued for an additional 18 hours, at which time the reaction was quenched with dilute aqueous sodium hydroxide solution. Extraction of the aqueous layer with 1,2-dichloroethane was followed by combination of the organic layers and concentration in vacuo. Purification of the residue was effected by reversed-phase HPLC (Gradient: 5% to 60% acetonitrile in water) to provide the product as a yellow oil. Yield: 1 mg, 0.0025 mmol, 7%. LCMS m/z 403.6 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.66-3.70 (m, 2H), 3.96-4.00 (m, 2H), 4.02 (s, 2H), 5.34 (m, 1H), 6.38 (d, J=5.2 Hz, 1H), 7.10 (dd, J=8.8, 8.8 Hz, 2H), 7.38 (t, J=4.9 Hz, 1H), 7.44 (dd, J=8.9, 5.4 Hz, 2H), 8.09 (d, J=5.2 Hz, 1H), 8.24 (br s, 1H), 8.77 (d, J=5.0 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:24])[CH:11]([CH:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)O)[CH2:12][C:13]=2[O:14]C)=[C:4]([CH3:25])[CH:3]=1>C(O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([CH:9]2[C:10](=[O:24])/[C:11](=[CH:16]/[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)/[CH2:12][C:13]2=[O:14])=[C:6]([CH3:8])[CH:7]=1
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(C(O)C2CCCCC2)C1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Br)cc(C)c1C1C(=O)C/C(=C\C2CCCCC2)C1=O
Yield: 19.6 %

Procedure:
A solution of 2-(4-bromo-2,6-dimethyl-phenyl)-5-(cyclohexyl-hydroxy-methyl)-3-methoxy-cyclopent-2-enone (1.38 g, 3.4 mmol) in ethanol (27.6 ml) and 2N aqueous hydrochloric acid (13.8 ml) is subjected to microwave irradiation at 130° C. for 40 minutes. The reaction mixture is concentrated under vacuum to remove ethanol. The aqueous layer was extracted with ethyl acetate (3×100 ml) and combined organic layers are dried with sodium sulfate and concentrated under vacuum to obtain crude mass. The compound was purified by column chromatography to give 2-(4-bromo-2,6-dimethyl-phenyl)-4-[1-cyclohexyl-meth-(E)-ylidene]-cyclopentane-1,3-dione (250 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:13][C@H:14]1[CH:18]=[CH:17][C:16](=[O:19])[N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].F.[K]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:18]2[CH2:17][C:16](=[O:19])[N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:14]2[CH3:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C[C@H]1C=CC(=O)N1C(=O)OC(C)(C)C
Reactant: COc1ccc(B(O)O)cc1Cl
Agent: F
Agent: [K]
Product: COc1ccc([C@@H]2CC(=O)N(C(=O)OC(C)(C)C)[C@H]2C)cc1Cl
Temperature: 60 °C
Yield: 49.3 %

Procedure:
To a 100 mL RBF were added (3-chloro-4-methoxyphenyl)boronic acid (1.89 g, 10.14 mmol), (S)-tert-butyl 2-methyl-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (1 g, 5.07 mmol), hydroxy(cyclooctadiene)rhodiumRhodium(I) dimer (0.116 g, 0.254 mmol), potassium hydrogen fluoride (1.58 g, 20.28 mmol). The mixture was degassed and filled back with N2. Dioxane (45 mL) and water (5 mL) were then added. The mixture was degassed again and filled with N2. The reaction mixture was heated at 60° C. overnight. It was diluted with EtOAc (200 mL), washed with water, brine. Organic layer was dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography, eluted with 30% EtOAc/Hexane to give (2S,3S)-tert-butyl 3-(3-chloro-4-methoxyphenyl)-2-methyl-5-oxopyrrolidine-1-carboxylate (intermediate J1, 0.85 g) as white crystalline solid. 1H NMR (500 MHz, CDCl3): δ 7.20 (s, 1H), 7.05 (d, 1H), 6.87 (d, 1H), 4.08 (m, 1H), 3.86 (s, 3H), 2.95 (m, 2H), 2.53 (m, 1H), 1.52 (s, 9H), 1.41 (d, 3H).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][CH2:7][CH:8]1[O:13][C:12]2=[CH:14][S:15][CH:16]=[C:11]2[O:10][CH2:9]1)C.C(O)C.[OH-].[K+]>O>[O:13]1[CH:8]([CH2:7][O:6][CH2:5][C:4]([OH:17])=[O:3])[CH2:9][O:10][C:11]2=[CH:16][S:15][CH:14]=[C:12]12
Reactant: CCOC(=O)COCC1COc2cscc2O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COCC1COc2cscc2O1
Temperature: 35 °C

Procedure:
(2,3-Dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-acetic acid ethyl ester (10.2 g, 40 mmol) was dissolved into ethanol (100 mL) and water (50 mL), blanketed by nitrogen. Potassium hydroxide (2.9 g) was added and the mixture was heated at 35° C. for 30 min. The solvents were then removed by distillation, ethyl acetate (50 mL), ice-water (50 mL) and concentrated hydrochloric acid (5 mL) were added and the mixture was vigorously stirred. Subsequently, the organic phase was separated, washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulphate and concentrated. Finally the raw product was recrystallized from ethyl acetate/hexanes (1/1) resulting in pure (2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-acetic acid as demonstrated by NMR and mass spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([NH2:9])=[O:8])[CH3:2].[Cl:15][CH2:16][C:17](=O)[CH2:18]Cl>>[Cl:15][CH2:16][C:17]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[O:8][CH:18]=1
Reactant: O=C(CCl)CCl
Reactant: CCOc1cc(C(N)=O)ccc1OC
Product: CCOc1cc(-c2nc(CCl)co2)ccc1OC
Yield: 49.4 %

Procedure:
Using 29.4 g of 3-ethoxy-4-methoxybenzamide and 57 g of 1,3-dichloro-2-propanone and following the procedure of Reference Example 55, 19.9 g of white powdery 4-chloromethyl-2-(3-ethoxy-4-methoxyphenyl)oxazole was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][OH:36]>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]([CH2:33][CH2:34][CH2:35][OH:36])[CH3:31])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: CNCCCO
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN(C)CCCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and 3-(methylamino)propan-1-ol following the procedure outlined in Example 18, Step 2 (modifications: 22° C., 60 h). 1H NMR (300 MHz, DMSO-d6):):δ: 9.64 (s, 1H), 8.41 (s, 3H), 7.90 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 4.54 (s, 2H), 3.98 (t, J=6.9 Hz, 2H), 3.43 (t, J=6 Hz, 3H), 2.37-2.25 (4H, m), 2.14 (d, J=9.3 Hz, 8H), 1.76 (t, J=6.9 Hz, 2H), 1.37 (m, 6H). MS (ESI): 483.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=[O:5].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>>[CH2:12]([O:5][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CCCCCCCO
Reactant: CC(CC(=O)O)CC(C)(C)C
Product: CC(C)CCCCCCCOC(=O)CC(C)CC(C)(C)C

Procedure:
The preparation from 3,5,5-trimethylhexanoic acid and isodecyl alcohol (mixture of methyl branched primary decanols from Hoechst) was analogous to Example 3; colorless liquid of medium viscosity; B.P. (1.3 mbar)=148°-154° C.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[O:30])[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[K+].C(O)C.O>C(O)(=O)C>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][C:25](=[O:30])[C:26]([OH:28])=[O:27])=[CH:22][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)C(=O)O)cc1

Procedure:
A mixture of 5 g. of methyl (4-hexadecylaminophenyl)pyruvate, 5 g. of potassium hydroxide and 50 ml. of a 1:1 ethanol:water solution is heated to 50° for 3 hrs. While hot, the reaction mixture is neutralized with acetic acid and cooled. The precipitate is collected, dried and recrystallized, yielding (4-hexadecylaminophenyl)pyruvic acid.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(F)cc3)CC2)c(OC)nc1C
Yield: 81 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin 3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11]CC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(OCC)(=O)C>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:9]([CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:11])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC)C(=O)Nc1ccc(Cl)cc1
Temperature: 130 °C

Procedure:
Diethyl 2-ethylmalonate (8.76 ml) and p-chloroaniline (4 g) were dissolved by heating at 130° C. for 11 hours, and the mixture was cooled and dissolved in ethyl acetate, and further, the mixture was washed successively with 1N hydrochloric acid, aqueous sodium bicarbonate solution, and water, and concentrated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with chloroform to give the oily desired product (6.66 g).
Reaction SMILES: O.Cl.Cl[CH2:4][CH2:5][N:6]([CH3:8])[CH3:7].[OH:9]/[N:10]=[C:11]1/[C:12]2[N:13]([CH:20]=[CH:21][CH:22]=2)[C:14]2[C:18]([CH3:19])=[CH:17][S:16][C:15]/1=2.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:7][N:6]([CH2:5][CH2:4][O:9]/[N:10]=[C:11]1/[C:12]2[N:13]([CH:20]=[CH:21][CH:22]=2)[C:14]2[C:18]([CH3:19])=[CH:17][S:16][C:15]/1=2)[CH3:8]
Reactant: Cc1csc2c1-n1cccc1/C2=N/O
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1csc2c1-n1cccc1/C2=N/OCCN(C)C
Yield: 77 %

Procedure:
1.32 g of water and then 3.91 g of 1-chloro-2-(N,N-dimethylamino)ethane hydrochloride and 5 g of (Z)-8-hydroxyimino-3-methylthieno[2,3-d]pyrrolo[1,2-a]pyrrole (Preparation 36) are added to 6.99 g of sodium carbonate in 200 ml of anhydrous acetone. The reaction mixture is heated at reflux for 40 hours, then the acetone is removed and the residue is taken up in 100 ml of water and then extracted with 200 ml of diethyl ether. The ethereal phase is washed with water, decanted off and then dried over magnesium sulfate, and subsequently concentrated to dryness to yield the title product in the form of an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:32]([F:33])=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[CH2:23][O:22][C:21]4=[O:30])[CH2:16][CH2:15]3)=[O:13])=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:3][CH2:2]1.[C:36](OC(=O)C)(=[O:38])[CH3:37].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:36]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:32]([F:33])=[CH:31][C:11]([C:12]([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[CH2:23][O:22][C:21]4=[O:30])[CH2:18][CH2:19]3)=[O:13])=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:3][CH2:2]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC2CCNCC2)c(F)cc1C(=O)N1CCC(N2C(=O)OCc3ccccc32)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCN(C(C)=O)CC2)c(F)cc1C(=O)N1CCC(N2C(=O)OCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 1-(1-(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one of Example 16 (200 mg, 0.41 mmol) in DCM (5 mL) at ambient temperature was added acetic anhydride (77 mg, 0.75 mmol) and DIEA (0.17 mL, 1.0 mmol). The solution was stirred at ambient temperature for 24 h, diluted with DCM (20 mL), washed with saturated aqueous NaHCO3 (50 mL), dried (MgSO4), and filtered. The solvent was removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using a gradient elution of 2-5% MeOH-DCM. 1-(1-(4-(N-acetyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl) -4H-3,1-benzoxazin-2(1H)-one was obtained as an amorphous solid.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1([C:10]([OH:20])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:11][C:12]#[CH:13])[CH2:9][CH2:8]1.CI>CCCCCC.O1CCCC1.C(OCC)(=O)C>[Cl:6][C:7]1([C:10]([OH:20])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:11][C:12]#[C:13][CH3:1])[CH2:8][CH2:9]1
Reactant: C#CCC(O)(Cn1cncn1)C1(Cl)CC1
Reactant: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC#CCC(O)(Cn1cncn1)C1(Cl)CC1
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
26.9 ml (63 mmol) of n-butyllithium in hexane are added at -30° C., with stirring under and a nitrogen atmosphere, to a mixture of 6.76 g (30 mmol) of 4-(1-chlorocyclopropyl)4-hydroxy-5-(1,2,4-triazol-1-yl)-1-pentine and 60 ml of absolute tetrahydrofuran. After the end of the addition, stirring is continued at 0° C. for 15 minutes, and then a solution of 4.68 g (33 mmol) of methyl iodide in 30 ml of absolute tetrahydrofuran is added dropwise. Stirring is then continued for an hour at 20° C. The reaction mixture is worked up by diluting with ethyl acetate and subjecting it several times to extraction by shaking with saturated aqueous ammonium chloride solution. The organic phase is dried over sodium sulphate and filtered and the filtrate is concentrated under reduced pressure. This gives 7.2 g of a product which consists to the extent of67.6% of 5-(1-chlorocyclopropyl)-5-hydroxy-6-(1,2,4triazol-1-yl-2-hexine. For purification, the product is chromatographed on silica gel using ethyl acetate. 4.8 g (67% of theory) of 5-(1-chlorocyclopropyl)-5-hydroxy-6-(1,2,4-triazol-1-yl)-2-hexine are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[N:19]=[CH:20][N:21](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=3)(O)[CH2:9]2)=[CH:4][CH:3]=1.Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[N:19]=[CH:20][NH:21][CH:22]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: OC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC(c2ccc(F)cc2)c2ccccc21
Agent: Cl
Solvent: O
Product: Fc1ccc(C2C=C(c3c[nH]cn3)c3ccccc32)cc1

Procedure:
3-(4-Fluorophenyl)-1-(1-trityl-1H-imidazol-4-yl)indan-1-ol (2.22 g) in 22 ml of a 2 M HCl solution was heated at 70° C. for 2 hr. Water was added. The mixture was extracted with methylene chloride. Then methylene chloride phase was extracted with 2 M HCl solution. All combined water layers were made basic and extracted with methylene chloride. The organic phase was washed with water and dried. The solvent was removed under reduced pressure. The crude 4-[3-(4-fluorophenyl)-3H-inden-1-yl]-1H-imidazole which was the mixture of isomers (the ratio 73:27) was purified by flash chromatography (elution with a dichloromethane-methanol gradient).
Reaction SMILES: [CH2:1]1[CH:5]2[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[C:8]3[CH2:15][C:4]2([C:10]2=[CH:11][CH:12]=[CH:13][CH2:14][C:9]=32)[CH2:3][NH:2]1.[O-2].[Mg+2].[CH:22]1([C:25](Cl)=O)[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][N:2]2[CH2:3][C:4]34[CH2:15][CH:8]([C:7]5[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=5[CH:5]3[CH2:1]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]4=2)[CH2:24][CH2:23]1
Reactant: O=C(Cl)C1CC1
Reactant: C1=CCC2=C3CC4(CNCC4c4ccccc43)C2=C1
Agent: [Mg+2]
Agent: [O-2]
Product: c1ccc2c(c1)C1CC3(CN(CC4CC4)CC23)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a slurry of 1.34 g of 2,3,7,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole Example 3) and 3 g of magnesium oxide is added 0.93 g of cyclopropanecarbonyl chloride, and the mixture is stirred at room temperature overnight. The filtered mixture is concentrated; the residue is dissolved in methylene chloride, and the solution is washed with base, dried, and concentrated. The residue is heated under reflux with 0.57 g of lithium aluminum hydride in tetrahydrofuran overnight. To the cooled mixture is added, in turn, 0.6 ml of water, 0.6 ml of 15% aqueous sodium hydroxide solution, and 1.8 ml of water; the mixture is filtered, and the filtrate is concentrated to give 1.35 g of 2-cyclopropylmethyl-2,3,8,12b-tetrahydro-1H-3a, 8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole as an oil; nmr spectrum: τ 2.7- 3.2 (m, 8); 6.0-8.0 (m, 8) and 8.8-10.0 (m, 5). It is converted to the hydrochloride which is crystallized from isopropyl alcohol. The melting point of the hydrochloride is erratic and depends upon the rate of heating. Extending drying of the hydrochloride at 120°-130° for 8 hours at 0.1 micron gives a solvent-free product, m.p. 251°-252°, with decomposition.
Reaction SMILES: [F:1][C:2]1([F:27])[CH:10](O)[C:9]2[N:5]([C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[C:7]3[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[N:12]([CH3:19])[C:8]3=2)[CH2:4][CH2:3]1.[CH3:28][C:29]1[O:30][CH:31]=[CH:32][CH:33]=1>C(#N)C.[Au](Cl)(Cl)Cl>[F:27][C:2]1([F:1])[CH:10]([C:31]2[O:30][C:29]([CH3:28])=[CH:33][CH:32]=2)[C:9]2[N:5]([C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[C:7]3[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[N:12]([CH3:19])[C:8]3=2)[CH2:4][CH2:3]1
Reactant: Cc1ccco1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(O)C(F)(F)CC3
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: Cc1ccc(C2c3c4c(c(-c5cccc(F)c5)n3CCC2(F)F)c(=O)n(C)c(=O)n4C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Gold (III) chloride (4 mg, 0.012 mmol) was added to a suspension of 9,9-difluoro-5-(3-fluorophenyl)-10-hydroxy-1,3-dimethyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (47 mg, 0.12 mmol) and 2-methylfuran (15 μL, 0.16 mmol) in acetonitrile (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was evaporated under vacuum, the residue was dissolved in DCM (5 mL) and washed with water (5 mL). The organic phase was passed through a hydrophobic frit evaporated under vacuum. Purification by mass directed HPLC using the following conditions afforded the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)[CH2:6][CH2:5]1.Br[CH2:28][CH:29]([O:32][CH3:33])[O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O1CCOCC1>[Cl:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:29]([O:32][CH3:33])([O:30][CH3:31])[CH3:28])[CH2:5][CH2:6]3)=[CH:11][N:12]2[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[CH:17][CH:16]=1
Reactant: COC(CBr)OC
Reactant: NCCN1CCC(c2cn(-c3ccc(F)cc3)c3cc(Cl)ccc23)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(C)(NCCN1CCC(c2cn(-c3ccc(F)cc3)c3cc(Cl)ccc23)CC1)OC

Procedure:
To a solution of 3-[1-(2-aminoethyl)-4-piperidyl]-6-chloro-1-(4-fluorophenyl)-1H-indole 7b (11 g)in dioxan (100 ml) were added 2-bromo-1,1-dimethoxyethane (5.6 g), potassium carbonate (5 g) and a potassium iodide crystal. The mixture was refluxed for 16 hours. After cooling inorganic salts were filtered off and dioxan evaporated leaving crude 6-chloro-3-[1-[N-(1,1-dimethoxyethyl)-aminoethyl]-4-piperidyl]-1-(4-fluorophenyl)-1H-indole as an oil. The crude product was purified by column chromatography on silica gel (eluted with ethyl acetate/methanol 1:1). Yield: 6 g as an oil. The thus obtained alkylated aminoderivative (6 g) was dissolved in dichloromethane (100 ml) and 2-propylisocyanate (1.1 g) was added. After refluxing for 2 hours dichloromethane was evaporated and the title compound 16a was purified by column chromatography on silica gel (eluted with ethyl acetate/methanol 1:1). Yield: 4.9 g as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:17])=[O:5])[CH3:2].[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:17])=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc2c(Cl)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(Cl)cccc2c1NC1CCCC1

Procedure:
4,8-Dichloro-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.93 mmol) was treated with cyclopentylamine following general procedure B to afford 8-chloro-4-cyclopentylamino-quinoline-3-carboxylic acid ethyl ester (220 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (165 mg) following general procedure E.