Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([OH:28])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:49])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:28][C@@H:16]1[CH2:17][CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:49])[CH2:19]2)[C@@H:25]2[C@@H:15]1[C@H:6]1[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]1
Reactant: C[C@]12CCCCC1C[C@@H](O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1C[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 89 %

Procedure:
The title compound (II-bt) was prepared in 89% yield from 3,3:17,17-bis(ethylendioxy)-7α-hydroxyandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.34 (d, 1H), 3.75 (m, 1H), 2.50-1.00 (m, 20H), 0.96 (s, 3H), 0.78 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH3:24][C:25]1([O:28][CH2:27]1)[CH3:26]>O>[CH3:24][C:25]([OH:28])([CH3:27])[CH2:26][O:19][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:7]3[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:10][CH:11]=[N:12]2)=[CH:17][CH:16]=1
Reactant: CC1(C)CO1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(O)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
To a flask containing 4-(4-nitrophenoxy)quinolin-7-ol (14.45 g, 45.33 mmol) was added a solution of sodium hydroxide (3.63 g, 90.66 mmol) in water/95% EtOH (90 mL/10 mL) followed by isobutylene oxide (12.12 mL, 136 mmol, pre-cooled to 0° C.). After stirring at 45° C. for 10 minutes, more isobutylene oxide (12.12 mL, 136 mmol, pre-cooled to 0° C.) was added. The reaction was continued to stir for additional 12 hours. The mixture was cooled to room temperature and continued to stir for 4 hours, then cooled to 0° C. and stirred for additional 10 minutes. The resulted solid was filtered, and then dissolved in DCM (130 mL). The solution was filtered and concentrated in vacuo. The residue was washed with petroleum ether (30 mL), and dried in vacuo at 45° C. overnight to afford the title compound as a yellow solid (6.86 g, 42.7%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=[O:9])[C:5]2[CH:13]=[C:14]([Cl:23])[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][C:4]=2[O:3]1.Cl>C(O)(=O)C.O>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:5]2[CH:13]=[C:14]([Cl:23])[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][C:4]=2[O:3]1
Reactant: CCOC(=O)Cn1c(=O)oc2cc(-c3ccccc3)c(Cl)cc21
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cn1c(=O)oc2cc(-c3ccccc3)c(Cl)cc21
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 2-oxo-5-chloro-6-phenyl-3-benzoxazolineacetate (1.5 g) in acetic acid (10 ml) was added conc.hydrochloric acid (5 ml). The reaction mixture was stirred at 60° C. for 1.5 hours and then cooled to ambient temperature. The resultant mixture was diluted with water to precipitate crystals, which were separated by filtration, washed with water, dried and then recrystallized from a mixture of chloroform and acetone to give 2-oxo-5-chloro-6-phenyl-3-benzoxazolineacetic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:15]=[C:16]([C:20]([NH:22][C:23]3[CH:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH:33]=[CH:32][C:24]=3[C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH:17]=[N:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]2[CH:15]=[C:16]([C:20]([NH:22][C:23]3[CH:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH:33]=[CH:32][C:24]=3[C:25]([OH:27])=[O:26])=[O:21])[CH:17]=[N:18][CH:19]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccn2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccn2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Trifluoroacetic acid (4.0 mL) was added to the obtained tert-butyl 2-(5-phenylpyridine-3-carboxamido)-4-(pyridin-2-yl)benzoate (0.13 g), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration. Dioxane (3.0 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.19 mL) were added to the obtained solid, followed by stirring at room temperature for 1 hour. A 10% aqueous solution of citric acid and ethyl acetate were added to the reaction mixture, and the solid substance was collected by filtration to obtain 74 mg of 2-(5-phenylpyridine-3-carboxamido)-4-(pyridin-2-yl)benzoic acid as a white solid.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8](=[O:12])[CH:9](Br)[CH3:10].[CH3:13][O:14][C:15]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[C:16]=1/[CH:17]=[CH:18]/[S:19]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH2:29])[CH:28]=1)(=[O:21])=[O:20]>CO>[CH3:13][O:14][C:15]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[C:16]=1/[CH:17]=[CH:18]/[S:19]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH:29][CH:9]([CH3:10])[C:8]([O:7][CH3:6])=[O:12])[CH:28]=1)(=[O:21])=[O:20]
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(N)c2)c(OC)c1
Reactant: COC(=O)C(C)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)Nc1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)ccc1OC
Temperature: 25 °C

Procedure:
Sodium acetate (0.4 mol) was dissolved in methanol (200 mL). Methyl-2-bromopropionate (40 mmol) was added and the resulting mixture was heated at reflux for 10 min. The heated mixture was cooled to room temperature (25° C.), and (E)-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxybenzenamine (0.1 mol) was added. The resulting mixture was heated at reflux for 1 h. The hot reaction mixture was allowed to cool to room temperature (25° C.), and then poured into ice water (500 mL). A solid precipitate formed. The precipitate was separated by filtration and recrystallized from ethanol to provide the desired methyl(E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)propanoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([S:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1SCc1ccccc1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A solution of the product of Example 2A (7.72 g, 31.26 mmol), sodium carbonate (3.31 g, 31.26 mmol) and benzyl mercaptan (3.90 mL, 30.21 mmol) in absolute ethanol (50 mL) was stirred at reflux for 6 hours, cooled to 25° C. and added to water (200 mL). The precipitate was collected by filtration, washed with water and dried to give the title compound (10.71 g, 98%). 1H NMR (300 MHz, CDCl3): δ 8.26 (d, J=9.19 Hz, 1 H), 7.36 (m, 10 H), 6.91 (d, J=2.57 Hz, 1 H), 6.78 (dd, J=9.19, 2.57 Hz, 1 H), 5.06 (s, 2 H), 4.12 (s, 2 H).
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22]([O:24]CC3C=CC=CC=3)=[O:23])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22]([OH:24])=[O:23])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C1CCCc2c1c1ccccc1n2C(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1CCCc2c1c1ccccc1n2C(=O)c1ccccc1

Procedure:
A solution of 5.6 g. benzyl 9-benzoyl-1,2,3,4-tetrahydrocarbazole-4-carboxylate in 250 ml. ethyl alcohol containing 0.5 g. 10% palladium-on-charcoal was subjected to a hydrogen atmosphere at 40 p.s.i., while being heated with an infrared lamp and agitated, until uptake of hydrogen ceased. The mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, the resulting residue was dissolved in ether, the ether solution was extracted with dilute potassium bicarbonate, the bicarbonate extract was acidified with 3N-hydrochloric acid and extracted with ether and the ether extract was dried and evaporated to dryness. The resulting residue was crystallized from ether-pentane and a solution of the resulting crystals in 5% potassium bicarbonate solution was acidified with 3N hydrochloric acid and the resulting solid was filtered and washed with water to give 1.3 g. of the title compound; m.p. 70°-80°C.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:9]=[C:10]([C:18]([OH:20])=O)[C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1)([O-:7])=[O:6]>CN(C)C=O>[N+:5]([C:8]1[CH:9]=[C:10]([C:18]([Cl:3])=[O:20])[C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1)([O-:7])=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c1OCCO2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])cc2c1OCCO2
Yield: 100 %

Procedure:
112 ml of thionyl chloride, 56 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid were introduced into a 250 ml balloon flask provided with a stirrer, a thermometer and a reflux condenser. The mixture was stirred and 1 ml of dimethylformamide was added with heating. After stirring for one hour at the reflux temperature, the excess of thionyl chloride was removed by distillation under vacuum. 61 g of 7-nitro-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 108° C.; yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: Nc1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 226.8 %

Procedure:
To 3-chloroaniline (10 g, 0.078 mol) was added portionwise acetic anhydride (32 g, 0.314 mol) in such a manner as to keep the temperature of the reaction mixture below 85° C. The reaction mixture was then stirred at 90° C. for 4 hours and then cooled to room temperature. The reaction mixture was then poured carefully into ice water, extracted with ethyl acetate and dried over sodium sulfate. The solvent was removed, yielding 30 g of N-acetyl-3-chloroaniline.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].[S:18]1[C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[N:20]=[C:19]1[CH2:27][NH2:28]>C(O)(C)C>[N+:1]([C:4]1[C:5]([NH:28][CH2:27][C:19]2[S:18][C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[N:20]=2)=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NCc1nc2cnccc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1nc2cnccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-nitro-2,6-dichloropyridine (106 mg, 0.55 mmol) in isopropanol (3 mL) was sequentially added Na2CO3 (116 mg, 1.1 mmol) and intermediate R (100 mg, 0.61 mmol). The reaction mixture was stirred at room temperature overnight, and then concentrated. The residue was extracted with EtOAc. The organic layer was separated, concentrated, and purified by chromatography on silica gel to afford the title compound. MS (m/z): 322 (M)+.
Reaction SMILES: [F:1][CH:2]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[F:3].[Li+].CC([N-]C(C)C)C.[NH2:20][C:21]1[C:30]2[N:29]=[CH:28][C:27]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[CH3:41])=[CH:26][C:25]=2[C:24]2[CH:42]=[CH:43][C:44]([CH:46]=[O:47])=[CH:45][C:23]=2[N:22]=1>C1COCC1>[NH2:20][C:21]1[C:30]2[N:29]=[CH:28][C:27]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[CH3:41])=[CH:26][C:25]=2[C:24]2[CH:42]=[CH:43][C:44]([CH:46]([OH:47])[C:2]([P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])([F:3])[F:1])=[CH:45][C:23]=2[N:22]=1
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C=O)ccc4c3c2)c(C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)C(O)c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
To a solution of diethyl difluoromethylphosphonate (3.0 equiv.) in THF (0.3 M) at −78° C. under nitrogen atmosphere was added dropwise 2M LDA (3.0 equiv., commercial grade). The reaction was stirred at −78° C. for 25 min, and a solution of 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (2-2) (1.0 equiv.) in THF (0.1 M) was added slowly. The reaction was stirred at −78° C. for 1 hour, 0° C. for 1 hour, and then warmed to room temperature over 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-hydroxyethylphosphonate (2-3) as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1C=CC=CC=1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OCCO
Reactant: O=Cc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: c1cc(C2OCCO2)ccn1

Procedure:
A stirred solution of pyridine-4-carboxaldehyde (8.7 ml, 90 mmol), ethylene glycol (10 ml, 180 mmol) and p-toluene sulfonic acid (18.8 g, 99 mmol) in benzene (70 ml) was refluxed overnight. A Dean-Stark apparatus was used to remove water azeotropically from the reaction. After ˜15 h the mixture was cooled, then made basic with aq. NaOH (20% w/v, ˜30 ml). The benzene layer was isolated and the aqueous layer was washed with dichloromethane until no more product came out (˜5×60 ml). The combined organic phases were dried (Na2SO4) and solvent removed in vacuo to give the pure 4-(1,3 dioxolan-2-yl) pyridine [Registry No. 61379-59-7] as a pale yellow liquid that solidified under vacuum (12.57 g, 92%). 1H NMR (300 MHz, CDCl3): δ 4.06 (4H, m, O—(CH2)2—O), 5.82 (1H, s, O—CH—O), 7.39 (2H, d, J=6-Hz, H-3, H-5), 8.63 (2H, d, J=6 Hz, H-2, H-6) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:31]1[CH:32]=[CH:33][CH:34]=[N:35][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:34]4[CH:33]=[CH:32][CH:31]=[CH:36][N:35]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Brc1cccnc1
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cc(-c3ccccn3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Yield: 66.2 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.1 mmol) which was prepared according to the procedure in Step F of Example 26, 5-bromopyridine (0.21 mL, 2.2 mmol) and cesium carbonate (1.08 mg, 3.3 mmol) in water (3 mL) and N,N-dimethylformamide (10 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2.5 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by column chromatography (9:1 hexanes/ethyl acetate to ethyl acetate, then 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to give 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (282 mg, 65%) as a brown oil: ESI MS m/z 387, 389 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[Sn](CCCC)(CCCC)CCCC)([CH3:3])[CH3:2].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1>>[CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[C:29]1[CH:30]=[CH:31][C:26]([C:25]([F:34])([F:33])[F:24])=[CH:27][CH:28]=1)([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Reactant: FC(F)(F)c1ccc(I)cc1
Product: CC(C)Oc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O
Yield: 49.3 %

Procedure:
In a manner similar to Example 9, Step 1, 3-isopropoxy-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione (3.00 g, 6.99 mmol), 4-trifluoromethyl-iodobenzene (2.09 g, 7.69 mmol), benzylchlorobis(triphenylphos-phine)palladium (II) (0.318 g, 0.419 mmol) and cuprous iodide (0.12 g, 0.629 mmol) were reacted together to give 0.98 g (45%) of 3-isopropoxy-4-(4-trifluoromethyl-phenyl)-cyclobut-3-ene-1,2-dione which was of sufficient purity to use in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[N:17]=[CH:18][C:19]3[C:25](=[O:26])[N:24]([C:27]4[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:28]=4[CH3:36])[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.C1COCC1>[Pd].CO>[NH2:33][C:31]1[CH:30]=[CH:29][C:28]([CH3:36])=[C:27]([N:24]2[CH2:23][CH2:22][C:20]3[N:21]=[C:16]([NH:15][C:4]4[CH:5]=[CH:6][C:7]([N:8]5[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]5)=[C:2]([CH3:1])[CH:3]=4)[N:17]=[CH:18][C:19]=3[C:25]2=[O:26])[CH:32]=1
Reactant: Cc1cc(Nc2ncc3c(n2)CCN(c2cc([N+](=O)[O-])ccc2C)C3=O)ccc1N1CCN(C)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncc3c(n2)CCN(c2cc(N)ccc2C)C3=O)ccc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
To a solution of 2-[3-Methyl-4-(4-methyl-piperazin-1-yl)-phenylamino]-6-(2-methyl-5-nitro-phenyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (100 mg, 0.198 mmol) in the mixed solvent of THF (5 ml) and methanol (5 ml) was added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 6-(5-Amino-2-methyl-phenyl)-2-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one [19] (Yield: 81.72 mg, 86.9%) as a off white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(=O)([O-])O.[Na+]>ClCCl>[CH3:29][S:30]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[CH:11][CH:10]=2)[CH2:3]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Reaction time: 4 h

Procedure:
(S)-3-Hydroxy-1-(4-pyrrolidinophenethyl)pyrrolidine (6.30 g, 23.4 mmol) was dissolved in 100 ml of dichloromethane. Diisopropylethylamine (5.28 ml, 30.0 mmol) and methanesulfonyl chloride (2.34 ml, 30.0 mmol) were added to the obtained solution at 0° C. and they were stirred for 4 hours. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with dichloromethane and methanol (10:1), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (S)-3-methanesulfonyloxy-1-(4-pyrrolidinophenethyl)pyrrolidine in the form of a light yellow oily substance (7.50 g, 49%).
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.[OH-].[K+].[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[CH:24]=[CH2:25]>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:25][CH2:24][C:20]3[S:21][CH:22]=[CH:23][C:19]=3[CH3:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1sccc1C
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2sccc2C)C=CN(C)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (250 mg, 1.25 mmol) in NMP (1 mL) were added powdered KOH (490 mg, 8.75 mmol) and 3-methyl-2-vinyl-thiophene (310 mg, 2.25 mmol), and the reaction mixture stirred at 90° C. for 5 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-[2-(3-methyl-thiophen-2-yl)-ethyl]-2,5-dihydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.25 (d, 1H), 7.22 (s, 1H), 7.1 (d, 1H), 7.02 (d, 1H), 6.7 (d, 1H), 4.41 (s, 2H), 4.3 (t, 2H), 2.42 (bs, 2H), 3.2 (t, 2H), 3.0 (s, 3H), 2.61 (bs, 2H), 2.4 (s, 3H), 1.6 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH3:6][O:7][CH2:8][CH2:9]Br.C(N(CC)CC)C>C(#N)C>[CH3:6][O:7][CH2:8][CH2:9][N:2]([CH2:3][CH2:4][OH:5])[CH3:1]
Reactant: COCCBr
Reactant: CNCCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCN(C)CCO
Yield: 31 %

Procedure:
A mixture of 2-(methylamino)ethanol (5.4 g, 72 mmol), 2-bromoethyl methyl ether (10 g, 72 mmol) and triethylamine (10 ml, 72 mmol) in acetonitrile (70 ml) was refluxed overnight. After cooling, the solid was filtered and the filtrate was evaporated. The residue was triturated with ether. The ether layer was separated and evaporated to give 2-(N-(2-methoxyethyl)-N-methylamino)ethanol (3g, 31%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][O:9]2)=[CH:4][C:3]=1[F:15].C([Li])CCC.[I:21]I>C1COCC1.CCCCCC>[F:15][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[I:21])[O:9][CH2:8][CH:7]([CH2:12][CH2:13][CH3:14])[CH2:6]2
Reactant: CCCC1COc2cc(Br)c(F)cc2C1
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC1COc2cc(I)c(F)cc2C1
Reaction time: 1.5 h

Procedure:
10.6 g (38.8 mmol) of 7-bromo-6-fluoro-3-propylchroman are initially introduced in 100 ml of THF, and 27 ml (43.0 mmol) of a 15 percent solution of n-butyllithium in hexane are added dropwise. After 90 min, 10.0 g (39.4 mmol) of iodine, dissolved in 50 ml of THF, are added, the mixture is stirred for 1 h, and the cooling is removed. The batch is diluted with MTB ether, washed with water and with sat. sodium hydrogensulfite soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is filtered through silica gel with heptane/toluene (4:1), giving 6-fluoro-7-iodo-3-propylchroman as a colourless solid, which is sufficiently pure for further reaction.