Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[C:13]1[CH:18]=[CH:17][C:16]([O:19]C2CCCCO2)=[CH:15][CH:14]=1)([CH3:3])[CH3:2].Cl>O1CCOCC1>[CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnc2c(-c3ccc(OC4CCCCO4)cc3)ncnc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)n1cnc2c(-c3ccc(O)cc3)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Compound 52C (149 mg, 0.44 mmol) in dioxane (3 ml) was treated with HCl (4N in dioxane) (0.55 ml, 2.2 mmol) and stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and dried to give a light gray solid 52D in 94% yield: 1H NMR (300 MHz, DMSO-d6) δ ppm 10.16 (1H, s), 8.90 (1H, s), 8.76 (1H, m), 8.73 (2H, m), 6.97 (2H, m), 4.91 (1H, septet), 1.60 (6H, d).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[CH3:3][CH:2]([CH3:4])[CH2:1][NH:5][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6]
Reactant: CC(C)CN
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of 18.20 g (0.25 mol) isobutylamine in 50 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 100 ml of ethyl acetate. This gave 26.93 g (0.17 mol, 72% yield) of a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C@H:10]([OH:12])[CH3:11])=[CH:6][N:5]=[C:4]2[CH:13]=[CH:14][S:15][C:3]=12.Cl.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]#[N:26])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:12][C@@H:10]([C:9]1[N:17]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]#[N:26])[CH2:20][CH2:19]2)[C:2]2=[C:3]3[S:15][CH:14]=[CH:13][C:4]3=[N:5][CH:6]=[C:7]2[CH:8]=1)[CH3:11]
Reactant: C[C@@H](O)C#Cc1cnc2ccsc2c1Cl
Reactant: N#CC[C@H]1CC[C@H](N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: C[C@@H](O)c1cc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of (2R)-4-(7-chlorothieno[3,2-b]pyridin-6-yl)but-3-yn-2-ol (0.055 g, 0.23 mmol), (trans-4-aminocyclohexyl)acetonitrile hydrochloride (0.040 g, 0.23 mmol), cesium carbonate (0.19 g, 0.58 mmol), palladium acetate (5.2 mg, 0.023 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (27 mg, 0.046 mmol) in toluene (1.1 mL) was purged with N2 for 3 times. The resulting mixture was stirred at 100° C. for 2 h, then at 120° C. for 2 h. The mixture was filtered. The filtrate was concentrated under reduced pressure, diluted with MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.4 mg, 1.8%). LCMS calculated for C19H22N3OS (M+H)+: m/z=340.1. Found: 340.1.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C@@H:4]2[CH2:3]1.CC(C)([O-])C.[K+].Br[C:25]1[CH:30]=[N:29][C:28]([CH:31]2[CH2:33][CH2:32]2)=[CH:27][N:26]=1>O1CCCC1>[CH:31]1([C:28]2[N:29]=[CH:30][C:25]([O:1][C@@H:2]3[CH2:17][N:5]4[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:9][C@@H:4]4[CH2:3]3)=[N:26][CH:27]=2)[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](O)C[C@H]2C1
Reactant: Brc1cnc(C2CC2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (7S,8aS)-tert-butyl 7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (Wuxi Pharma, 0.485 g, 2 mmol) in tetrahydrofuran (0.3 mL) was added potassium tert-butoxide (2.8 mL, 1 M in tetrahydrofuran, 2.8 mmol) followed by a solution of 2-bromo-5-cyclopropylpyrazine (446 mg, 2.24 mmol) in tetrahydrofuran (1 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was purified by chromatography on silica gel (ethyl acetate) to give the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.39 (s, 9H), 1.90 (m, 2H), 2.09 (m, 1H), 2.40 (m, 3H), 2.90 (m, 2H), 3.08 (m, 1H), 3.28 (m, 1H), 3.86-4.08 (m, 2H), 5.27 (m, 1H), 8.11 (m, 2H); MS (ESI) m/z 361 (M+H)+.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[N:17]=1)[C:9]([O:11]C)=[O:10])=O.[OH-].[Na+].Cl>O1CCCC1>[NH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[N:17]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)no2)c(NC(=O)C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)ccc1-c1nc(-c2ccc(C(F)(F)F)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of methyl 3-trifluoroacetylamino-4-[3-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-5-yl]benzoate (0.800 g), 1 M aqueous sodium hydroxide solution (5.1 ml) and tetrahydrofuran (10 ml) was stirred at room temperature for 1 hr. After cooling, 1 M hydrochloric acid was added to acidify the reaction mixture. The crystals were collected by filtration to give 3-amino-4-[3-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-5-yl]benzoic acid (0.570 g, yield 97%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: >300° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][O:10][CH2:11][CH2:12][N:13]2[C:21]3[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17](OC4C=CC=CC=4)[C:16]=3[N:15]=[C:14]2[CH3:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:36].Cl>>[CH3:31][C:14]1[N:13]([CH2:12][CH2:11][O:10][CH2:9][C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:36])[C:16]=2[N:15]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCC#Cc3ccccc3)c2c1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Product: Cc1nc(N)c2nc(C)n(CCOCC#Cc3ccccc3)c2c1C
Temperature: 150 °C
Yield: 41.2 %

Procedure:
1-[2,6,7-Trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]eth-2-yl (3-phenylprop-2-ynyl) ether (5.4 g, 13.122 mmol) from Part H and ammonium acetate (54 g) were combined in a glass pressure vessel. The vessel was sealed with a teflon screw cap, and the reaction mixture was heated to 150° C. for 45 hours. The reaction was essentially complete, and the resulting reaction solution was cooled with an ice bath, acidified to a pH of 1 with 10% hydrochloric acid, and washed with dichloromethane (3×500 mL). The combined organic portions were washed with 10% hydrochloric acid (4×). The acidic aqueous portions were combined, basified with potassium hydroxide pellets to a pH of 14. The resulting brown solids were filtered off and recrystallized from methanol. A first crop of 0.6 g was collected for use in Example 5, and a second crop was collected and found to contain about 2% of the 4-hydroxy compound by NMR analysis. The second crop was returned to the mother liquor, and dichloromethane was added until all solids were dissolved. 1M Hydrochloric acid in diethyl ether (20 mL) was added to the resulting solution, and the solids that formed were filtered off, and dissolved in water, which was basified to a pH of 14 with potassium hydroxide pellets. The resulting solution was washed with dichloromethane (3×). The organic portions were combined, washed with water (2×) and brine (2×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid (1.8 g) was dissolved in dichloromethane (150 mL), and 1M hydrochloric acid in diethyl ether (5.3 mL) was added to the resulting solution. The acidified solution was concentrated under reduced pressure. The resulting solids were dissolved in water, and this aqueous solution was filtered to remove an oily sludge. The filtrate was basified with a few drops of 20% potassium hydroxide and then 1N potassium hydroxide to a pH of 13. The fine white precipitate that formed was filtered off, rinsed with diethyl ether, and dried under vacuum for 18 hours to provide 1.8064 g of 2,6,7-trimethyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 186.8-187.5° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:3]=1.C[O:27][B:28](OC)[O:29]C>>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:7]1[C:6]2[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:3]=[C:2]([B:28]([OH:29])[OH:27])[C:10]=2[N:9]=[C:8]1[CH3:11]
Reactant: COB(OC)OC
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1
Product: Cc1nc2c(B(O)O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1

Procedure:
The titled compound was prepared from 4-(4-bromo-1-(3-chlorobenzyl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.65 g, 1.545 mmol) using Method A with trimethylborate to give the product (109 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.82 (s, 3H) 3.22 (m, 4H) 3.78 (m, 4H) 5.69 (s, 2H) 7.19 (m, 1H) 7.33-7.48 (m, 4H) 7.78 (s, 1H); MS (ES+) 386.0 m/z.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:8]=2)[N:6]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1ccc(I)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(I)cc2c1O
Temperature: 25 °C

Procedure:
4-Iodoaniline (8.60 g) and diethyl ethoxymethylenemalonate (7.90 mL) are heated at 130° C. for 1 hour. The reaction is cooled to room temperature and 60 mL diphenyl ether is added. The solution is heated at 250° C. for 1.5 hours with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the resulting solid is filtered, washed with hexanes, and dried to yield 11.20 g of ethyl 4-hydroxy-6-iodoquinoline-3-carboxylate. A mixture of this ester (0.58 g) and 4chlorobenzylamine (4.0 mL) are heated at 180° C. for 1.5 hours. The reaction is cooled and poured into 50 mL diethyl ether. The resulting solid is filtered, triturated in ethyl acetate, and filtered again to give the desired product (0.50 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[C:21]1([CH2:27]C#N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:27]2[O:3][N:1]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4[N:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:13]=[CH:12][CH:11]=4)=[CH:6][C:5]=23)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#CCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2)cc1
Product: c1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4)cc23)cc1

Procedure:
The title compound, light grey solid (37 mg, 29%), MS (ISP) m/z=338.3 [(M+H)+], mp 163° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-phenyl-1H-pyrazole (intermediate A) (100 mg, 353 μmol) and commercially available 2-phenyl-acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[C:8]([CH:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13])(=O)[CH3:9].C(O)(=O)C>C1(C)C=CC=CC=1>[OH:14][CH2:15][CH2:16][C:11]1[C:8]([CH3:9])=[N:1][C:2]2[N:3]([N:4]=[C:5]([CH3:7])[CH:6]=2)[C:12]=1[OH:13]
Reactant: Cc1cc(N)n[nH]1
Reactant: CC(=O)C1CCOC1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc2nc(C)c(CCO)c(O)n2n1
Temperature: 25 °C
Yield: 85788 %

Procedure:
A solution of 3-amino-5-methylpyrazole (25.0 g, 0.26 mole), α-acetyl-γ-butyrolactone (34.5 g, 0.27 mmol) and acetic acid (5 mL) in toluene (350 mL) was heated under reflux for three hours. After cooling to room temperature, the resulting crystals were collected by filtration and washed with ethyl acetate, to give the title compound (48.0 g) as white crystals.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:6][N:5]=[C:4]([N:16]=CN(C)C)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1>CCO>[NH2:16][C:4]1[N:3]=[C:2]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)[C:7]([S:8]([NH:11][C:12]([CH3:13])([CH3:14])[CH3:15])(=[O:9])=[O:10])=[CH:6][N:5]=1
Reactant: Cc1cccc(N)c1
Reactant: CN(C)C=Nc1ncc(S(=O)(=O)NC(C)(C)C)c(Cl)n1
Solvent: CCO
Product: Cc1cccc(Nc2nc(N)ncc2S(=O)(=O)NC(C)(C)C)c1
Yield: 85 %

Procedure:
To a mixture of 4-chloro-2-[[(dimethylamino)methylene]amino]-N-(1,1-dimethylethyl)-5-pyrimidinesulfonamide, prepared according to the process of Example 1, Step 6 (44.62 g, 0.139 mol) in EtOH (1800 mL) was added metatoluidine (59.8 g, 0.558 mol) and heated to reflux for 10 hours. After cooling, the solvent was removed in vacuo and the residue extracted into EtOAc (1 liter). The solution was twice washed with 1N HCl, washed with water and then with saturated NaCl. The organics were dried over MgSO4 and evaporated in vacuo to give a colorless solid, m.p. 174°-178° C. in 85% yield. Used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(N)cn2)C1
Yield: 93.4 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with tert-butyl piperidin-3-ylcarbamate (695 mg, 3.5 mmol) followed by reduction to afford the desired product (847 mg, 93%) as a purple solid: ESI MS m/z 293 [C15H24N4O2+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14](OCC)=[O:15])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1NCCN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 45B (6 g, 22.87 mmol) in tetrahydrofuran (45.7 mL) was added to lithium aluminum hydride in tetrahydrofuran (30.9 mL, 61.8 mmol) dropwise with an addition funnel under nitrogen over 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then carefully quenched with water and 1 N NaOH (aqueous). The product was extracted once with dichloromethane, dried over Na2SO4 and concentrated to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.37-7.17 (m, 5H), 4.48 (t, J=5.4, 1H), 3.60 (t, J=6.5, 1H), 3.42 (q, J=13.1, 2H), 3.27-3.15 (m, 2H), 2.80 (dt, J=2.7, 11.4, 1H), 2.73-2.55 (m, 4H), 1.92 (td, J=3.0, 10.8, 1H), 1.81-1.72 (m, 1H), 1.60 (t, J=10.1, 1H); MS (ESI+) m/z 206.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH2:9][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[Cl:25]C1C=C2N(C3C=CC=CC=3[N+]([O-])=O)CC3(CCN(/C(/C([O-])=O)=C/C([O-])=O)CC3)C2=CC=1.C(O)C.Cl>[Fe].O>[ClH:1].[ClH:25].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21
Reactant: O=C([O-])/C=C(\C(=O)[O-])N1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1cc(Cl)ccc12
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21

Procedure:
A mixture of 2.1 g of 6-chloro-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], free base of Example 33, 95 ml of 95% ethyl alcohol, 7.5 ml of water and 4.4 g of iron powder is acidified with 0.2 ml of concentrated hydrochloric acid and then refluxed under nitrogen for 10 minutes. Thereafter, the mixture is permitted to cool before being filtered through celite. The filtrate is concentrated under vacuum leaving an oily residue which is basified. The alkaline mixture is extracted with ether and then dried. The product is converted to a solid dihydrochloric acid salt which is recrystallized from a methyl alcoholether mixture to provide off-white prisms, mp 270°-273° C. (after darkening) of 1-(2-aminophenyl)-6-chlorospiro[indoline-3,4'-piperidine] dihydrochloride.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[CH3:10]>Cl.C(Cl)Cl>[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C@@H:6]1[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[OH:8])[CH3:10]
Reactant: CCOc1ccccc1O
Reactant: CCN1CC2OC2C1
Agent: Cl
Solvent: ClCCl
Product: CCOc1ccccc1O[C@@H]1CN(CC)C[C@H]1O

Procedure:
A mixture of 17.0 g. (0.15 mole) of 1-ethyl-3,4-epoxypyrrolidine, 22.1 g. (0.16 mole) of o-ethoxyphenol and 3 drops of concentrated hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and washed with three 50-ml. portions of 5% sodium hydroxide and one 50-ml. portion of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel to give 8.1 g. (21%) of an oil which crystallized on standing. The solid was recrystallized from cyclohexane to yield a tan solid, m.p. 73°-75° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:11]([O:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CC[C@H](CO)O1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CC[C@H](COCc2ccccc2)O1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-5-hydroxymethyl-dihydro-furan-2-one (5 g, 43.06 mmol) in tetrahydrofuran (130 mL) is added sodium hydride (2.58 g, 60% oil dispersion, 64.59 mmol) and tetrabutylammonium iodide (spatula) and stirred for 30 min. To the mixture is added benzyl bromide (6.18 mL, 51.67 mmol) and refluxed for 3 h. The mixture is cooled and diluted with ethyl acetate (150 mL), washed with a saturated solution of ammonium chloride (150 mL) and brine. The mixture is dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound, 8.87 g (100%), as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][CH2:11][CH2:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:19][CH:20]=O>CO>[C:2]1([C:1]2[CH:19]=[CH:20][N:9]3[C:8]=2[CH2:12][CH2:11][CH2:10]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCl
Reactant: c1ccc(CC2=NCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: c1ccc(-c2ccn3c2CCC3)cc1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
2-Benzyl-1-pyrroline (Example 1b, 85%, 74 g, 0.395 mol), dissolved in MeOH (360 ml), is treated with NaHCO3 (38 g, 0.45 mol), and the mixture is cooled to 5° C. A solution of chloroacetaldehyde (45% strength in water, 68 g, 0.4 mol), dissolved in MeOH (100 ml) is added dropwise to the solution at this temperature, and the mixture is stirred for 18 h with exclusion of light.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:7]=1[CH3:16])=[O:5].Br.[C:23](O)(=O)[CH3:24].[C:27](O)(=O)C>O>[CH:24]1([CH2:13][O:12][C:10]2[C:9]([O:14][CH3:15])=[CH:8][C:7]([CH3:16])=[C:6]([C:4](=[O:5])[C:3]3[C:2]([Cl:1])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:21])[CH:11]=2)[CH2:23][CH2:27]1
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OC
Reactant: CC(=O)O
Agent: Br
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OCC1CC1
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2,6-dichloro-4',5'-dimethoxy-2'-methylbenzophenone (Compound 1; 2.5 g, 7.7 mmol), hydrogen bromide/acetic acid (33%, 10 ml) and glacial acetic acid (10 ml) is stirred for 1.5 h at 75° C., poured into water (100 ml) and twice extracted with dichloromethane (50 ml each). The extracts are combined, dried, and concentrated in vacuo. The resulting oil is applied onto the top of a flash chromatography column (silica gel, 30 g). Elution is carried out with toluene and toluene/acetone, 9:1 (500 ml each). The fractions containing the material with an Rf =0.54 (silica gel; toluene/acetone, 9:1) are combined and the solvent is evaporated in vacuo until a final volume of 20 ml is reached. The solution is then extracted three times with aqueous sodium hydroxide (2N; 30 ml each). The aqueous layer is acidified with hydrochloric acid (6M) and the precipitate is collected by vacuum filtration and dried to give Compound 5 as colorless crystals, 1.1 g, (45.9% y) mp 152° C.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].C([O:8][C:9](=O)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]([F:24])[CH:13]=1)[CH3:11])C.C(O)(C)C>O1CCCC1>[F:24][C:14]1[CH:13]=[C:12]([CH:10]([CH3:11])[C:9](=[O:8])[CH2:4][C:3]#[N:5])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC#N
Reactant: CCOC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C(=O)CC#N)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 55 %

Procedure:
After 60% sodium hydride (6.5 g, 0.163 mmol) was suspended in tetrahydrofuran under nitrogen atmosphere, the mixture was refluxed for 0.5 h, then added dropwise acetonitrile (7.6 g, 0.185 mol) and ethyl-2-(2-fluoro-4-biphenylyl)-propionate described above in tetrahydrofuran (100 ml). After refluxed for 2 h, the mixture was cooled at room temperature and added isopropylalcohol. After stirring for a while, the mixture was evaporated under reduced pressure to a residue, which was made acid with 2N hydrochloric acid and extracted with chloroform. The extracts were washed with water, dried over, and evaporated under reduced pressure to a residue, which was chromatographed and recrystallized with ethanol to afford 4-(2-fluoro-4-biphenylyl)-3-oxo-pentanenitril (18.0 g, 55% yiled) as pale yellow crystalline material: mp 84°-85° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:17]([CH3:27])[C:16]=2[CH:28]=1.I[CH3:30]>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH2:21][CH:22]([CH3:30])[C:23]([O:25][CH3:26])=[O:24])[N:17]([CH3:27])[C:16]=2[CH:28]=1
Reactant: CI
Reactant: COC(=O)CCCc1nc2ccc(Br)cc2n1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CCc1nc2ccc(Br)cc2n1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.6 M in THF, 6.15 ml) was added to a solution of methyl 4-(6-bromo-1-methyl-1H-benzimidazol-2-yl)butanoate (1.02 g) in THF (20 ml) at −78° C. After being stirred at −78° C. for 30 min, iodomethane (0.612 ml) was added to the reaction mixture. The mixture was stirred at room temperature under Ar atmosphere for 2 h. The mixture was quenched with saturated NH4Cl solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 solution and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (440 mg) as a pale yellow solid.