Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=O)C.[Cl:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33](Cl)[CH:32]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[ClH:27].[OH:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Reactant: ClCCCc1ccnc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCCCc1ccncc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg, 1.06 mmol), (prepared as described for the starting material in Example 1), 4-(3-chloropropyl)pyridyl hydrochloride 410 mg, 2.1 mmol), potassium carbonate (438 mg) and potassium iodide (40 mg) in DMF (15ml) was heated at 60° C. for 15 hours. After cooling to ambient temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was diluted with methanol (20 ml) and 2M sodium hydroxide (2 ml) was added. After stirring for 1 hour, the reaction mixture was diluted with water (20 ml) and concentrated hydrochloric acid (1 ml) was added. The resulting solid was filtered off and was purified by preparative C18 HPLC using a gradient of methanol/water (0% to 80%) as eluant. After evaporation of the methanol, concentrated hydrochloric acid (0.3 ml) was added and the solution was evaporated to dryness. After trituration with acetone, the solid was filtered off and dried under vacuum to give 4-(3-hydroxy4-methylanilino)-6-methox-y-7-(4-pyridylpropoxy)quinazoline hydrochloride (305 mg, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1>[CH3:9][S:10]([NH:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:8]=[CH:7][CH:6]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(Br)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
The m-bromo aniline was dissolved in 40 mL of pyridine and cooled to 0° C. followed by addition of methansulfonyl chloride dropwise via syringe. After 10 minutes, the solution was warmed to room temperature and stirred for 4 hours. Upon concentration the residue was partitioned between 350 mL of H2O and 500 mL of dichloromethane in a separatory funnel. The organics were separated and washed with 100 mL of 3N HCl, 200 mL of sat'd NaHCO3 and dried over MgSO4. Upon filtration and concentration in vacuo an off-white solid was obtained. This product was recrystallized from dichloromethane/hexanes to afford 6.7 g (90%) of the desired product as white needles.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br.O>C(O)(=O)C>[Br:16][C:7]1[CH:6]=[CH:5][C:4]([O:8][CH3:9])=[CH:3][C:2]=1[CH:1]=[O:10]
Reactant: BrBr
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)c(C=O)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of m-anisaldehyde (25.2 g) and anhydrous sodium acetate (37.6 g) in acetic acid (150 ml) is added bromine (30.8 g) and the resulting solution stirred 45° C. overnight, then at room temperature for about 4 hours. The reaction mixture is poured into water (300 ml), stirred for 15 minutes, then filtered and the solid residue dissolved in toluene. The toluene solution is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is recrystallized from hexanes to give the desired product.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[CH:11]1[CH2:15][C:14](=O)[N:13]([CH3:17])[C:12]1=O.C(OCC)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[CH:11]1[CH2:15][CH2:14][N:13]([CH3:17])[CH2:12]1
Reactant: CN1C(=O)CC(C2C=Cc3ccccc3C2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN1CCC(C2C=Cc3ccccc3C2)C1

Procedure:
The 3-(1,2-dihydro-2-naphthalenyl)-1-methyl-2,5-pyrrolidinedione, 60 g, is taken up in dioxane and added dropwise to a suspension of 40 g of lithium aluminum anhydride (LAH) in 2 l. diethyl ether. After 5 hours at reflux, the mixture is decomposed with K2CO3 solution and filtered. Evaporation of the organic layer leaves 42.8 g of 3-(1,2-dihydro-2-naphthalenyl)-1-methylpyrrolidine which is distilled at 125°-150°/0.2 mm IR and NMR consistent, 28 g yield (54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzaldehyde (21 g, 69.8 mmol) in methanol (200 mL) was added slowly NaBH4 (2.64 g, 69.8 mmol) portionwise. The mixture was stirred at room temperature overnight. After removing the solvent, the residue diluted with DCM. The resulting suspension was filtered, the filtrate was concentrated in vacuo to afford the title compound (17.6 g, 55.2 mmol, 79% yield) as yellow solid. LCMS: rt=1.71 min, [M+H+]=303, 305
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[C:17]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14]=1[NH:26][C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30].CCOCC>ClCCl>[F:12][C:13]1[CH:18]=[C:17]([S:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:9])[CH:16]=[CH:15][C:14]=1[NH:26][C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:30])[F:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2)cc1F)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)c2ccccc2)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.3 %

Procedure:
m-Chloroperbenzoic acid (55%, 0.157 g) was added to a solution of (R)-N-[2-fluoro-4-(phenylthio)phenyl]2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 7) (0.212 g) in dichloromethane (5 ml) and the mixture was stirred at ambient temperature for 90 minutes. Ether (20 ml) was added and the solution was washed with saturated aqueous sodium carbonate solution (2×10 ml) and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 20-30% ethyl acetate/hexane to give the title compound (0.138 g) as a gum. NMR: 1.55 (s, 3H), 7.5-7.6 (m, 4H), 7.66 (d, 1H), 7.74 (m, 2H), 7.87 (t, 1H), 9.8 (br s, 1H); MS: 374 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:38][CH2:39][C:40]1[C:41]([OH:48])=[N:42][C:43]([CH3:47])=[CH:44][C:45]=1[CH3:46]>ClCCl>[OH:48][C:41]1[C:40]([CH2:39][NH:38][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:45]([CH3:46])[CH:44]=[C:43]([CH3:47])[N:42]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccn1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccn3)cc2)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 20.1 %

Procedure:
To a solution of 4-(1-(pyridin-2-yloxy)ethyl)benzoic acid (160 mg, 0.66 mmol), 1-hydroxybenzotriozole (135 mg, 1.0 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg, 1.0 mmol), triethylamine (0.3 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.66 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(pyridin-2-yloxy)ethyl)benzamide as a white solid (50 mg, 40%). LRMS (M+H+) m/z: 377.17. found 377. HPLC Purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.06-8.04 (m, 1H), 7.80-7.68 (m, 3H), 7.44-7.42 (m, 2H), 6.93-6.84 (m, 2H), 6.17 (q, J=6.6 Hz, 1H), 5.84 (s, 1H), 4.27 (d, J=4.8, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.55 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[Se:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)=[C:12]([F:23])[C:11]=1[F:24])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC(OC)(C)C.O.Cl>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[Se:20][C:19]([CH:21]=[CH2:1])=[CH:18][CH:17]=2)=[C:12]([F:23])[C:11]=1[F:24])[CH3:8]
Reactant: CCOc1ccc(-c2ccc(C=O)[se]2)c(F)c1F
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2ccc(OCC)c(F)c2F)[se]1
Reaction time: 1.5 h

Procedure:
3.0 g (8.4 mmol) of methyltriphenylphosphonium bromide are initially introduced in 50 ml of THF at 0° C., and 0.89 g (7.9 mmol) of potassium tertbutoxide is dissolved in 7 ml of THF is added. After 1.5 h at RT, 2.0 g (6.4 mmol) of 5-(4-ethoxy-2,3-difluorophenyl)selenophene-2-carbaldehyde are added, and the batch is stirred for 2.5 h. The mixture is diluted with MTBE, and water and 2 N hydrochloric acid are added. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=10:1→5:1). Further purification is carried out by recrystallisation from n-heptane; 2-(4-ethoxy-2,3-difluorophenyl)-5-vinylselenophene is obtained as a yellow-orange solid.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:38]([O:45][NH2:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>C1COCC1>[CH2:38]([O:45][N:46]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)CCC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reactant: NOCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=NOCc1ccccc1)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Yield: 51.9 %

Procedure:
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (1.0 g, 2.96 mmol) (Example 1) and carbonyldimidazole (0.51 g, 3.11 mmol) were stirred for 18 hours at room temperature under nitrogen. A slurry of O-Benzylhydroxylamine (0.57 g, 3.55 mmol) and triethylamine (0.49 mL, 3.55 mol) in THF (5 mL) was added in one portion and the resulting mixture refluxed for 18 hours, filtered, and washed with THF (50 mL). The filtrate was concentrated and columned on silica gel eluting with 50% ethyl acetate in hexanes to give 4-benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (0.68 g, %C,H,N found: 76.01, 6.89, 6.26).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:53])([CH3:52])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:47])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][C:30]([O:36]CC4C=CC(OC)=CC=4)=[C:31]([O:33][CH2:34][CH3:35])[CH:32]=3)=[CH:23][C:22]=2[F:46])=[CH:14][C:13]=1[C:48]([F:51])([F:50])[F:49])(C(C)(C)C)(C)C>Cl>[CH2:34]([O:33][C:31]1[C:30](=[O:36])[NH:29][CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][C:10]([CH3:52])([CH3:53])[CH2:9][OH:8])=[C:13]([C:48]([F:50])([F:51])[F:49])[CH:14]=3)=[O:47])=[C:22]([F:46])[CH:23]=2)[CH:32]=1)[CH3:35]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: Cl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(C)(C)CO)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A mixture of N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (3 g, 3.97 mmol) and HCl (4 mol/L in 1,4-dioxane, 20 mL) was stirred at 25° C. for 2 h. The mixture was concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) twice to give a white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (1528.59 mg, 2.94 mmol, 73.9% yield): 1H NMR (400 MHz, CD3OD) δ: 7.94 (d, J=2.0 Hz, 1H), 7.74-7.67 (m, 1H), 7.44-7.38 (m, 2H), 7.37-7.27 (m, 3H), 7.22 (d, J=2.0 Hz, 1H), 4.11 (q, J=6.8 Hz, 2H), 3.78 (s, 2H), 3.32-3.30 (m, 2H), 2.77 (s, 2H), 1.45 (t, J=6.8 Hz, 3H), 0.82 (s, 6H); ES-LCMS m/z 521 (M+1).
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[C:9](Cl)[N:8]=[C:7]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:6]=1>CO>[NH2:4][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[C:9]([O:2][CH3:1])[N:8]=[C:7]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:6]=1
Reactant: COc1ccccc1Oc1c(N)nc(-c2ncccn2)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(N)nc(-c2ncccn2)nc1OC

Procedure:
6.55 g of sodium methylate were added at room temperature to a solution of 4-amino-6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine in 200 ml of methanol and the solution was subsequently heated at reflux for 32 hours. The methanol was removed on a rotary evaporator, the residue was taken up in methylene chloride and washed with 1N hydrochloric acid. The organic phase was dried over magnesium sulphate, the solvent was finally removed in a water-jet vacuum. The crude product was chromatographed on silica gel with methylene chloride/ methanol (10/1) as the eluent. 4-Amino-6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine was obtained as a lemon-yellow powder MS: 325 (M).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[Cl:51])=[C:41]([S:52]([CH3:55])(=[O:54])=[O:53])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[Cl:51])=[C:41]([S:52]([CH3:55])(=[O:53])=[O:54])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1Cl
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(-c2ccccc2Cl)c(S(C)(=O)=O)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-2′-chloro-2-(methylsulfonyl)biphenyl (Intermediate 215), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>CO.ClCCl.[Pd]>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(C2=CCCC2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
1-(1-Cyclopentenyl)-4-nitro-benzene (225 mg, 1.19 mmol) in methanol (10 mL) and dichloromethane (2.5 mL) was treated with 10% Pd/C (70 mg) and stirred under H2 atmosphere for 1 h at room temperature. The reaction was filtered and concentrated in vacuo to provide 4-cyclopentylaniline (180 mg, 94% yield). 1H NMR (400.0 MHz, MeOD) δ 7.01 (d, J=8.2 Hz, 2H), 6.73-6.70 (m, 2H), 2.88 (dd, J=2.3, 17.3 Hz, 1H), 2.00-1.95 (m, 2H), 1.80-1.75 (m, 2H), 1.70-1.64 (m, 2H), 1.56-1.49 (m, 2H).
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22](=[O:27])C(Cl)(Cl)Cl)=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[CH:3][CH:2]=1.CS(C)=O.[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>C(#N)C>[C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:38][CH2:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:27])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[CH:5][CH:6]=1
Reactant: O=C(c1ccc2n1Cc1ccccc1N(Cc1ccc(-c3ccccc3)cc1)C2)C(Cl)(Cl)Cl
Reactant: NCc1cccnc1
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(Cc1ccc(-c3ccccc3)cc1)C2
Yield: 12 %

Procedure:
To a solution of 10-(1,1′-biphenyl-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (0.93 g, 2.65 mmol) and N,N-dimethylaniline (0.51 mL, 3.98 mmol) in dry dichloromethane (30 mL) at 0° C. under nitrogen was added dropwise trichloroacetyl chloride (0.33 mL, 2.92 mmol). The ice bath was removed and the reaction mixture stirred at room temperature for 19 hours. The reaction mixture was then quenched by the addition of 2 M sodium hydroxide (30 mL) then partitioned between additional dichloromethane (75 mL) and 2 M sodium hydroxide (75 mL). The separated organic phase was washed with 2 M sodium hydroxide (75 mL) and water (75 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow syrup (2.12 g). Purification by flash chromatography using a solvent gradient of 1-5% ethyl acetate in hexane afforded 1-{10-[(1,1′-biphenyl)-4-ylmethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}-2,2,2-trichloroethanone (0.88 g, 67%) as a cream foam. To a solution of 1-{10-[(1,1′-biphenyl)-4-ylmethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}-2,2,2-trichloroethanone (0.4 g, 0.807 mmol) and dimethyl sulfoxide (0.29 mL, 4.034 mmol) in dry acetonitrile (5 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (0.17 mL, 1.613 mmol) and the reaction mixture was heated to reflux for 2 days. The cooled mixture was concentrated in vacuo, the semi-solid residue dissolved in ethyl acetate (50 mL), filtered and concentrated in vacuo to afford a dark brown syrup. Purification by flash chromatography using a solvent gradient of 0.5 to 3% methanol in dichloromethane afforded an orange semi-solid that was crystallized from dichloromethane/hexane to give the title compound (0.047 g, 12%) as a cream solid, m.p. 161-165° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[F:31][C:32]([F:46])([F:45])[C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:36][C:35]2[CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=[C:33]([C:32]([F:31])([F:45])[F:46])[CH:34]=2)[CH:6]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.50 g, 0.0012 mol) in DMF (10 mL), was added 3,5-bis (trifluoromethyl)-benzyl bromide (0.50 g, 0.0016 mol) and powdered potassium carbonate (1.55 g, 0.011 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.57 g in 77% yield. 1H NMR (CDCl3) δ 7.61 (s, 1H), 7.50 (s, 2H), 7.24 (m, 12H), 6.83 (d, 1H), 6.62 (s, 1H), 6.59 (dd 1H), 4.19 (t, 1H), 3.68 (s, 2H), 3.67 (s, 3H), 3.60 (t, 2H), 3.56 (d, 2H), 3.14 (d, 2H), 2.64 (t, 2H), 1.83 (t, 2H); 13C NMR (CDCl3) δ 173.3, 160.3, 144.3, 136.7, 132.8, 130.9, 130.1, 129.9, 129.7, 129.5, 128.0, 125.9, 123.7, 122.9, 122.3, 116.2, 114.5, 114.4, 66.6, 61.1, 59.7, 53.4, 52.1, 51.3, 42.6, 28.1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:10])[CH3:9])[C:4](=O)[CH:3]1[CH2:12][CH2:13][C:14](=O)[CH3:15].Cl.[NH2:18]O>C(O)C>[CH3:15][C:14]1[CH:13]=[CH:12][C:3]2[CH:2]([CH3:1])[CH2:7][CH2:6][CH:5]([CH:8]([CH3:10])[CH3:9])[C:4]=2[N:18]=1
Reactant: NO
Reactant: CC(=O)CCC1C(=O)C(C(C)C)CCC1C
Agent: Cl
Solvent: CCO
Product: Cc1ccc2c(n1)C(C(C)C)CCC2C
Temperature: 150 °C

Procedure:
2 g of 1-methyl-4-isopropyl-2-(3'-oxobutyl)-cyclohexan-3-one, 1.2 g of hydroxylamine hydrochloride and 100 ml of ethanol are added to a 250 ml autoclave. The autoclave is heated at 150°C for 5 hours. Thereupon, the ethanol is distilled off and the residue taken up in 40 ml of 20% potassium hydroxide solution. The mixture is extracted with diethyl ether, the extract dried over sodium sulphate and the ether subsequently distilled off. The residue is purified over a silica gel column (0.05 to 0.2 mm particles) using CHCl3 as the eluant. On distillation, there is obtained 2,5-dimethyl-8-isopropyl-5,6,7,8-tetrahydroquinoline (formula IV) with a boiling point of 70°-72°C/0.4 mm Hg.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:17]2[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=2[N:15]=1>ClC(Cl)Cl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:18]2[C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[N:15]=[C:14]2[NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 120 °C
Reaction time: 43 h
Yield: 40.5 %

Procedure:
A mixture of 9.8 parts of ethyl 4-amino-1-piperidinecarboxylate and 15 parts of 2-chloro-1-(4-fluorophenylmethyl)-1H-benzimidazole was heated to 120° C. The mixture was stirred at 120° C. during 43 hours. After cooling, 100 parts of trichloromethane were added and the whole was thouroughly stirred. The mixture was washed with water. The aqueous layer was separated and the organic mixture was filtered and evaporated. The collected solid material was dissolved in 100 parts of water and subsequently 100 parts of 20% sodium hydroxide solution were added. The precipitate was filtered and dried in vacuo at 50° C., yielding 12.1 parts (40.5%) of ethyl 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 181° C. (compound 21).