Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(ON=O)CC(C)C.I[CH2:10][I:11].[NH2:12][C:13]1[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:16]([CH2:22][CH2:23][CH3:24])=[N:15][C:14]=1C#N>C(Cl)(Cl)Cl>[I:11][C:10]1[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:16]([CH2:22][CH2:23][CH3:24])=[N:15][C:14]=1[C:13]#[N:12]
Reactant: ICI
Reactant: CCCc1nc(C#N)c(N)n1CC(C)C
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCCc1nc(C#N)c(I)n1CC(C)C
Temperature: 25 °C
Yield: 51.3 %

Procedure:
A solution of isoamylnitrite (106.3 g, 0.908 mol) and diiodomethane (1.296 kg, 4.84 mol) in chloroform (500 mL) was heated at 70° C. under a nitrogen atmosphere. A solution of 5-amino-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile (50.0 g, 0.242 mol) in chloroform (500 mL) was heated to 70° C. was added over a period of 30 minutes while maintaining the reaction temperature at 68° C. to 70° C. during the addition. The reaction was heated for an additional 10 minutes, allowed to cool to room temperature, and concentrated under reduced pressure at 75° C. The residue was purified by column chromatography on silica gel (eluting sequentially with dichloromethane, 1% methanol in dichloromethane, 2% methanol in dichloromethane, and 3% methanol in dichloromethane) to provide 39.4 g (51.3%) of 5-iodo-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile as a tan oil that solidified upon standing.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:10]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Salicylaldehyde (50 mmoles) was dissolved in dry dimethylformamide (DMF) (100 ml) at room temperature. Benzyl bromide (75 mmoles) was then added followed by the potassium carbonate (125 mmoles) and the mixture stirred at room temperature for 48 h. The mixture is then filtered to remove the potassium carbonate and the filtrate is mixed with ethyl acetate. The organic phase is washed with water (3×200 ml), brine and dried over MgSO4. The solution is then filtered and evaporated in vacuo to provide the crude material. Solid products are washed with ethyl ether to provide the clean desired product or in the case of aldehydes which are oils, they are purified by silica gel chromatography.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].[CH3:16][O-:17].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[S:6][C:7]=1[O:17][CH3:16])#[N:2]
Reactant: COC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C#N)c(OC)s1
Yield: 73 %

Procedure:
Methyl 4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (2 g, 8 mmol) was refluxed with 0.5 M sodium methoxide in methanol (16 mL) for 15 minutes. The solution was cooled, the crystallized solid collected on a Buchner funnel and washed with methanol (50 mL) to give methyl 4-cyano-5-methoxythiophene-2-carboxylate (1.145 g, 73%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.87 (s, 1H) 4.19 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].Br[C:23]1[C:28]([C:29]2([OH:33])[CH2:32][CH2:31][CH2:30]2)=[CH:27][CH:26]=[CH:25][N:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[C:28]([C:29]4([OH:33])[CH2:32][CH2:31][CH2:30]4)=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: OC1(c2cccnc2Br)CCC1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ncccc1C1(O)CCC1
Yield: 46.1 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (340 mg, 1.1 mmol) and 1-(2-bromopyridin-3-yl)cyclobutanol (228 mg, 1.0 mmol) according to the method of Example 6 Step 4. Purification by flash column chromatography eluting with a 0-10% diethyl ether/dichloromethane gradient gave 1-(2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}pyridin-3-yl)cyclobutanol (200 mg, 46%). 1H NMR (500 MHz, CDCl3) δ 8.61 (1H, s), 8.29 (1H, d, J=2.2 Hz), 8.10-8.04 (2H, m), 8.01 (1H, d, J=8.7 Hz), 7.95 (1H, dd, J=1.6, 8.6 Hz), 7.88-7.81 (2H, m), 7.73-7.64 (2H, m), 7.40 (1H, dd, J=4.5, 7.8 Hz), 7.23-7.15 (2H, m), 5.01 (1H, s), 2.78-2.68 (4H, m), 2.42-2.34 (1H, m), 1.86-1.78 (1H, m); m/z (ES+) 434 [MH+].
Reaction SMILES: ClCCl.[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:13][Si:14](Cl)([CH3:16])[CH3:15].[Na+].[Cl-]>C(N(CC)CC)C>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: OCc1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
300 ml of dichloromethane followed by 60 g of triethylamine are added to 30 g of 4-hydroxymethyl-phenol introduced into a 500 ml flask maintained under a hydrogen atmosphere. The temperature of the obtained solution is brought to 10° C. and 64 g of trimethylsilyl chloride are added thereto in about one hour, keeping the temperature at 10° C. Thus, the temperature is left to spontaneously rise to 25° C., maintaining such conditions for one hour. Then, the reaction of the substrate is controlled under TLC. Upon ascertaining the disappearance of the initial product, 200 ml of an aqueous saturated NaCl solution are added and the two-phase system is stirred vigorously for 10′ and then the two phases are decanted. The lower organic phase is washed with two 200 ml portions of deionised water and then concentrated to residue, obtaining a yellowish oil. Such residue is recovered using 500 ml of DMF in a 2-liter flask and a solution constituted by 3 g of Lithium acetate in 60 ml of water is added to the obtained solution. The mixture is maintained at 25° C. for one hour, then the removal of the trimethylsilyl group on the phenolic hydroxyl is controlled under TLC. Then, 650 ml of a saturated NaCl solution and 455 ml of toluene are added to the reaction mixture and the mixture is stirred vigorously for 10′, then the two phases are left to decant. The upper organic phase is then washed with two 650 ml portions of deionised water and concentrated under vacuum, obtaining 33 g of the desired product (70% yield).
Reaction SMILES: B(Br)(Br)[Br:2].[F:5][C:6]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:7]=1[CH2:8]O>>[F:5][C:6]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:7]=1[CH2:8][Br:2]
Reactant: BrB(Br)Br
Reactant: Cc1ccc(F)c(CO)c1
Product: Cc1ccc(F)c(CBr)c1
Temperature: 7.5 °C

Procedure:
An oven dried round bottom flask is charged with boron tribromide (13 mL, 140 mmol) and is cooled to −30-45° C. 2-Fluoro-5-methyl-benzyl alcohol (6.5 g, 46 mmol) is then added slowly after which time the reaction is allowed to warm to room temperature.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCN1CCNCC1
Reaction time: 24 h
Yield: 88 %

Procedure:
A mixture of benzyl 4-(2-(tert-butyldimethylsilyloxy)ethyl)piperazine-1-carboxylate (Method 90, 2.1 g, 5.55 mmol) and Pd/C (0.059 g, 0.55 mmol) in methanol (30 mL) was stirred under H2 (g) for 24 hours. The reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure to give 1.20 g, (88%) of a yellow oil. 1H NMR: CD3Cl 3.74 (t, 2H), 2.90 (m, 4H), 2.51 (m, 6H), 0.88 (s, 9H), 0.04 (s, 6H).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]2[C:30](Cl)=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:32])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1(B(O)O)[CH2:35][CH2:34]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]2[C:30]([CH:33]3[CH2:35][CH2:34]3)=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:32])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: O=C(O)c1cc(Cl)c(OCC2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(C2CC2)c(OCC2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-chloro-2-fluorobenzoic acid (480 mg, 0.94 mmol), cyclopropylboronic acid (162 mg, 1.88 mmol), potassium phosphate (797 mg, 3.67 mmol), palladium acetate (21 mg, 0.047 mmol) and tricyclohexylphosphine tetrafluoroborate (36 mg, 0.094 mmol) in toluene (10 mL) and water (0.5 mL) was stirred under a nitrogen atmosphere at 100° C. for 18 h. The reaction mixture was cooled down, quenched with water (50 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford product (320 mg, 46%, crude) as oil which was used in the next step without further purification. LCMS (ESI) m/z: 458.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:13]CCCO2)[CH:5]=[CH:6][CH:7]=1.[CH3:14][CH:15]1[O:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1.CC([O-])(C)C.[Na+].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][CH:19]1[CH2:18][N:17]([C:2]2[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=2)[CH:8]=[O:13])[CH2:16][CH:15]([CH3:14])[O:20]1
Reactant: Brc1cccc(C2OCCCO2)c1
Reactant: CC1CNCC(C)O1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1CN(c2cccc(C=O)c2)CC(C)O1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A mixture containing 2-(3-bromophenyl)-1,3-dioxane (136; 2.0 g, 8.23 mmol), 2,6-dimethylmorpholine (122; 1.14 g, 9.88 mmol), Pd2(dba)3 (50 mg), NaOt-Bu (1.39 g, 14.0 mmol) and BINAP (100 mg) in 20 mL of toluene was stirred at reflux for 5 h. Upon cooling to room temperature, enough cold 1N HCl (50 mL) was added to adjust the pH The resulting reaction mixture was stirred at room temperature for 1 h. NaOH(aq) was added to adjust the pH=11. The aqueous mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Purification by chromatography (petroleum ether:EtOAc=10:1) afforded 3-(2,6-dimethylmorpholino)benzaldehyde 137 as a yellow oil (1.36 g, yield: 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:13]([C:11]2[C:10]([CH3:16])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)=[O:15])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])#[N:24]
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)O
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.2 g), 5-amino-2-neopentyloxybenzonitrile (1.3 g), triethylamine (1.7 g) and diethyl cyanophosphate (1.3 g) were added to dimethylformamide (10 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (0.4 g), melting point: 181–182° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:31])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27]C(=O)C)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.[OH-].[Na+]>Cl>[NH2:27][CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:31])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NC(C)=O)CC4)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N)CC4)cc3)nc2c1
Yield: 95.8 %

Procedure:
A mixture of N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)acetamide (0.250 g, 0.59 mmol) and 2 M HCl (20 mL) was heated at reflux for 24 hours. The mixture was basified with 2 M NaOH to pH 8, extracted with CH2Cl2 (3×150 mL), dried over anhydrous MgSO4, filtered, and concentrated to afford 2-(4-(4-aminopiperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one as a yellow solid (0.215 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][NH2:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH2:15]([O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH:20]=O)[CH3:16]>>[Cl:1][CH:2]1[CH2:3][CH:20]([C:19]2[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:18]=2[O:17][CH2:15][CH3:16])[N:14]([CH2:13][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:8]
Reactant: CCOc1cccc(F)c1C=O
Reactant: NCc1ccc(OC(F)(F)F)c(Cl)c1
Product: CCOc1cccc(F)c1C1CC(Cl)C(=O)N1Cc1ccc(OC(F)(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B), 10F (GP10F), and 10D (GP10D) using commercially available (3-chloro-4-(trifluoromethoxy)phenyl)methanamine and synthesized 2-ethoxy-6-fluorobenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.00 min.; [M+H]+: 465.77 g/mol.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[C:22]12[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:27]C(=O)O[C:23]2=[O:24].C(Cl)(Cl)Cl>ClCCl>[NH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=1[C:23]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1)=[O:24]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1ccccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 1 h

Procedure:
A solution of 4-aminomethyl-1-diphenylmethylpiperidine (2.5 g, 9.15 mmol) in dichloromethane (10 ml) was added to a suspension of isatoic anhydride (1.0 g, 6.1 mmol) in dichloromethane (25 ml) at room temperature. The reaction mixture was stirred for 1 hour and then poured into chloroform and washed with 5% NaHCO3 solution. The organic layer was concentrated. The residue was dissolved in dichloromethane (25 ml) and poured into hexane (400 ml) to give 2-amino-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide as precipitate (100%): mp 153°-154° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:10](C(=O)C(F)(F)F)[CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>C(O)CCC>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:10][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C(CC(C)C)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CC(=O)c1ccc2c(c1)CNC(CC(C)C)C2
Yield: 84.9 %

Procedure:
To 40 mg of 7-acetyl-3-isobutyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline were added 1 mL of 3 N hydrochloric acid and 0.5 mL of n-butanol, followed by reflux overnight. After completion of the reaction, to the reaction liquid was added an aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed by evaporation to obtain 24 mg (yield 85%) of a title compound as a yellow oily substance.
Reaction SMILES: C1(=O)NC(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[CH:40]=[C:39]2[C:35]([C:36]([C:61]#[N:62])=[C:37]([C:42]3[CH:43]=[N:44][CH:45]=[C:46]([CH:48]([N:50]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:49])[CH:47]=3)[N:38]2[CH3:41])=[CH:34][CH:33]=1.P.O.NN.Cl>C1COCC1.C(OCC)(=O)C.C(O)C>[NH2:50][CH:48]([C:46]1[CH:47]=[C:42]([C:37]2[N:38]([CH3:41])[C:39]3[C:35]([C:36]=2[C:61]#[N:62])=[CH:34][CH:33]=[C:32]([Cl:31])[CH:40]=3)[CH:43]=[N:44][CH:45]=1)[CH3:49]
Reactant: CC(c1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(N)c1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ammonium acetate (0.567 g, 7.207 mmol) is added to a solution of 2-(5-acetyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (0.470 g, 1.441 mmol) in MeOH (10 mL), and the reaction is stirred at 50° C. for 48 h. Sodium triacetoxyborohydride (2.251 g, 10.09 mmol) is added and the reaction is stirred for 24 h at 50° C. Additional sodium triacetoxyborohydride (2.251 g, 10.09 mmol) is added and the reaction is stirred for another 24 h at 50° C. It is then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 6-chloro-2-[5-(1-hydroxy-ethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile and minor amounts of 2-[5-(1-amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile. The mixture is redissolved in THF (5 mL) and phthalimide (0.181 g, 1.206 mmol) and triphenylphosphine (0.172 g, 0.804 mmol) are added, followed with di-isopropylazodicarboxylate (0.157 mL, 0.804 mmol). The reaction is stirred at room temperature for 4 h. It is then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo, to give a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to afford a mixture of 6-chloro-2-{5-[1-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-pyridin-3-yl}-1-methyl-1H-indole-3-carbonitrile and triphehyl phosphine. The mixture is redissolved in ethanol (5 mL). Hydrazine hydrate (65%) (0.411 mL, 8.506 mmol) is added and the reaction is stirred at room temperature overnight. It is then acidified with 2M aqueous HCl and concentrated in vacuo. The residue is redissolved in dichloromethane and filtered through celite to remove the precipitate formed. The organic layer is washed with water. The aqueous layer is separated and basified to with 4M aqueous NaOH, and then extracted with dichloromethane thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford 2-[5-(1-amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile as a solid. MS (ESI) m/z 311.1 (M+H)+
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:32]5[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]5)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCNCC1
Reactant: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)Cl)cc3)nc21
Product: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)N4CCC(O)CC4)cc3)nc21
Yield: 62 %

Procedure:
The same reaction procedure as in Example 49 was performed, except that the compound obtained in Example 181 was used in place of the compound obtained in Example 48, and 4-hydroxypiperidine was used in place of N-methylpiperazine. In this manner, 72 mg (62%) of the captioned compound was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:9](=[O:17])[NH:8][C:7]1=[O:18].Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:31](=[CH:32][CH:33]=1)[C:26]1([CH2:30][CH2:29][NH:28][CH2:27]1)[CH2:25][CH2:24]2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN1C(=O)CCC1>[ClH:1].[Cl:20][C:21]1[CH:22]=[C:23]2[C:31](=[CH:32][CH:33]=1)[C:26]1([CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[CH:11]=[C:10]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[C:9](=[O:17])[NH:8][C:7]3=[O:18])[CH2:27]1)[CH2:25][CH2:24]2
Reactant: O=c1[nH]c(=O)n(CCCCCl)cc1-c1cccs1
Reactant: Clc1ccc2c(c1)CCC21CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]c(=O)n(CCCCN2CCC3(CCc4cc(Cl)ccc43)C2)cc1-c1cccs1
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A mixture of 1-(4-chlorobutyl)-5-(thiophen-2-yl)pyrimidine-2,4(1H,3H)-dione (Prep23, 50 mg, 0.18 mmol), 5-chloro-2,3-dihydrospiro[indene-1,3′-pyrrolidine]hydrochloride (Prep10, 66 mg, 0.27 mmol), potassium carbonate (112 mg, 0.81 mmol), sodium iodide (108 mg, 0.72 mmol) and NMP (1 ml) was stirred at 70° C. overnight. Then it was cooled down to room temperature and diluted with water and extracted with ethyl acetate. The EA phase was evaporated and the crude purified by preparative TLC (TLC analysis performed by eluting with EA) to give the free base of the title compound (72 mg). The compound was purified by preparative HPLC and treated with a 1N solution of HCl-ether and freeze-dried give the title compound (51 mg, y=58%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.C(OC([NH:37][C:38]1[CH:39]=[C:40]([CH3:59])[C:41]([N:44](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:42][CH:43]=1)=O)(C)(C)C>>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][NH:44][C:41]3[C:40]([CH3:59])=[CH:39][C:38]([NH2:37])=[CH:43][N:42]=3)[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Product: Cc1cc(N)cnc1NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
The title compound was synthesized by procedure analogous to Step 2 of Example 11 from 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from Step 1 of Example 5 and di-tert-butyl {5-[(tert-butoxycarbonyl)amino]-3-methylpyridin-2-yl}imidodicarbonate from Step 2 of this example.