Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@@H:19]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH2:20][CH2:21][O:22]CC2C=CC=CC=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[ClH:35]>CO.[Pd]>[ClH:35].[OH:22][CH2:21][CH2:20][C@@H:19]([N:14]1[C:15](=[O:18])[CH2:16][CH2:17][NH:11][CH2:12][CH2:13]1)[C:30]([N:31]([CH3:33])[CH3:32])=[O:34]
Reactant: CN(C)C(=O)[C@@H](CCOCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)[C@@H](CCO)N1CCNCCC1=O
Reaction time: 16 h
Yield: 99 %

Procedure:
A solution of 1.85 g (4.00 mmol) 4-((R)-3-benzyloxy-1-dimethylcarbamoyl-propyl)-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester in 57 ml of methanol was treated with a solution of 3.96 ml of 1 M aq. hydrochloric acid solution and 0.20 g of Pd/C (10%) and was stirred over H2-atmosphere for 16 h. After filtration, the solution was evaporated, dissolved in methanol and evaporated (3×), followed with dichloromethane and evaporated (3×) under reduced pressure to yield 1.10 g (99%) of the titled compound as a white foam. MS: 244.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:24][O-:25].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:24])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCNc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Reaction time: 4 h
Yield: 44 %

Procedure:
6-Amino-9-benzyl-8-bromo-2-(2-methoxyethyl)aminopurine (68 mg, 0.18 mmol) was dissolved in 28% sodium methoxide in methanol (30 ml) and the solution was refluxed on heating under stirring for 4 hours. The reaction mixture was concentrated in vacuo to dryness and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (26 mg, yield 44%).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)(C)C>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([OH:16])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: OC1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
5H-Dibenzo[a,d]cyclohepten-5-one (10 g) is dissolved in 80 ml of isopropyl alcohol and sodium borohydride (1.8 g) is added at once. The mixture is stirred at room temperature for two hr. 5 ml of water are added to quench the reaction and the solvent is evaporated. The residue is taken up in diethyl ether and washed with water, dried over MgSO4 and evaporated. 9.8 g (98% yield) of 5H-dibenzo-[a,d]-cyclohepten-5-ol is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CC(C)=O.C(=O)=O.[Li]CCCC.[C:22]([N:26]1[C:30]([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]([CH:38]2[CH2:41][C:40](=[O:42])[CH2:39]2)=[N:27]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([N:26]1[C:30]([NH:31][C:32](=[O:37])[C:33]([F:36])([F:34])[F:35])=[CH:29][C:28]([CH:38]2[CH2:41][C:40]([C:2]3[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=3)([OH:42])[CH2:39]2)=[N:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)n1nc(C2CC(=O)C2)cc1NC(=O)C(F)(F)F
Reactant: N#Cc1cccc(Br)c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(C2CC(O)(c3cccc(C#N)c3)C2)cc1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
To a stirring solution of 3-bromobenzonitrile (12.6 g, 69.0 mmol) in 245 mL of THF at −78° C. (acetone/CO2 bath) was added a solution of n-BuLi (27.6 ml, 69 mmol, 2.5 M in hexanes). After 15 min, a solution of N-[2-tert-butyl-5-(3-oxo-cyclobutyl)-2H-pyrazol-3-yl]-2,2,2-trifluoro-acetamide (4.0 g, 11.5 mmol in 200 mL of THF) was added. After one hr, the reaction mixture was quenched cold by the addition of a saturated NH4Cl solution, and was then allowed to warm to room temperature. The reaction mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure. Purification of this material was accomplished by MPLC using a Biotage® column, eluting with 25% EtOAc/hexanes. The product-containing fractions were collected and concentrated to yield the title compound (4.6 g, 98% yield). LRMS m/z (APCI+) 407 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].Br[CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>>[C:6]([C:5]1([C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH2:12][CH2:11][CH2:10]1)#[N:7]
Reactant: BrCCCBr
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C1(C#N)CCC1

Procedure:
The method described in Part A of Example 64 was used to treat ethylcyanoacetate (45 mL, 420 mmol) with 1,3-dibromopropane (51 mL, 510 mmol) and potassium carbonate (146 g, 1.06 mol) to provide ethyl 1-cyanocyclobutanecarboxylate as an orange oil containing about 15 mole % 1,2-dibromopropane.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]2[C@@H:21]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C:32]4=[O:37])=[CH:27][CH:26]=3)=[O:23])[CH2:20]S[CH2:18]2)=[O:16])=[CH:10][CH:9]=1>O.CO>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]2[C@@H:21]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C:32]4=[O:37])=[CH:27][CH:26]=3)=[O:23])[CH2:20][S:3](=[O:5])(=[O:2])[CH2:18]2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=S([O-])OO
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CSCN1C(=O)Nc1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CS(=O)(=O)CN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.1 A solution of 4.54 g (54.0 mmol) of sodium hydrogencarbonate and 3.60 g (27.0 mmol) of 2-(S)-thiazolidine-4-carboxylic acid in 50 ml of water is heated to 80° C., and 8.46 g (54.0 mmol) of 4-chlorophenyl isocyanate are added. The reaction mixture is stirred at this temperature for 1 hour. The mixture is allowed to cool, and the precipitate formed is filtered off. The filtrate is acidified using 1N HCl, and the precipitate formed is filtered off and dried, giving (S)-3-(4-chlorophenylcarbamoyl)thiazolidine-4-carboxylic acid as a colourless solid; ESI 287. 3.2 498 mg (2.60 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) are added to a solution of 573 mg (2.00 mmol) of (S)-3-(4-chlorophenylcarbamoyl)thiazolidine-4-carboxylic acid and 384 mg (2.00 mmol) of 4-(4-aminophenyl)morpholin-3-one in 4 ml of dimethylformamide (DMF), and the mixture is stirred at room temperature for 18 hours. The reaction mixture is added to saturated sodium hydrogencarbonate solution, and the precipitate formed is filtered off, giving 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(S)-thiazolidine-3,4-dicarboxamide (“A3”) as a colourless solid; ESI 461. 3.3 A solution of 1.9 g of oxone in 30 ml of water is added to a suspension of 450 mg (0.976 mmol) of “A3” in 50 ml of methanol, and the reaction mixture is stirred at room temperature for 24 hours. The reaction mixture is added to water, and the precipitate formed is filtered off and dried, giving 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(S)-1,1-dioxo-1λ6-thiazolidine-3,4-dicarboxamide (“A4”) as a colourless solid; ESI 493.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[I-].C([N+]1(C)[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)C1C=CC=CC=1>C(O)C.O>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([N:1]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[CH:3][CH:4]=1
Reactant: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Reactant: COc1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N2CCC(=O)CC2)cn1
Reaction time: 0.75 h
Yield: 74 %

Procedure:
To a solution of 5-amino-2-methoxypyridine (375 mg, 3.02 mmol) and K2CO3 (49 mg, 0.355 mmol) in ethanol (7 mL) at 80° C. was added a slurry of 1-benzyl-1-methyl-4-oxopiperidinium iodide in water (5 mL) over a 10 minute period. After 45 minutes, the reaction mixture was cooled and partitioned between dichloromethane (10 mL) and water. The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (1:1 Hexanes:EtOAc) to afford 1-(6-methoxypyridin-3-yl)piperidin-4-one (459 mg, 74%) as a light orange solid. 1H NMR (CDCl3) δ: 2.56 (t, J=5.7 Hz, 4H), 3.42 (t, J=5.7 Hz, 4H), 3.87 (s, 3H), 6.69 (d, J=9.3 Hz, 1H), 7.32 (dd, J=9.0, 3.0 Hz, 1H), 7.85 (d, J=3.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[S:19][C:18]([NH:20][C:21](=[O:30])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:17][C:16]=1C(OC)=O)[CH:2]=[CH2:3].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][C:6]=1[C:15]1[S:19][C:18]([NH:20][C:21](=[O:30])[C:22]2[C:23]([F:29])=[CH:24][CH:25]=[CH:26][C:27]=2[F:28])=[N:17][CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(F)(F)F)cc1-c1sc(NC(=O)c2c(F)cccc2F)nc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOc1ccc(C(F)(F)F)cc1-c1cnc(NC(=O)c2c(F)cccc2F)s1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
Into a solution of Compound 63 (30 mg, 0.06 mmol) in 2 mL MeOH was added NaOH (50 mg). The solution was heated to reflux for 30 minutes. After cooling to room temperature, the solvent was removed, and the residue was dissolved in 4 mL of DMF and 1 mL of water. The mixture was heated to 150° C. for 16 hours. The mixture was diluted with 20 mL of Et2O and the solution was washed with brine, dried and concentrated. The residue was purified on silica (eluted with 10-50% of ethyl acetate in hexanes) to give Compound 65 (7.9 mg, 30%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([O:14][CH3:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[OH-].[Na+]>O.CO>[CH3:15][O:14][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[C:3]([OH:16])=[O:2]
Reactant: COC(=O)C(OC)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(C(=O)O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 96.9 %

Procedure:
A mixture of (RS)-methoxy-(3-nitro-phenyl)-acetic acid methyl ester (1.039 g) and NaOH (0.239 g) in water (0.75 ml) and methanol (10 ml) was stirred at 0° C. for 4.5 h. The reaction mixture was then concentrated (rotavapor, high vac.) and the residue (light yellow solid) was taken in water (25 ml). The resulting solution was acidified to pH˜1 by dropwise addition of 3.0 N HCl. This was extracted with EtOAc (50 ml+25 ml). The combined organics were dried (MgSO4), filtered and concentrated (rotavapor) to leave the crude (RS)-methoxy-(3-nitro-phenyl)-acetic acid (0.944 g) as a light yellow solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.C(Cl)(Cl)Cl.NC1C=C(OC2C=CC(C(O)C)=CC=2)C=CC=1N>C(O)C.O=[Mn]=O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(O)c1ccc(Oc2ccc3[nH]cnc3c2)cc1
Agent: O=[Mn]=O
Agent: CC(O)c1ccc(Oc2ccc(N)c(N)c2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(=O)c1ccc(Oc2ccc3[nH]cnc3c2)cc1

Procedure:
Crude 1-[4-(1H-benzimidazol-5-yloxy)phenyl]ethanol was dissolved in 75 mL of 1:1 ethanol:chloroform and stirred with MnO2 (1.4 g, 10 equivalents based on step 2 starting material) at 80 degrees Centigrade for approximately 18 hours. A second 1.4 g of MnO2 was added and the reaction was heated for an additional 24 hours. A third 1.4 g of MnO2 was added and the reaction was heated for an additional 24 hours. The reaction was filtered through celite and concentrated onto basic alumina. The crude product was purified by silica gel column chromatography to give 1-[4-(1H-benzimidazol-5-yloxy)phenyl]ethanone and an impurity that was carried forward to the next step. (M+1) 253.0, 1.41 min (LC/MS method B).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH3:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[CH3:9])=[CH:4][CH:3]=1
Reactant: Oc1ccccn1
Reactant: CC(Br)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(c1ccc(Br)cc1)n1ccccc1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.2 %

Procedure:
To a solution of 1-bromo-4-(1-bromoethyl)benzene (200 mg, 0.76 mmol) and pyridin-2-ol (87 mg, 0.91 mmol) in N,N-dimethylformamide (30 mL) was added cesium carbonate (496 mg, 1.52 mmol). The mixture was stirred at room temperature for 12 hours. And then solvent was removed to give a residue. The residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:10) to give 1-(1-(4-bromophenyl)ethyl)pyridin-2(1H)-one (161 mg, 76%) LRMS (M+H+) m/z: calcd 277.0. found 277.
Reaction SMILES: [C:1]([C:5]1([C:28]([NH2:30])=[O:29])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][N:6]1C(OCC1C=CC=CC=1)=O)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:4])([CH3:3])[CH3:2]>Br.C(O)(=O)C>[C:1]([C:5]1([C:28]([NH2:30])=[O:29])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][NH:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1(C(N)=O)c2[nH]c3ccccc3c2CCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(C)C1(C(N)=O)NCCc2c1[nH]c1ccccc21
Yield: 77.5 %

Procedure:
1.62 g of tert.butyl 2-benzyloxycarbonyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide were dissolved in 10 ml of a 45% solution of hydrogen bromide in acetic acid. After 30 minutes the solution was evaporated and the residue was taken up in water. After filtration the filtrate was washed three times with diethyl ether and then neutralized by the addition of saturated aqueous sodium bicarbonate solution. The product was extracted from the now turbid aqueous layer with ethyl acetate. The combined organic extractswere dried over anhydrous magnesium sulphate and evaporated to give 0.84 g of tert.butyl 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide as a white crystalline solid of melting point 144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11]I>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CI
Product: COc1ccc(C=O)cc1Cl

Procedure:
Following a similar procedure to that described in reference example 3, but starting from 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde and using methyl iodide instead of 2-iodopropane, the title compound of the example was obtained as an oil (97% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.N#N.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]1
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCN(C)CC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.7 %

Procedure:
To a solution of 3-fluoro-4-(4-methylpiperazin-1-yl)aniline (11.01 g, 52.60 mol) in anhydrous CH2Cl2 (200 mL) was added trimethylaluminum (158 mL, 158 mmol, 1.0 M in toluene) slowly under N2. The mixture was stirred at rt for 20 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (9.92 g, 63.10 mmol) in anhydrous CH2Cl2 (20 mL). The reaction mixture was stirred at rt for another 5 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (CH2Cl2/MeOH (V/V)=5:1) to give the title compound as a white solid (11.31 g, 68%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH2:23][CH3:24])([OH:22])[C:8]2[CH:13]=[CH:12][C:11]([O:14]CC3C=CC=CC=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[H][H]>[Pd].C1C=CC=CC=1>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH2:23][CH3:24])([OH:22])[C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CCC(O)(c1ccc(OCc2ccccc2)cc1)c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Product: CCC(O)(c1ccc(O)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
of 4-trifluoromethyl-4'-benzyloxy-α-ethyl-benzhydrol are dissolved in 270 ml. of benzene, and the solution is hydrogenated in the presence of 13.5 g. of a 10% palladium-on-charcoal catalyst. When the uptake of the calculated amount of hydrogen is complete (about 80 minutes), the catalyst is filtered off, benzene is distilled off under reduced pressure, and the residue is crystallized from a mixture of ethyl acetate and n-hexane. 19 g. of the named compound are obtained, melting at 126° to 127° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[O:41]1[C:45]2[CH:46]=[CH:47][C:48]([CH2:50][NH2:51])=[CH:49][C:44]=2[O:43][CH2:42]1>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([NH:51][CH2:50][C:48]2[CH:47]=[CH:46][C:45]3[O:41][CH2:42][O:43][C:44]=3[CH:49]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1NC1CCCC1
Reactant: NCc1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.6 %

Procedure:
To a mixture of 2-cyclopentylamino-5-nitrobenzoic acid (1.00 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.15 g), 1-hydroxybenzotriazole (810 mg) in anhydrous dimethylformamide (10 mL) was added (1,3-benzodioxol-5-ylmethyl)amine (725 mg), and the mixture was stirred for 15 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with an aqueous saturated sodium bicarbonate solution, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of chloroform and methanol (50:1). The obtained product was triturated with diisopropyl ether and recrystallized from a mixture of hexane and ethyl acetate to give 2-cyclopentylamino-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (1.51 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1.[CH3:15][NH:16][CH3:17].C1COCC1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:16]([CH3:17])[CH3:15])=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1
Reactant: CNC
Reactant: COc1cnc(Cl)c2ccc(F)cc12
Solvent: C1CCOC1
Product: COc1cnc(Cl)c2ccc(N(C)C)cc12
Temperature: 100 °C
Yield: 70 %

Procedure:
To 1-chloro-6-fluoro-4-methoxyisoquinoline (200 mg, 0.945 mmol) was added dimethylamine 2 M in THF (2 ml, 4.00 mmol) and the solution was heated to 100° C. in a sealed tube for 16 h. The reaction was cooled and the volatiles were removed under vacuum. The crude residue was purified by silica gel chromatography using DCM as eluent. The product factions were collected and the solvent removed under vacuum to give 1-chloro-4-methoxy-N,N-dimethylisoquinolin-6-amine (150 mg, 70% yield). MS m/z 237.1 (M++1).
Reaction SMILES: Cl[C:2]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:4][N:3]=1.[C:25]([C:27]1([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28]1)#[CH:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:2]([C:26]#[C:25][C:27]3([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:3][CH:4]=[C:5]([CH:16]=2)[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:19][CH:20]=1
Reactant: C#CC1(O)CCCC1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(C#CC2(O)CCCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 112, using 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide and 1-ethynylcyclopentanol as starting materials to yield the product as colorless solid, MS (ISP) 439.1, 441.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH:17]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[CH2:9][NH:8][CH2:16]3)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(C3CC3)c(N3CCOCC3)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: c1c2c(cc(N3CCOCC3)c1C1CC1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-cyclopropyl-6-morpholin-4-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown solid. MS (m/e): 245.4 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[N:6]=1)=[O:4].[Br:12]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:12])=[C:7]([NH2:11])[N:6]=1)=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1cccc(N)n1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Br)c(N)n1
Reaction time: 40 h

Procedure:
To a solution of 6-amino-pyridine-2-carboxylic acid methyl ester (10 g, 66.0 mmol) in chloroform (450 mL) was added bromine (3.4 mL, 66.0 mmol) in CHCl3 (100 mL) at room temperature and stirred for 40 hours. The reaction mixture was diluted with CHCl3 and washed with saturated sodium thiosulfate solution and water. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel column chromatography using ethyl acetate/hexane as eluent. The title compound obtained as yellow solid (3.3 g, 22%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:7][CH2:8][N:9]([S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1(CCCOC)CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C1(CCCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
4-(3-Methoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (3.36 g) was dissolved under an argon atmosphere in pyridine (80 ml), benzensulfonyl chloride (2.59 g) was added and the mixture was stirred overnight at RT. The pyridine was evaporated off, the residue dissolved in AcOEt and washed with 0.05M HCl and brine. The layers were separated, the organic layer was dried over sodium sulphate, the solvent was then removed in vacuo and the crude oil was purified by flash chromatography over silica gel (AcOEt/heptane gradient from 0 to 25%) to give 1-benzenesulfonyl-4-(3-methoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (4.15 g) as a yellow semi-solid. MS (ESI): 370.16 (MH+).