Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[CH:33]2>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:23])[N:5]=[CH:4][N:3]=[C:2]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[CH:33]2
Reactant: Cn1ccc2cc(O)ccc21
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCCCC1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4c(ccn4C)c3)ncnc2cc1OCC(C)N1CCCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Nitrogen was bubbled through a mixture of 4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline (400 mg, 1.24 mmol), (prepared as described for the starting material in Example 180), potassium carbonate (500 mg, 3.62 mmol), 5-hydroxy-1-methylindole (231 mg, 1.57 mmol), (prepared as described for the starting material in Example 291), and DMA (5.0 ml) for 5 minutes. The mixture was then stirred at 90° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by trituration with methanol to give 6-methoxy-4-(1-methylindol-5-yloxy)-7-(2-piperidinopropoxy)quinazoline (447 mg, 83%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Yield: 60.8 %

Procedure:
The product of Example 13D (106 mg, 0.1546 mmol) was treated with trifluoroacetic acid (3 mL) in methylene chloride (3 mL) at room temperature for 30 minutes. The solvents were removed by rotary evaporation and the residual oil taken up in ethyl acetate (75 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel flash chromatography with 5% methanol/methylene chloride provided the title compound as a light yellow solid (55 mg, 61%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.13-3.31 (m, 1 H) 5.60 (s, 2 H) 6.63 (d, J=8.82 Hz, 2 H) 6.88 (d, J=8.46 Hz, 1 H) 7.14 (d, J=8.46 Hz, 2 H) 7.52 (d, J=8.82 Hz, 2 H) 7.64 (d, J=8.46 Hz, 1 H) 7.73 (d, J=8.82 Hz, 2 H) 7.78 (dd, J=8.27, 1.65 Hz, 1 H) 7.94 (d, J=1.47 Hz, 1 H) 8.59 (s, 1 H) 8.88 (d, J=8.82 Hz, 1 H) 10.16 (s, 1 H) 10.28 (s, 1 H); MS (ESI+) m/z 585/587 (M+H)+, MS (ESI−) m/z 583/585 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].C(Br)C.[NH3:13].O=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]#[N:13]
Reactant: N
Reactant: Cc1c(Cl)cccc1Cl
Agent: O=O
Solvent: CCBr
Product: N#Cc1c(Cl)cccc1Cl
Yield: 86.7 %

Procedure:
300 g of this catalyst was placed in a fluidized bed reactor, 1.5 inches in inside diameter and 100 cm high, and was heated therein at 360° C. To this catalyst layer were fed air, 2,6-dichlorotoluene containing 2% of ethyl bromide, and ammonia at rates of 75.2 N liters, 38.2 g, and 15.7 N liters per hour, respectively. The ratio of 2,6-dichlorotoluene:oxygen:ammonia was 1:3:3. 2,6-dichlorobenzonitrile was obtained in an amount of 34.7 g per hour. The quantity of unreacted 2,6-dichlorotoluene was 0.8 g. Conversion was 97.9%, yield was 86.7%, and selectivity was 88.5%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Fc1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401 (c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 4-fluorobenzeneboronic acid (Avocado Chemical Company) (35 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (3:1 hexane:EtOAc), the title compound as an off-white solid. MS (ESI, pos. ion) n/z: 323 (M+1). Mp: 134.5-135.0° C.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]#[C:3][CH2:4][CH3:5].C1(N=C=NC2CCCCC2)CCCCC1.O[N:24]1[C:29](=[O:30])[C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[N:26]=[N:25]1>C1COCC1>[O:30]=[C:29]1[N:24]([O:6][C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[N:25]=[N:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]1=2
Reactant: O=c1c2ccccc2nnn1O
Reactant: CCC#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: C#CCCC(=O)On1nnc2ccccc2c1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Pentynoic acid (200 mg, 2.04 mmol) was dissolved in THF (4 mL). The solution was cooled in a brine-icewater bath. A solution of dicyclohexylcarbodiimide (421 mg, 2.04 mmol) in THF (2 mL) was added. 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (333 mg, 2.04 mmol) was added after 5 minutes. The reaction mixture was stirred 1 h at −10° C. and then 2 h at room temperature. TLC indicated full conversion of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (eluent: ethyl acetate). Precipitated salts were filtered off. The filtrate was concentrated in vacuo and crystallized from hexane (4 mL). The crystals were filtered off and dried. Yield: 450 mg, 93%. RF=0.8 (ethyl acetate).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:34][C:32]1[CH:33]=[C:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:27])=[O:26])[CH:29]=[C:30]([Cl:35])[CH:31]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3cc(Cl)cc(Cl)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2cc(Cl)cc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
Lithium hydroxide monohydrate (0.013 g, 0.30 mmol) was added to a stirred solution of {4-[4-(3,5-dichlorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.039 g, 0.075 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(3,5-dichlorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.026 g, 69%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s, 1 H) 8.25 (d, J=8.31 Hz, 2 H) 8.15 (s, 2 H) 8.07 (s, 1 H) 8.00 (dd, J=8.80, 6.20 Hz, 1H) 7.90 (s, 1 H) 7.55 (d, J=8.31 Hz, 2 H) 7.38 (t, J=9.00 Hz, 1 H) 6.66 (d, J=11.74 Hz, 1 H) 3.83 (s, 2 H) 2.04 (s, 3 H). MS calcd. for C25H16Cl2FO4S [(M−H)−] 501, obsd. 501.0.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:17]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O.O>[C:17]([NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:31])=[CH:33][CH:34]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2)cc1
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (28.7 g) in acetone (400 ml) and water (200 ml) is added potassium carbonate (38.8 g) and further thereto is added 4-benzoylaminobenzoyl chloride (56 g) under ice-cooling. The mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography and recrystallized from methanol to give 1-[4-(benzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (57 g) as white powder, m.p. 202.5°-203.5° C.
Reaction SMILES: N1C=CC=CC=1[C:7](O)=[O:8].[CH:10]1[CH:11]=[CH:12][C:13]2N(O)N=[N:16][C:14]=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:39][O:40][C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]2[C:42]=1[C:43](=[O:65])[NH:44][C:45]([C:53]1[CH:58]=[CH:57][C:56]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:55][CH:54]=1)=[N:46]2>C1COCC1>[CH3:39][O:40][C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]2[C:42]=1[C:43](=[O:65])[NH:44][C:45]([C:53]1[CH:58]=[CH:57][C:56]([N:59]3[CH2:60][CH2:61][NH:62][CH2:63][CH:64]3[C:7](=[O:8])[C:12]3[CH:11]=[CH:10][N:16]=[CH:14][CH:13]=3)=[CH:55][CH:54]=1)=[N:46]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: O=C(O)c1ccccn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4C(=O)c4ccncc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of picolinic acid (0.066 g, 0.54 mmol) in THF (20 mL) was added HOBt (0.079 g, 0.59 mmol), EDCl (0.113 g, 0.59 mmol), Et3N (0.08 mL, 0.59 mmol) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g, 0.54 mmol). The resulting solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resulting solid was purified by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.160 g, 62%): 1H NMR (300 MHz, DMSO-d6): δ 11.69 (s, 1H), 8.53-8.70 (m, 1H), 8.11 (d, J=8.9 Hz, 2H), 7.86-8.04 (m, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.44-7.57 (m, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H), 3.74-3.97 (m, 8H), 3.53-3.68 (m, 2H), 3.41-3.53 (m, 2H), 3.23-3.39 (m, 2H). APCI MS m/z 472 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 4-chloro-2-fluoro-nitrobenzene (28.5 mmol), 1-methylpiperazine (28.5 mmol) and K2CO3 (37.0 mmol) in DMF is stirred at 100° C. for 16 h and diluted with water and EtOAc. The phases are separated and the aqueous phase is extracted with EtOAc. The organic phase and the extracts are combined, washed sequentially with water and brine, dried over Na2SO4 and dried in vacuo. The resultant residue is chromatographed (silica gel, 10% methanol in EtOAc as eluent) to afford the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=1.C(N(CC)CC)C>C(O)C>[C:33]([C:29]1[CH:28]=[C:27]([N:23]2[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=3[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=3)=[O:8])[CH2:25][CH2:24]2)[CH:32]=[CH:31][N:30]=1)([OH:35])=[O:34]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: O=C(O)c1cc(Cl)ccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(N2CCC(CNc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 81.8 %

Procedure:
Using a similar procedure to that described in Example 52, 5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethyl)aminobenzamide (166 mg, 0.44 mmol), 4-chloropicolinic acid (103 mg, 0.66 mmol), triethylamine (89 mg, 0.88 mmol, and ethanol (3 mL) yielded 180 mg (82%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(C(C)C)CC)(C)C.ClCCl.[C:22]12([C:32](Cl)=[O:33])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:32]([C:22]23[CH2:31][CH:26]4[CH2:25][CH:24]([CH2:30][CH:28]([CH2:27]4)[CH2:29]2)[CH2:23]3)=[O:33])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1c(N)cccc1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1NC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Bromo-2-methylaniline (800 mg) and diisopropylethylamine (1667 mg) were added to dichloromethane (12 mL). 1-Adamantanecarbonyl chloride (940 mg) was added and the solution was stirred at room temperature for 16 hours. The solution was diluted with 50% ethyl acetate (hexanes), washed three times with 1 M aqueous HCl, washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent volume was partially reduced under vacuum, and the solid material precipitated out of solution, which was isolated by filtration to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](C)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH2:16][CH3:17]>>[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:3]=2)=[CH:20][CH:19]=1)[CH2:16][CH3:17]
Reactant: Cc1ccc(-c2cccc(Br)c2)nc1
Reactant: CCCc1ccc(B(O)O)cc1
Product: CCCc1ccc(-c2cccc(-c3ccccn3)c2)cc1
Yield: 128.5 %

Procedure:
2-(3-bromophenyl)-5-methylpyridine (20.0 g, 81.1 mmol) was reacted with 4-n-propylphenylboronic acid (15.9 g, 96.7 mmol) under standard Suzuki coupling condition. Kugelrohr distillation at 230° C. yielded 28.5 g of a viscous yellow liquid that was then purified by silica gel column chromatography with 15/85 ethyl acetate/hexane as the eluent, affording 14.0 g of pure material plus an additional impure fraction.
Reaction SMILES: [Cl:1]/[C:2](/[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:3]\[C@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[C-:19]#[N:20].[Na+].O.[O:23]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[F:38])[CH:33]=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1CCCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:19]([CH:33]([O:34][C:7]([C@H:6]1[C@H:4](/[CH:3]=[C:2](\[Cl:1])/[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]1([CH3:11])[CH3:10])=[O:8])[C:32]1[CH:35]=[CH:36][C:37]([F:38])=[C:30]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:31]=1)#[N:20]
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: [C-]#N
Reactant: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: O
Product: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Yield: 77 %

Procedure:
3.4 g (0.0112 mole) of (+)-trans-Z-3-(2-chloro-2-(4-chloro-phenyl)-vinyl)-2,2-dimethyl-1-cyclopropanecarboxylic acid chloride, dissolved in 10 ml of cyclohexane, were added dropwise to a mixture of 50 ml of cyclohexane, 0.87 g of sodium cyanide, 1.3 ml of water, 2.42 g (0.0112 mole) of 3-phenoxy-4-fluorobenzaldehyde and 0.2 g of tetrabutylammonium bromide at 20°-25° C., whilst stirring, and the mixture was then stirred at 20°-25° C. for 4 hours. 100 ml of toluene were then added to the reaction mixture and the mixture was extracted twice by shaking with 60 ml of water each time. The organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 4.4 g (77% of theory) of (+)-trans-Z-3-(2-chloro-2-(4-chloro-phenyl)vinyl)-2,2-dimethyl-cyclopropane-carboxylic acid (±)-α-cyano-3-phenoxy-4-fluoro-benzyl ester were obtained as a viscous oil with an optical rotation [α]D of +58.2° (C=100 mg in 10 ml of CHCl3).
Reaction SMILES: [NH:1]=[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[CH2:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[OH-:22].[Na+]>O>[C:14]1([C:13]2[NH:1][C:2]([C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([OH:22])=[O:11])=[N:3][CH:12]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: N=C1c2ncccc2C(=O)N1CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccnc1-c1ncc(-c2ccccc2)[nH]1
Temperature: 25 °C

Procedure:
To the suspension of 7-imino-6-(2-oxo-2-phenylethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (825 mg, 3.11 mmol) in 1N NaOH (6.22 ml) 40 ml of water were added, and the reaction mixture heated to reflux for 1.5 hours. After cooling to room temperature the mixture was diluted with 100 ml of water, and the pH adjusted to 2-3 by addition of 2N HCl. The resulting precipitate was filtered off and dried to give 414 mg of the title compound as solid; ESI-MS [M+W]: 266.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Cl)[Cl:28]>C1(C)C=CC=CC=1.O.CC(O)=O>[ClH:28].[CH2:19]([C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([CH3:15])=[N:8][C:7]=1[OH:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: ClCCl
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3ccccc3)c2cc1OC
Product: Cl
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (51 mg, 233 μmol) in toluene (1 mL) in a 2 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.12 mL, 0.24 mmol) at RT followed by benzyl bromide (30 mg, 251 μmol) and the mixture was stirred at 110° C. for 15 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (5 mL) before extraction with CH2Cl2 (20 mL). The organic phase was isolated and the aqueous phase was acidified with AcOH (5 drops) and then further extracted with CH2Cl2. The organic phase was combined, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave, after evaporation and drying, 4-benzyl-6,7-dimethoxy-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.2 M HCl solution in MeOH (1 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-benzyl-6,7-dimethoxy-1-methylisoquinolin-3-ol hydrochloride 1 as a pale brown solid (31 mg, 38% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]([O:16][Si](CC)(CC)CC)[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]1)(=[O:3])=[O:4]
Reactant: CC[Si](CC)(CC)OC(C1CCN(S(C)(=O)=O)CC1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC(C(O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
1-Methanesulfonyl-4-[2,2,2-trifluoro-1-(triethyl-siloxy)ethyl]piperidine (300 mg, 0.999 mmol) was dissolved in tetrahydrofuran (2.4 mL). To this, a 1 mol/L aqueous hydrogen chloride solution (2.4 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give Compound EAG (198 mg, yield: 95%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH3:8][O:9][CH:10]([CH:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:11]([O:13][CH3:14])=[O:12]>FC(F)(F)C(O)=O>[CH3:8][O:9][CH:10]([CH:15]([S:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCS
Reactant: COC(=O)C(OC)C(O)c1ccccc1CCCCCCCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(OC)C(=O)OC
Reaction time: 0.17 h

Procedure:
To trifluoroacetic acid (100 ml) under argon and cooled to 0° C., was added methyl 3-mercaptopropanoate (0.5 ml, 4.5 mmoles). The mixture was stirred for 10 minutes, after which the ice bath was removed. Methyl 2-methoxy-3-hydroxy-3-[2-(8-phenyloctyl)phenyl]propanoate (1.5 g, 4 mmoles) was added and the mixture stirred for 18 hours. The reaction mixture was evaporated and diluted in methylene chloride. The organic layer was washed with 10% sodium hydroxide (ice cold) followed by ice water. The organic layer was dried over magnesium sulfate, filtered and evaporated. Flash chromatography on silica gel provided the desired product.