Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([C:23]([F:26])([F:25])[F:24])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:27])[CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[Cl:27][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:28])=[O:2])[CH:17]=[CH:16][C:15]=1[N:18]1[C:22]([C:23]([F:26])([F:24])[F:25])=[N:21][N:20]=[N:19]1
Reactant: COC(=O)C(CC1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(CC1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Temperature: 47.5 °C
Yield: 61.2 %

Procedure:
A solution of 2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid methyl ester (634 mg, 1.52 mmol) in ethanol (10 mL) was treated with a 1N aqueous sodium hydroxide solution (3 mL). The solution was heated at 45-50° C. for 5 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (50 mL) and extracted with diethyl ether (1×60 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid (375 mg, 61%) as a viscous oil: EI-HRMS m/e calcd for C17H18ClF3N4O2 (M+) 402.1070, found 402.1067.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([F:11])=[C:6]([I:12])[C:3]=1[C:4]#[N:5].CCN(CC)CC.[CH:20]1([C:23]2[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=2)[CH2:22][CH2:21]1>C(#N)C>[Cl:1][C:2]1[N:9]=[C:8]([NH:28][C:25]2[CH:24]=[C:23]([CH:20]3[CH2:22][CH2:21]3)[NH:27][N:26]=2)[C:7]([F:11])=[C:6]([I:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)nc(Cl)c(F)c1I
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1c(Cl)nc(Nc2cc(C3CC3)[nH]n2)c(F)c1I
Temperature: 80 °C
Yield: 29.5 %

Procedure:
The crude 2,6-dichloro-5-fluoro-4-iodonicotinonitrile (8.0 g, 25.2 mmol), Et3N (3.3 g, 32.8 mmol) and 5-cyclopropyl-1H-pyrazol-3-amine (3.1 g, 25.2 mmol) were placed in ACN (50 ml) and the resulting solution was heated to 80° C. for 24 hours. The reaction was cooled to room temperature, filtered, and the resulting solid was washed with cold ACN, dried, and collected to give the title compound (3.0 g, 29%). MS: Calcd.: 403. Found: [M+H]+ 404.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.CO>[CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(C)O)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
1-(4-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)ethanone (30 mg, 0.067 mmol) synthesized in Example (39b) was dissolved in a mixed solvent of tetrahydrofuran (3.0 mL) and methanol (1.0 mL), and sodium borohydride (10 mg, 0.264 mmol) was added, followed by stirring at room temperature for 3 hours under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (10 mL) was added, and extraction was carried out with ethyl acetate (10 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-60%) to afford the desired compound (27.5 mg, yield 91%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](C(C)C)=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:15]=[N:16][N:17]([CH3:18])[C:3]=12.[CH:19](C1C2C(=O)C3N(C)N=CC=3NC=2C=CC=1)([CH3:21])[CH3:20].ClC1C2C=CC(F)=CC=2N=C2C=NN(C)C=12.C(C1C=CC2C(=O)C3N(C)N=CC=3NC=2C=1)(C)C>>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][C:8]([CH:19]([CH3:21])[CH3:20])=[CH:7][C:6]=2[N:5]=[C:4]2[CH:15]=[N:16][N:17]([CH3:18])[C:3]=12
Reactant: CC(C)c1cccc2[nH]c3cnn(C)c3c(=O)c12
Reactant: CC(C)c1cccc2nc3cnn(C)c3c(Cl)c12
Agent: CC(C)c1ccc2c(=O)c3c(cnn3C)[nH]c2c1
Agent: Cn1ncc2nc3cc(F)ccc3c(Cl)c21
Product: CC(C)c1ccc2c(Cl)c3c(cnn3C)nc2c1

Procedure:
A mixture of 9-chloro-8-isopropyl-1-methyl-1H-pyrazolo[4,3-b]quinoline and 9-chloro-6-isopropyl-1-methyl-1H-pyrazolo[4,3-b]quinoline (EXAMPLE 10, step 2) was treated according to the procedure of step 3 in EXAMPLE 3 instead of 9-chloro-6-fluoro-1-methyl-1H-pyrazolo[4,3-b]quinoline. The title compound and 6-isopropyl-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one were separable by column chromatography on silica gel eluting with methanol/dichloromethane (1:30).
Reaction SMILES: [NH2:1][C:2]1[C:3](N)=[N:4][C:5]2[C:10]([C:11]=1CC(C)C)=[CH:9][CH:8]=[CH:7][CH:6]=2>C(O)=O>[CH2:5]([N:4]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:3]1)[CH:10]([CH3:11])[CH3:9]
Reactant: CC(C)Cc1c(N)c(N)nc2ccccc12
Solvent: O=CO
Product: CC(C)Cn1cnc2cnc3ccccc3c21
Temperature: 112.5 °C
Reaction time: 3 h
Yield: 196.2 %

Procedure:
3-Amino-4-isobutyl amino quinoline (215 gm, 1.0 mole) was dissolved in formic acid (1000 ml) and further refluxed the reaction mass to 110-115° C. Reflux was maintained for 8-10 hrs. After completion of reaction excess formic acid was removed under reduced pressure and 3.5 L of water was added to the concentrated mass. This diluted mass was then basified with 30% NaOH to pH (10 to 11) at 20° C. The reaction mass was further cooled to 10° C. and stirred for further 3 hrs to obtain solid. The solid was filtered, washed with water and dried to get the title compound (221 gm, 98%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8]P(OCC)(OCC)=O)=[O:7].[CH:17](=O)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>O1CCCC1>[C:6]([O:5][CH2:4][CH3:3])(=[O:7])/[CH:8]=[CH:17]/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC/C=C/C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC/C=C/C=C/C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% wt., 3.11 g) was suspended in dry tetrahydrofuran (200 ml) and cooled to 0° C. O,O-Diethyl ethoxycarbonylmethyl phosphonate (15.43 ml) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and cooled to −78° C. after which (E)-dec-2-enal (11.90 ml) was added dropwise. Stirring was continued at this temperature for 2 h, after which the mixture was warmed to room temperature. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated. The crude product was purified by column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][OH:19]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1
Reactant: CNc1ccc(Br)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCO)c1ccc(Br)cc1
Yield: 19 %

Procedure:
4-bromo-N-methylaniline (700 mg, 3.76 mmol) was dissolved in DMF (20 mL), K2CO3 (1.56 g, 11.29 mmol) and 2-bromoethanol (1.41 g, 11.29 mmol) were added in. The mixture was reacted at 100° C. for 2 days. Then it was extracted by EA and brine, washed by brine, dried over Na2SO4, concentrated and purified by flash chromatography, (PE: EA=10:1 to 3:1) to give 164 mg brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([C:21]([CH3:23])=[CH2:22])=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([CH:21]([CH3:22])[CH3:23])=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1
Reactant: C=C(C)c1cc(S(C)(=O)=O)cc2c1cc1n2CCC1CC(=O)OC
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1CCn2c1cc1c(C(C)C)cc(S(C)(=O)=O)cc12
Reaction time: 0.75 h

Procedure:
To the product of Step 2 (130 mg, 0.39 mmol) in EtOH (3 mL) was added Pd/C 10% (40 mg). The mixture was hydrogenated with a Parr hydrogenator at 50 psi for 45 minutes, filtered on a pad of celite, and the filtrate evaporated to dryness and used as such in the next step.
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+].Br.Br[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.O.C(Cl)Cl>[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])=[C:6]2[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: BrCc1ccncc1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(C)nc(O)c(Cc3ccncc3)c2cc1OC
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (197 mg, 899 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (1.20 mL, 2.40 mmol) at RT followed by 4-(bromomethyl)pyridine hydrobromide (250 mg, 988 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 (50 mL). The organic layer was 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 90:10) gave 70 mg of 6,7-dimethoxy-1-methyl-4-(pyridin-4-ylmethyl)isoquinolin-3-ol as a yellow solid. This free base was dissolved in MeOH (5 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.15 M HCl solution in MeOH (7 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(pyridin-4-ylmethyl)isoquinolin-3-ol hydrochloride 11 as a yellow solid (78 mg, 25% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[OH:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:24]3[CH2:25][CH2:26][CH2:27][CH:22]([CH2:21][OH:20])[CH2:23]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: OCC1CCCNC1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCCC(CO)C3)s2)c(C)[nH]c1=O
Yield: 54.7 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 3-hydroxymethylpiperidine as described in Step 5, Example 24 to give the title compound as a solid (54.7% yield). LC/MS: RT 2.63 min; m/e 397 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 7.6 (1H, d); 7.4 (1H, s); 7.24 (1H, d), 4.6 (1H, br s), 3.6 (21H, m), 3.2 (1H, m), 2.4 (2H, q), 2.36 (3H, s), 2.1 (1H, t), 1.8-1.4 (5H, m), 1.1 (3H, t), 0.94 (1H, m).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:7][CH:8]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:12])[CH:11]=1)(=[O:3])[CH3:2].Br[CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:22][CH2:23][NH:24][C:25]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CC(=O)OCc1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc(OCCNC(=O)OC(C)(C)C)c(OCc2ccccc2)cn1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a solution of 6.1 g of (5-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)methyl acetate in 50 mL of dimethyl sulfoxide, 5.0 g of tert-butyl (2-bromoethyl)carbamate and 10 g of potassium carbonate were added, and the mixture was stirred at 80 to 90° C. for 6 hours 30 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=99:1 to 98:2 obtain 3.8 g of (5-(benzyloxy)-4-(2-((tert-butoxycarbonyl)amino)ethoxy)pyridin-2-yl)methyl acetate as a brown oily substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C=O)C>[Si:15]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: Nc1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
To 1.00 g (8.1 mmol) of 3-hydroxymethylaniline in 25 mL of DMF was added 0.61 g (8.9 mmol) of imidazole and 1.35 g (8.9 mmol) of tert-butyldimethylsilyl chloride. The reaction was stirred at room temperature for 18 h and poured into 12 volumes of water. The product was extracted with ether and the combined organic layers were washed successively with water and brine, dried over sodium sulfate, filtered and concentrated to a golden oil. The oil was purified by flash chromatography eluting with a 20% ethyl acetate/hexanes mixture to give 1.2 g (62%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:23]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].O>CN(C=O)C>[CH2:1]([N:8]([C:23]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(C(F)(F)F)c1F
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C#N)cccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of 3.05 g (11.0 mmol) of the product of Example 121 in 15 mL of DMF was added 0.484 g (12.1 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at room temperature and then 1.89 g (10.0 mmol) of 2-fluoro-3-(trifluoromethyl)benzonitrile in 2 mL of DMF was added. The reaction mixture was stirred at 90° C. for 18 hr, poured into water and extracted with ether. The combined organics were washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude solid was triturated with ether to provide 3.33 g (75%) of the desired product as a white solid. Electrospray Mass Spec 447.2(M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[CH3:13])=[N:10][CH:9]=[CH:8][CH:7]=2.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cnc2cccnc2c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cnc2cccnc2c1CBr
Temperature: 80 °C

Procedure:
To 3-methoxy-4-methyl-1,5-naphthyridine (0.26 g) dissolved in carbontetrachloride (6 ml) was added N-bromosuccinimide (1.2 eq) and benzoyl peroxide (0.3 eq) and heated at 80° C. for 4 h. The reaction was partitioned between satd. NaHCO3 and DCM, and the DCM layer then dried over Na2SO4 to give the title compound (120 mg) after concentration. MS (ESI+) for m/z 252 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].N1C=CC=CC=1.[CH2:16]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Reactant: Nc1cccc(CO)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 15.5 g of m-aminobenzyl alcohol and 36.21 g of pyridine in 250 ml of tetrahydrofuran, cooled to 0° C. is added over 40 minutes a solution of 42 g of p-tetradecyloxyphenylacetyl chloride in 250 ml of tetrahydrofuran. The mixture is stirred overnight at room temperature and the solvent is evaporated. The residue is partitioned between water and chloroform with some heating to afford a complete solution. The hot chloroform solution is washed with warm water and warm dilute hydrochloric acid. The organic layer is dried and evaporated to a residue which is crystallized from carbon tetrachloride to give 40 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:8]([NH:14][CH2:15][CH3:16])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=O.Cl[CH:21]([C:27]([O-:29])=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl>CN(C)C1C=CN=CC=1.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[N:14]([CH2:15][CH3:16])[C:27](=[O:29])[C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(Cl)C(=O)[O-]
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)c2ccc(C)nc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 50 ml dichloroethane solution containing 7.5 g of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine were added 5 ml of monoethyl chloromalonate and 6.5 g of 4-dimethylaminopyridine. The whole was stirred at room temperature for 30 minutes, and then further under heating at an oil bath temperature of 80° C. for 30 minutes. The reaction mixture was cooled to room temperature and, after adding 1M hydrochloric acid, extracted with chloroform. The organic layer was washed with saturated brine and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (hexane-ethyl acetate to chloroform-ethyl acetate) to obtain 7.10 g of ethyl 4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-carboxylate as colorless crystals.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[I:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([I:22])=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide was prepared according to method C with triethylamine (2.23 mL; 15.90 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.5 g; 6.36 mmol) and 4-iodobenzoyl chloride (1.82 g; 6.68 mmol) in dichloromethane (75 mL). The mixture was stirred for 20 minutes at room temperature and was evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to provide 1.22 g (45%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: OCCNCCO
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Product: OCCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1

Procedure:
According to the method in example 29, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and diethanolamine were converted to yield 2-[{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol as light yellow oil, MS: 464 (MH+,1Br).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg]Br.[Cl-].[NH4+]>C(OCC)C>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:23])([OH:15])[CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[Mg]Br
Reactant: O=C1CCC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CCC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a clear colorless solution of (R)-3-(dibenzylamino)cyclohexanone (5.697 g, 19.42 mmol) in dry diethyl ether (300 mL) was added a solution of 3 M methylmagnesium bromide (8.09 mL, 24.27 mmol) dropwise slowly at 0° C. The reaction mixture was stirred at 0° C. for 15 min and the ice-bath was then removed. The reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, as indicated by LCMS and TLC, the cloudy solution was slowly poured into a saturated aqueous solution of ammonium chloride (250 mL). The ether layer was separated, and the aqueous layer was re-extracted with ether (250 mL). The combined ether layers were dried over magnesium sulfate concentrated and purified by silica gel chromatography (0%-80% ethyl acetate in hexanes) to yield two diastereomeric isomers of (3R)-3-(dibenzylamino)-1-methylcyclohexanol (isomer I and isomer 2). Isomer 1 (2.704 g, 45%) was obtained as a white solid and isomer 2 (1.866 g, 31%) as a colorless oil, which still contained a small amount of impurities. Isomer 2 was used without further purification in the next step.