Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:16][CH2:15]2)=[CH:5][CH:4]=1.FC1C=CC(C(=O)CCC)=CC=1>>[C:25]1([CH:23]([OH:24])[CH2:22][CH2:21][CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([CH2:13][C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:3]([Cl:2])=[CH:4][CH:5]=3)[CH2:19][CH2:18]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(CCCN1CCC(Cc2ccc(Cl)c3ccccc23)CC1)c1ccccc1
Agent: CCCC(=O)c1ccc(F)cc1
Agent: Cl
Product: OC(CCCN1CCC(Cc2ccc(Cl)c3ccccc23)CC1)c1ccccc1

Procedure:
When the procedure of Example 37, 4-[4-((4-chloro-1-naphthyl)methyl)-1-piperidyl]-1-phenyl-1-butanone hydrochloride is substituted for 4-[4-(2-naphthyl)hydroxymethyl)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone, α-phenyl-4-[(4-chloro-1-naphthyl)methyl]-1-piperidinebutanol is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5](=[CH:10][CH:11]=1)[CH2:6][C:7]([OH:9])=O>C(Cl)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[O:14][C:7](=[O:9])[CH2:6][C:5]2=[CH:10][CH:11]=1
Reactant: Cc1ccc(CC(=O)O)c(C(=O)O)c1
Solvent: CC(=O)Cl
Product: Cc1ccc2c(c1)C(=O)OC(=O)C2
Yield: 95.3 %

Procedure:
To 100ml of acetyl chloride, 5.4 g of 4-methylhomophthalic acid was added and the resulting mixture was heated to reflux for 4 hours. The solvent was evaporated under reduced pressure and the generated crystals were washed with ether to obtain 4.67 g of 4-methylhomophthalic anhydride.
Reaction SMILES: [F:1][C:2]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])([F:4])[F:3].[C:15]1([CH2:25][C:26]([OH:28])=O)[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[CH:17][CH:16]=1>>[F:1][C:2]([F:4])([F:3])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:26](=[O:28])[CH2:25][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22](=[O:24])[NH:14][C:11]3[CH:12]=[CH:13][C:8]([S:5]([C:2]([F:4])([F:1])[F:3])(=[O:7])=[O:6])=[CH:9][CH:10]=3)=[CH:19][CH:20]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:7]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Product: O=C(Cc1ccc(CC(=O)Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc1)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1

Procedure:
Same procedure as Example 20 except 4-aminophenyl trifluoromethyl sulfone and 1,4-phenylenediacetic acid were used. 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 2H, 2×NH), 8.04 (d, J=8.9 Hz, 4H), 7.99 (d, J=8.9 Hz, 4H), 7.84 (d, J=8.9 Hz, 2H), 7.23 (d, J=8.9 Hz, 2H), 3.71 (s, 4H, 2×CH2). MS 609 [M++1].
Reaction SMILES: O[C:2]1([C:17]2[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]1=[O:16].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[OH:26][C:25]1[C:17]([CH:2]2[C:6]3[CH:7]=[N:8][CH:9]=[CH:10][C:5]=3[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]2=[O:16])=[CH:18][C:19]2[O:23][CH2:22][O:21][C:20]=2[CH:24]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2cnccc21
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2cnccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one (0.15 g, 0.42 mmol), triethylsilane (1.60 mL, 10.0 mmol) and trifluroacetic acid (0.74 mL, 10.0 mmol) was stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate (100 mL), washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was triturated with diethyl ether to give the title compound as a white solid (not stable, turned to red in the air): MS (ES+) m/z 341.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Cc1cc(Cl)nc(N2CCCCC2)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C)nc(N3CCCCC3)n2)ccc1-n1cnc(C)c1
Yield: 79 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.30 mmol) and 4-chloro-6-methyl-2-piperidin-1-yl-pyrimidine (70 mg, 0.33 mmol, example 97a) in analogous manner as described in example 90. The crude product was purified by stirring with diethyl ether. It was obtained in 79% yield as a grey solid. MS ISP (m/e): 379.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.29 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.22 (d, 1H), 7.04 (d, 1H), 7.03 (s, 1H), 5.89 (s, 1H), 3.80 (s, 3H), 3.74 (m, 4H), 2.15 (s, 3H), 2.14 (s, 3H), 1.60 (m, 2H), 1.50 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:7]([C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](O)=[O:12])=[N:8][C:4]=2[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:48]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])(=[O:51])[NH:49][NH2:50].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[C:53]([O:52][C:48]([N:49]([C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[C:7]1[N:6]([C:18]([CH3:21])([CH3:19])[CH3:20])[C:5]2[CH:22]=[CH:23][C:2]([Br:1])=[CH:3][C:4]=2[N:8]=1)[NH2:50])=[O:51])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)n1c(-c2ccccc2C(=O)O)nc2cc(Br)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(N)C(=O)c1ccccc1-c1nc2cc(Br)ccc2n1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzoic acid (300 mg, 0.804 mmol) in DMF (8 mL), followed by the addition of HATU (611 mg, 1.607 mmol), tert-butyl carbazate (530 mg, 4.01 mmol) and iPr2NEt (520 mg, 4.02 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with EtOAc/water. The organic layer is separated, washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-5% MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford N-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzoyl]-hydrazinecarboxylic acid tert-butyl ester (390 mg). This material is dissolved in CH2Cl2 (3 mL), followed by the addition of trifluoroacetic acid (2 mL). The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated to afford 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzoic acid hydrazide (310 mg, 100%). LCMS (ESMS): m/z 387.75, 389.75 (M++1).
Reaction SMILES: [CH:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])=O.Cl.[NH2:23]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])#[N:23]
Reactant: NO
Reactant: CCOC(=O)c1c[nH]c(C=O)c1-c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1c[nH]c(C#N)c1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of ethyl 5-formyl-4-(nitrophenyl)-1H-pyrrole-3-carboxylate (24.55 g, 85.17 mmol) in pyridine (400 mL) was added hydroxylamine hydrochloride (6.51 g, 93.7 mmol). The solution was stirred at rt for 2 h, and then acetic anhydride (17.68 mL, 187.4 mmol) was added. The solution was heated (80° C.) for 17 h and then cooled to rt. The reaction mixture was partially concentrated in vacuo and then diluted with ethyl acetate (300 mL) and water (300 mL). The layers were separated and the aqueous layer was back extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness. The crude material was then triturated with dichloromethane-diethyl ether (1:1 v/v, 300 mL). The solid was collected, washed with diethyl ether (150 mL), and dried under vacuum to afford the desired product (18.94 g, 78%). 1H-NMR (300 MHz, DMSO-d6) 13.24 (br s, 1H), 8.25-8.32 (m, 2H), 7.92 (s, 1H), 7.69-7.76 (m, 2H), 4.13 (q, J=7.2 Hz, 2H), 1.16 (t, J=7.0 Hz, 3H); HPLC RT (Method A) 2.97 min; TLC Rf=0.20 (95:5 v/v CH2Cl2-EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][C:17]([CH3:35])([C:19]2[N:23]([CH3:24])[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[N:21][N:20]=2)[CH3:18])=[C:6]([C:8]2[O:9][CH:10]=[C:11]([C:13](O)=O)[N:12]=2)[CH:7]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C1CCN2C(=[N:55]CCC2)CC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][C:17]([CH3:18])([C:19]2[N:23]([CH3:24])[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])=[N:21][N:20]=2)[CH3:35])=[C:6]([C:8]2[O:9][CH:10]=[C:11]([C:13]#[N:55])[N:12]=2)[CH:7]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1-c1nc(C(=O)O)co1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1-c1nc(C#N)co1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3-oxazole-4-carboxylic acid (375 mg) was mixed with dichloromethane (10 ml), and triethylamine (0.52 ml) was added, followed by ice-cooling and addition of trifluoromethanesulfonic anhydride (0.316 ml). After stirring at room temperature overnight, it was further stirred at 40° C. for 3 hours. DBU (0.222 ml) was added to the reaction solution, followed by stirring for one hour. Trifluoroacetic anhydride was added to the reaction solution, followed by stirring at 40° C. for 3 hours, and trifluoroacetic anhydride (0.158 ml) and triethylamine (0.52 ml) were added thereto, followed by stirring at 40° C. for one hour. The reaction solution was cooled to room temperature and saturated aqueous sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was washed with water and then saturated brine in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=200:1), and the resulting residue was washed with diisopropylether to obtain, as a beige solid, 2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3-oxazole-4-carbonitrile (190 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[CH:9][C:8]=1[F:18])(=O)=O.C(N(CC)CC)C.[CH:28]([O:30]CCCC)=[CH2:29].Cl.C([O-])(O)=O.[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:18][C:8]1[CH:9]=[C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[CH:11]=[CH:12][C:7]=1[C:28](=[O:30])[CH3:29]
Reactant: C=COCCCC
Reactant: O=S(=O)(Oc1ccc(-c2cscn2)cc1F)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(-c2cscn2)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.6 %

Procedure:
To a stirred solution of 2-fluoro-4-(1,3-thiazol-4-yl)phenyl trifluoromethanesulfonate (3.47 g, 10.6 mmol) in DMF (11.7 ml) was added triethylamine (1.29 g, 12.72 mmol), butyl vinyl ether (5.31 g, 53 mmol), 1,3-bis(diphenylphosphino)propane (240 mg, 0.583 mmol), palladium acetate (120 mg, 0.53 mmol) successively, and the mixture was heated at 80° c. for 5 hours. The mixture was cooled down to room temperature. 2N HCl aqueous solution (30 ml) was added, and the mixture was stirred for 1 hour. The mixture was made neutral by addition of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (2.03 g, 87% yield).
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:22])[C:10]2[N:11]=[CH:12][N:13]([CH2:16][C:17]([O:19]CC)=[O:18])[C:14]=2[N:15]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl>O>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:22])[C:10]2[N:11]=[CH:12][N:13]([CH2:16][C:17]([OH:19])=[O:18])[C:14]=2[N:15]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)Cn1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(=O)Nc1nc2c(ncn2CC(=O)O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 11 (3.07 g, 10 mmol) and NaOH (0.8 g, 20 mmol) were dissolved in water (20 mL). The mixture was stirred at room temperature for 2 h. The pH was adjusted to 3 using 1M HCl, to obtain a white precipitate. The solution was filtered off, and the precipitate was washed with a small amount of cold water and dried in vacuo to give 5 as a white solid: yield 2.65 g (95%); MS(+ESI): m/z 280 [M+H]+; 1H NMR (400 MHz, d-DMSO): δ13.32 (s, 1H), 12.06 (s, 1H), 11.64 (s, 1H), 7.93 (s, 1H), 4.88 (s, 2H), 2.74 (septet, 1H, J=6.8 Hz), 1.10 (d, 6H, J=6.8 Hz); 13C NMR (400 MHz, CDCl3): δ180.63, 169.52, 155.29, 149.47, 148.52, 140.78, 120.17, 44.88, 39.38, 19.33.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[C:34]([Cl:38])[C:35]=1[CH:36]=O)[O:26][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29]>>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[NH:7][C:5]([C:4]1[CH:18]=[CH:19][C:20]2[N:21]=[C:36]([C:35]3[C:34]([Cl:38])=[CH:33][C:25]([O:26][CH2:27][C:28](=[O:29])[N:30]([CH3:31])[CH3:32])=[CH:24][C:23]=3[Cl:22])[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Reactant: CN(C)C(=O)COc1cc(Cl)c(C=O)c(Cl)c1
Product: CN(C)C(=O)COc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1

Procedure:
The title compound was prepared from 3,4-diamino-N-quinolin-2-yl-benzamide (from Example 6-17) and 2-(3,5-dichloro-4-formylphenoxy)-N,N-dimethyl-acetamide analogous to Example 6-17. 1H NMR (Methanol-d4, 400 MHz): δ 8.83 (d, 1H), 8.56 (d, 1H), 8.20 (t, 1H), 8.18 (t, 1H), 8.14 (d, 1H), 8.02 (m, 2H), 7.90 (d, 1H), 7.79 (t, 1H), 7.28 (s, 2H), 5.02 (s, 2H), 3.09 (s, 3H), 3.01 (s, 3H). MS (m/z) 534.2 (M+1); Retention time: 1.28 min (Method 10).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][CH:33]4[CH2:35][CH2:34]4)=[O:31])=[CH:25][C:24]=3[F:36])[CH:14]=2)=[N:11][CH:12]=1>CC(C)=O.O.C(O)(C(F)(F)F)=O>[CH:33]1([NH:32][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:10]5[CH:9]=[CH:8][C:7]([CH:2]=[O:1])=[CH:12][N:11]=5)[S:21][C:20]=34)=[C:24]([F:36])[CH:25]=2)=[O:31])[CH2:34][CH2:35]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1)NC1CC1
Solvent: O
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Yield: 84.6 %

Procedure:
A suspension of 320 (0.65 g, 1.3 mmol) in 5:2:1 acetone/water/TFA (100 mL) was heated to reflux for 6 h. The mixture was then cooled and concentrated. The resulting solid residue was suspended in water, isolated by suction filtration, washed with ethyl acetate and dried in vacuo yielding 321 (0.49 g, 1.1 mmol, 85% yield) which was used without further purification in the next step. MS: 449.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10](OC)=[O:11])=[N:6][C:7]=1[O:8][CH3:9].CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][OH:11])=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COC(=O)c1ccc(Br)c(OC)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: ClCCl
Product: COc1nc(CO)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a solution of methyl 5-bromo-6-methoxypicolinate (249 mg, 1.01 mmol) in dichloromethane (10 mL) added DIBAL-H in CH2Cl2 (1M, 3.04 mL) at −78° C. The reaction was immediately warmed to room temperature then stirred at room temperature for 1 hr. LCMS indicated that the reaction was complete. To the reaction mixture was added saturated aqueous NaK tartrate. It was stirred for 30 min. The reaction mixture was extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a white solid (205 mg, 93.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]([CH2:14][C:15]([NH:17][CH3:18])=O)[CH2:6]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH:7]([CH2:14][CH2:15][NH:17][CH3:18])[CH2:8]2
Reactant: CNC(=O)CC1Cc2cc(OC)c(OC)cc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC1Cc2cc(OC)c(OC)cc2C1
Yield: 68.7 %

Procedure:
37 g of N-[(5,6-dimethoxyindan-2-yl)methylcarbonyl]-N-(methyl)amine are treated with 8.5 g of LiAlH4 in 470 ml of tetrahydrofuran under reflux for 6 hours, then the mixture is hydrolysed and subsequently concentrated to yield, finally, 24 g of N-[(5,6-dimethoxyindan-2-yl)-ethyl)-N-(methyl)amine (yield 69%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](=[O:30])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH2:14][CH2:13]1.[BH4-].[Na+]>C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]([OH:30])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH2:14][CH2:13]1
Reactant: COc1ccccc1CC(=O)CCN1CCN(CC(=O)Nc2c(C)cccc2C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1CC(O)CCN1CCN(CC(=O)Nc2c(C)cccc2C)CC1
Reaction time: 16 h

Procedure:
To a solution of N-(2,6-dimethylphenyl)-2-{4-[4-(2-methoxyphenyl)-3-oxobutyl]piperazin-1-yl}acetamide (100 mg, 0.23 mmol) in ethanol (2 mL) was added sodium borohydride (50 mg), and the mixture was stirred for 16 hours. Excess borohydride was then quenched by the addition of saturated ammonium chloride solution. Dichloromethane (20 mL) was added, the mixture shaken, and the organic layer was separated, washed with water and concentrated under reduced pressure. The residue obtained was purified by preparative TLC using 10% methanol in dichloromethane as mobile phase to afford N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazin-1-yl}acetamide, a compound of Formula I.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:9]([CH2:14][NH:15][CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29](=[O:40])[C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][C:31]=1[CH2:38]Br.CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29](=[O:40])[C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][C:31]=1[CH2:38][N:15]([CH2:14][C:9]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:26])=[CH:13][CH:12]=[CH:11][N:10]=1)[CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1CNC1CCCc2cccnc21
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1NC(=O)OC(C)(C)C)C1CCCc2cccnc21

Procedure:
Using General Procedure A: Reaction of {2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-pyridin-3-yl}-carbamic acid tert-butyl ester in CH3CN with 2-bromomethyl-5-cyano-benzoic acid methyl ester, DIPEA, KI, and DMAP gave 2-{[(3-tert-butoxycarbonylamino-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a beige solid. 1H NMR (CDCl3) δ 1.65 (s, 9H), 1.68-1.71 (m, 1H), 1.85-1.93 (m, 1H), 2.08-2.12 (m, 1H), 2.27-2.28 (m, 1H), 2.81-2.86 (m, 2H), 3.79-3.91 (m, 7H), 4.02-4.07 (m, 1H), 4.50 (d, 1H, J=18.0 Hz), 7.02-7.06 (m, 1H), 7.12-7.18 (m, 1H), 7.43 (d, 1H, J=6.8 Hz), 7.54-7.59 (m, 1H), 8.00-8.09 (m, 3H), 8.41 (d, 1H, J=9.0 Hz), 8.67-8.71 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][C:24]([CH3:27])=[N:25][N:26]=2)=[N:10]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][C:24]([CH3:27])=[N:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nnc(C)s2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nnc(C)s2)=NC1c1ccc(F)cc1Br
Yield: 55.4 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-methyl-1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.04 g, 2 mmol) was reacted with morpholine-3-carboxylic acid (0.26 g, 2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.63 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7]1[C:16]2[O:15][CH2:14][C:13](=[O:17])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4].[C:18]1([CH:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:25][CH2:26][CH2:27]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C1COCC1>[C:3]([O:6][C:7]1[C:16]2[O:15][CH2:14][C:13](=[O:17])[N:12]([CH2:27][CH2:26][O:25][CH:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Oc1cccc2c1OCC(=O)N2
Reactant: BrCCOC(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc2c1OCC(=O)N2CCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Anhydrous THF (15 ml) was added to sodium hydride (106 mg) to form a suspension, and a solution of 8-acetoxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (498 mg) in anhydrous DMF (5 ml) was added to the resulting suspension, and the mixture was stirred at room temperature for 1 hour. 2-diphenylmethoxyethyl bromide (980 mg) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction solution was poured into a 3% citric acid aqueous solution, and then extracted with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by medium-pressure column chromatography (solvent:ethyl acetate/cyclohexane=1/3) to obtain the colorless oily object compound (640 mg, yield 66%).