Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.Cl.[F:28][C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:32]1[CH2:33][CH2:34][C:29]([F:28])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:30][CH2:31]1)=[O:26]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)O)cnc12
Reactant: FC1(c2ccccc2)CCNCC1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 71.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2-chloro-5-methylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (100 mg, 0.27 mmol) obtained in Example 66, step 2 and 4-fluoro-4-phenylpiperidine hydrochloride (86 mg, 0.40 mmol), the title compound (103 mg, 72%) was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][N:18]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:11][C:9]1[C:10]2[C:2]([C:22]3[C:14]([Cl:13])=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:17][CH2:16]4)=[CH:3][N:4]([CH3:12])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2Cl
Reactant: Cn1cc(Br)c2c(N)ncnc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc3c(c2Cl)CCN3C(=O)OC(C)(C)C)c2c(N)ncnc21
Temperature: 100 °C
Yield: 79.7 %

Procedure:
A mixture of 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (510 mg, 2.246 mmol), 1,1-dimethylethyl 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (853 mg, 2.246 mmol), Pd2(dba)3 (103 mg, 0.112 mmol) and Potassium Phosphate (K3PO4) (954 mg, 4.49 mmol) and (t-Bu)3PHBF4 (6.52 mg, 0.022 mmol) in 1,4-Dioxane (10 mL) and Water (3.3 mL) in a sealed tube was heated at 100° C. on a stirrer hot plate. At this time, LCMS analysis indicated good conversion, so the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL), and the combined organics dried over sodium sulfate and concentrated. The residue was dissolved in DCM (ca. 100 mL), concentrated to minimum volume (ca. 40 mL), then purified by flash chromatography (0-100% EtOAc in hexanes, 40-g silica gel column) to afford 1,1-dimethylethyl 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2,3-dihydro-1H-indole-1-carboxylate (0.716 g) as a yellow solid. LC-MS (ES) m/z=400 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (s, 9H), 3.14 (t, J=8.59 Hz, 2H), 3.74 (s, 3H), 3.96-4.07 (m, 2H), 5.73-6.04 (m, 2H), 7.15-7.26 (m, 2H), 7.57-7.80 (m, 1H), 8.13 (s, 1H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][CH2:23]I.[Sn]>CCO.CN(C=O)C.O.C1(C)C=CC=CC=1>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH:10]([CH3:11])[CH3:12])[C:13]([O:15][CH2:23][Cl:22])=[O:14])=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: ClCI
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Sn]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Yield: 37 %

Procedure:
To a solution of N-Boc-valine (10 g, 46.08 mmol) in EtOH (70 mL) was added Cs2CO3 (14.97 g, 46.06 mmol) in a solution of H2O (30 mL). The mixture was stirred at RT for 30 mins, co-evaporated with toluene to dryness, re-dissolved in DMF (100 mL) and cooled in an ice bath. Chloroiodomethane (81.1 g, 460.8 mmol) was added dropwise at 0° C. The mixture was stirred at RT in the dark (tin foil) for 12 h. The mixture was treated with H2O (200 mL), extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel eluted with PE:EA=100:1 to 60:1 to give (S)-chloromethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (37%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([O:1][C:12](=[O:13])[O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1)(=[S:7])[NH2:8]
Reactant: NC(=S)c1ccc(O)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: NC(=S)c1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 81 %

Procedure:
To a stirred suspension of p-hydroxythiobenzamide (1.04 mmol) in CH2Cl2 (10 ml) was added 4-dimethylaminopyridine (DMAP, 1.16 mmol) and 4-nitrophenyl chloroformate (1.15 mmol). The reaction mixture was stirred for 10 hr at room temperature. Thin layer chromatography indicated that the formation of the desired product completed. The solvent was removed and the residue was treated with diethyl ether; product a was recovered by filtration and used without further purification (yield 81%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH2:15][CH2:16][O:17][CH3:18]>[OH-].[Na+].O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: COCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCCOc1cc(C)c(C(C)=O)c(C)c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (800 mg, 4.9 mmol, 1.0 equiv) and 1-chloro-3-methoxypropane (528.97 mg, 4.9 mmol, 1.0 equiv) in 50% aqueous NaOH solution (10.0 mL) was stirred at 140° C. for 16 h. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure to give 1-(4-(3-methoxypropoxy)-2,6-dimethylphenyl)ethanone (987.8 mg, 4.2 mmol) as yellow oil in 86% yield: 1H NMR (DMSO-d6, 500 MHz) δ 6.56 (s, 2H), 4.02-4.04 (m, 2H), 3.53-3.55 (m, 2H), 3.36 (s, 3H), 2.45 (s, 3H), 2.23 (s, 6H), 2.02-2.04 (m, 3H); ESI-MS: m/z 237.7 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:19]([CH3:24])=[N:20][NH:21][C:22]=2[CH3:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.[CH2:36]([N:43]=[C:44]=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:19]([CH3:24])=[N:20][N:21]([C:44](=[O:45])[NH:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:22]=2[CH3:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: Cc1n[nH]c(C)c1Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nn(C(=O)NCc2ccccc2)c(C)c1Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To 3-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (514, 60.0 mg, 0.18 mmol) in dichloromethane (6.0 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.033 mL, 0.220 mmol) and benzyl isocyanate (29.4 mg, 0.220 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give crude compound (515, approx. 50 mg) that was used in the next step directly. MS (ESI) [M+H+]+=460.5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>CS(C)=O>[CH3:33][N:30]1[CH2:31][CH2:32][CH:27]([O:1][C:2]2[CH:3]=[C:4]([S:8]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH2:28][CH2:29]1
Reactant: O=S(=O)(c1cccc(O)c1)n1ccc2ccccc21
Reactant: CN1CCC(Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCC(Oc2cccc(S(=O)(=O)n3ccc4ccccc43)c2)CC1
Temperature: 42.5 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
1-(3′-Hydroxybenzenesulfonyl) indole, (0.36 mmol, 0.1 grams) (obtained from preparation 1), was dissolved in dimethyl sulfoxide (2 mL). Potassium carbonate (0.074 grams) was added and the resulting reaction mixture was stirred 40-45° C. for a period of one hour. In another round bottom flask, 4-chloro-N-methylpiperidine (0.54 mmol, 0.072 grams) was dissolved in dimethyl sulfoxide (1.5 mL). The content of the first flask were added to the second flask at 40-45° C. The resulting reaction mass was further heated to 140-145° C. and maintained there for a period of 5 hours while monitoring the reaction by thin layer chromatography. Cooled the reaction mass to room temperature, poured it onto water (25 mL) and extracted the product with ethyl acetate (30 mL×3). Combined organic extracts were dried over sodium sulfate and the volatiles were removed under the reduced pressure to obtain 0.110 grams crude compound. The compound was purified by column chromatography using silica gel (100-200 mesh), eluent being ethyl acetate and 1% triethylamine to obtain 50 mg of pure compound.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:45])[NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[C:29]6=[O:41])=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)[CH2:3][CH2:2]1.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][C@H:30]1[CH2:31][CH2:32][N:28]([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:19]3[S:20][C:13]4[C:14](=[N:15][CH:16]=[CH:17][C:12]=4[O:11][C:10]4[CH:42]=[CH:43][C:7]([NH:6][C:5]([NH:4][CH:1]5[CH2:3][CH2:2]5)=[O:45])=[CH:8][C:9]=4[F:44])[CH:18]=3)=[N:26][CH:25]=2)[C:29]1=[O:41]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1=O
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
To a solution of 107 (120 mg, 0.19 mmol) in DCM (20 mL) was added water (0.5 mL) and TFA (4 mL, 51.9 mmol). The reaction mixture was stirred at RT for 6 h, concentrated, diluted with ethyl acetate, and washed with 1N NaOH. The organic phase was collected and the aqueous phase was re-extracted with ethyl acetate. The combined organic layers (a lot of unsoluble material stayed on the walls of the separatory funnel which was dissolved in MeOH and combined with the organic layers) were concentrated. A 1N NaOH solution was added; the suspension was stirred for 30 min and the solid was collected by filtration. The crude product was purified by Biotage (SNAP 50 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 40/60 over 20 CV), to afford the title compound 108 (77 mg, 0.14 mmol, 76% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.77 (s, 1H), 8.55-8.51 (m, 2H), 8.36 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.81 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.2 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.65 (d, J=5.6 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 4.52 (d, J=15.2 Hz, 1H), 4.45 (d, J=15.2 Hz, 1H), 4.15-3.65 (m, 214), 3.58 (t, J=8.8 Hz, 1H), 3.30-3.14 (m, 2H), 2.59-2.52 (m, 1H), 2.34-2.23 (m, 1H), 1.77-1.65 (m, 1H), 0.68-0.62 (m, 2H), 0.45-0.37 (m, 2H). MS (m/z): 533.6 (M+H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3O[C:16](=O)[C:15]([C:19]#[N:20])=[C:14]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[CH2:29]1[CH2:33]O[CH2:31][CH2:30]1>>[N:21]1([C:14]2[CH:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)=[CH:7][CH:8]=3)[C:5]3[C:4]4[C:30](=[CH:29][CH:33]=[CH:2][CH:3]=4)[CH2:31][C:16]=3[C:15]=2[C:19]#[N:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc(-n3cccc3)cc2)oc1=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc(-n3cccc3)cc2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 6-(4-(1H-pyrrol-1-yl)phenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (345 mg), indanone-2 (132 mg) and NaH (47 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 224-226° C.; ESMS 416 (M++1); IR (KBr) 2211 cm−1 (CN); 1H NMR (200 MHz, CDCl3) δ 1.60-1.66 (m, 2H, CH2), 1.79-1.82 (m, 4H, 2CH2), 3.22-3.30 (m, 4H, 2CH2) δ 6.42 (t, J=2 Hz, 2H, CH), 6.82 (s, 1H, ArH), 6.93 (d, J=7.8 Hz, 1H, ArH), 7.07 (t, J=7.5 Hz, 1H, ArH), 7.17-7.24 (m; 4H, ArH & CH), 7.46-7.59 (m, 4H, ArH).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]2)[CH:3]=1.[CH3:27][Mg]Br>O1CCCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([OH:13])[CH3:27])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]2)[CH:3]=1
Reactant: O=Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a cooled solution of 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinoline-6-carbaldehyde (100 mg, 0.26 mmol) in tetrahydrofuran (20 mL) was added a solution of methyl magnesium bromide in tetrahydrofuran (0.13 mL, 0.39 mmol, 3 M) at 0° C. dropwise. After being stirred for 20 minutes at the temperature below 12° C., the mixture was concentrated in vacuo. The residue was purified by preparative TLC to give 100 mg of the desired product (yield was 96%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])/[C:9](/[S:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:22]\[C:21]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:20]=2[Cl:19])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: O=C(CSc1ccc(Br)cc1)c1ccc(Br)cc1
Product: O=C(/C(=C\c1ccc(Cl)cc1Cl)Sc1ccc(Br)cc1)c1ccc(Br)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 1. A solution of 1-(4-bromophenyl)-2-(4-bromophenylthio)ethanone (10 mmol) and 2,4-dichlorobenzaldehyde (10 mmol) was subjected to the procedure described as Method B in part C of Synthesis Example 1 and the product obtained was purified by column chromatography.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[C:5]=1[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl:33][C:34]1[CH:35]=[N:36][CH:37]=[C:38]([Cl:41])[C:39]=1Cl>CS(C)=O>[CH2:26]([O:25][CH2:24][CH2:23][C:5]1[C:6](=[O:22])[O:7][C:8]2[C:13]([C:4]=1[NH:3][C:39]1[C:38]([Cl:41])=[CH:37][N:36]=[CH:35][C:34]=1[Cl:33])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc2c(N)c(CCOCc3ccccc3)c(=O)oc2c1OC1CCCC1
Reactant: Clc1cncc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)c(CCOCc3ccccc3)c(=O)oc2c1OC1CCCC1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (230 mg, 60%, 5.8 mmol) was added portionwise to a solution of 4-amino-3-(2-(benzyloxy)ethyl)-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (800 mg, 1.86 mmol) and DMSO (20 mL). After 10 min at rt, 3,4,5-trichloropyridine (1.0 g, 5.47 mmol) was added. The reaction was then heated at 50° C. overnight, allowed to cool to rt, quenched with drops of water, poured into 0.5M KH2PO4 (15 mL), and then extracted with ethyl acetate (50 mL×2). The combined extracts were washed with brine (50 mL), dried, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate:petroleum ether) to give 3-(2-(benzyloxy)ethyl)-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]2[CH2:11][C:10]([CH2:13][C:14](OC(C)(C)C)=[O:15])([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[C:21]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:11][C:10]([CH2:13][CH2:14][OH:15])([OH:12])[CH2:9]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
To a solution of 1,1-dimethylethyl [1-(diphenylmethyl)-3-hydroxyazetidin-3-yl]acetate (333 mg, 0.94 mmol) in THF (3 mL) at 0° C. was added lithium aluminum hydride (940 μL of a 1.0 M solution in THF, 0.94 mmol). The mixture was stirred for 3 h 20 min while warming to rt. Water (36 μL) was added carefully to the solution, followed by 15% sodium hydroxide (36 μL) and more water (108 μL). The resulting precipitate was removed by filtration through celite, and the filtrate was concentrated to dryness yielding 1-(diphenylmethyl)-3-(2-hydroxyethyl)azetidin-3-ol (228 mg, 0.80 mmol, 85% yield) as a colorless syrup. 1H NMR (400 MHz, CDCl3): δ 7.38 (m, 4H), 7.26 (m, 4H), 7.19 (m, 2H), 4.37 (s, 1H), 3.92 (m, 2H), 3.32 (m, 2H), 2.96 (m, 2H), 2.07 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH2:25][Cl:26])=[O:22].Cl>C(Cl)(Cl)Cl>[Cl:26][CH2:25][CH2:24][O:23][C:21]([NH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)=[O:22]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=C(Cl)OCCCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](NC(=O)OCCCl)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (5.00 g) obtained in Reference Example 2(1) is dissolved in chloroform (60 ml), and thereto is added triethylamine (11 ml) under ice-cooling, followed by dropwise addition of a solution of 2-chloroethyl chloroformate (3.3 ml) in chloroform (10 ml). After stirring at room temperature for 2.5 hours, to the reaction solution is added 5% hydrochloric acid and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and then evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in chloroform/diisopropyl ether. The precipitates are collected by filtration and dried to give methyl trans-4-{[(2-chloroethoxy)carbonyl]amino}cyclohexanecarboxylate (5.11 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[C:8]1([OH:16])[CH2:14][CH:13]2[NH:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1.Br[CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].C([O-])([O-])=O.[K+].[K+].O>CC#N>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[N:15]1[CH:13]2[CH2:12][CH2:11][CH:10]1[CH2:9][C:8]([C:3]1[N:4]=[CH:5][CH:6]=[CH:7][N:2]=1)([OH:16])[CH2:14]2
Reactant: OC1(c2ncccn2)CC2CCC(C1)N2
Reactant: Clc1ccccc1C(Br)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OC1(c2ncccn2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Temperature: 22.5 °C

Procedure:
Under N2, a well stirred mixture of 3-pyrimidin-2-yl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (4.5 g, 14 mmol), 1,1′-(bromomethylene)bis(2-chlorobenzene) (5.0 g, 16 mmol) and K2CO3 (10.0 g, 72 mmol) in CH3CN (50 ml) was stirred under reflux and the reaction was followed by HPLC. After complete reaction (36 to 48 h) the mixture was cooled to 20-25° C., water (50 ml) was added and the suspension was stirred for 3 h. The product was filtered off, washed with water (2×25 ml) and dried to constant weight under vacuum and a slight stream of N2 at 50° C. Yield: 5.5 g (87% abs.). Assay (HPLC): 97% pure vs. standard.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]1[CH3:21])[CH3:4]>C(Cl)Cl>[CH3:21][C:6]1[N:5]([CH:3]([CH3:4])[CH:2]=[O:1])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15]
Reactant: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)CO
Solvent: ClCCl
Product: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)C=O
Yield: 52.9 %

Procedure:
To tert-butyl 1-(1-hydroxypropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (380 mg, 1.31 mmol) in CH2Cl2 (5 ml) were added DMP (610.6 mg, 1.44 mmol) at 25° C. for 18 h. After the reaction completed, the solution was purified by silica gel and concentrated under reduced pressure to give tert-butyl 2-methyl-1-(1-oxopropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a white oil (200 mg, yield 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH:15]([OH:28])[CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-:31].[K+]>C(O)(C)(C)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH:15]([OH:28])[CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([NH2:27])=[O:31])=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(OCC(O)Cn2ccc3cc(C#N)ccc32)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCCCCCOc1ccc(OCC(O)Cn2ccc3cc(C(N)=O)ccc32)cc1

Procedure:
455 mg (1.12 mmol) 1-[3-(4-Heptyloxyphenoxy)-2-hydroxypropyl]indole-5-carbonitrile are dissolved in 10 ml tert-butanol. Having added 1.10 g (22.4 mmol) pulverized, 88% potassium hydroxide, the batch is heated to 100° C. for 3 hours. After cooling the reaction solution, hydrolysis using 50 ml distilled water and neutralization with 1 N hydrochloric acid are carried out. The aqueous phase is extracted three times with ethyl acetate and the combined organic phases are washed once with water and then twice with saturated sodium chloride solution. Following drying on sodium sulfate, the solvent is removed on the rotary evaporator. The residue is purified on silica gel by means of column chromatography (flow agent: ethyl acetate), the product accruing as a solid.