Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.Cl>O1CCOCC1>[ClH:27].[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C@@H:7]3[CH2:8][CH2:9][CH2:10][CH2:11][N:6]3[CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[CH:19][CH:18]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CCN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
To the product from Example 58 (25 mg, 0.0612 mmol) in 1,4-dioxane (1 mL) was added 12N HCl (0.8 mL) and the resulting mixture was stirred at 55° C. for 5 h. The solvent was removed in vacuo to obtain the product as a solid. The oil was triturated with diethyl ether (4 mL) to obtain the title product as a white solid. (19 mg, 73%): MS; m/z 390 (M+H): LCMS (UV) 90%; 1H NMR (400 MHz, DMSO-d6) δ 1.5-1.54 (m, 1H), 1.77-1.79 (m, 4H), 1.95-1.98 (m, 1H) 2.79-2.84 (m, 2H), 3.05-3.1 (m, 1H), 3.37-3.47 (m, 3H), 3.64-3.69 (m, 1H), 4.27-4.29 (m, 2H), 6.94 (d, 2H, J=9.2 Hz), 7.04-7.06 (m, 4H), 7.4 (d, 2H J=8.8 Hz)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.Cl.[CH2:18]([NH2:20])[CH3:19].C(N(CC)CC)C>C(O)(C)C>[CH2:18]([NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1)[CH3:19]
Reactant: CCN
Reactant: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCNc1nc(-c2ccccc2)ncc1[N+](=O)[O-]
Yield: 93.3 %

Procedure:
A mixture of 4-chloro-5-nitro-2-phenylpyrimidine (3 g), ethylamine hydrochloride (1.6 g), triethylamine (3.9 g) and isopropanol (60 ml) is refluxed for three hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added chloroform and water. The chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from isopropanol to give the desired compound (2.9 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[CH3:26])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)N[C@@H]1CCc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (85 μL, 0.62 mmol) in methylene chloride (15 mL) was added dropwise 2-methylbenzoyl chloride (66 mg, 0.43 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3.5) as the eluent. Yield: 100 mg (80%) of the title compound as white crystals: mp 179-180° C.; [α]21D −22° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 363 (21, M+).
Reaction SMILES: [CH2:1]([C:5]1([CH:9]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH2:11][CH:12]=[O:13])[CH2:8][CH2:7][CH2:6]1)[CH2:2]CC.C([Si](OC(C1(CC)CCC1)C#C)(C)C)(C)(C)C>CCOC(C)=O.CCCCCC>[Si:15]([O:14][CH:9]([C:5]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH2:6]1)[CH2:10][CH2:11][CH:12]=[O:13])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CCCCC1(C(CCC=O)O[Si](C)(C)C(C)(C)C)CCC1
Agent: C#CC(O[Si](C)(C)C(C)(C)C)C1(CC)CCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC1(C(CCC=O)O[Si](C)(C)C(C)(C)C)CCC1

Procedure:
The title compound was prepared according to the procedure described for intermediate 2.6 from tert-butyl {[1-(1-ethylcyclobutyl)prop-2-ynyl]oxy}dimethylsilane. (intermediate 21.5). Rf 0.6 (EtOAc/hexanes 1/4).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: OB(O)c1ccccc1Cl
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure A using 2,8-dichloroquinoline 3-carbaldehyde (1.70 g, 7.5 mmol), 2-chlorophenyl boronic acid (1.29 g, 8.25 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.430 g, 0.375 mmol, 0.05 eq), and sodium carbonate (3.97 g, 37.5 mmol, 5 eq) in acetonitrile (57 mL) and water (19 mL). After purification, 8-chloro-2-(2-chlorophenyl)quinoline-3-carbaldehyde was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.25 (1H, s), 8.93 (1H, s), 8.14 (1H, d, J=8.6 Hz), 8.03 (1H, d, J=9.0 Hz), 7.55-7.64 (1H, t, J=8.0 Hz) Mass Spectrum (ESI) m/e=302.0 and 304.0 (M+1)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[CH:34]=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([N:36]1[CH:37]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[CH:34]=[N:35]1)[CH3:39]
Reactant: CCn1cc(CCl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)cn1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (1.29 g; compound B50) is reacted with 4-(chloromethyl)-1-ethyl-1H-pyrazole (434 mg; compound D16) in the presence of potassium carbonate (832 mg) in DMF (20 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 3/2 (v/v)] as a solid.
Reaction SMILES: C(O)(=O)C.O1CCCC1.FC(F)(F)C(O)=O.[Na:17].[Si]([O:25][C@@H:26]1[C@@H:31]([O:32][Si](C(C)(C)C)(C)C)[C@H:30]([O:40][Si](C(C)(C)C)(C)C)[C@@H:29]([CH2:48][S:49]([OH:52])(=[O:51])=[O:50])[O:28][C@@H:27]1[O:53][CH2:54][CH:55]([OH:77])[CH2:56][O:57][C:58](=[O:76])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]/[CH:66]=[CH:67]\[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])(C(C)(C)C)(C)C>O>[Na:17].[S:49]([CH2:48][C@H:29]1[O:28][C@H:27]([O:53][CH2:54][CH:55]([OH:77])[CH2:56][O:57][C:58](=[O:76])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]/[CH:66]=[CH:67]\[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])[C@H:26]([OH:25])[C@@H:31]([OH:32])[C@@H:30]1[OH:40])([OH:52])(=[O:50])=[O:51]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)CO[C@H]1O[C@H](CS(=O)(=O)O)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)CO[C@H]1O[C@H](CS(=O)(=O)O)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
Into 7 mL of a solution of acetic acid, tetrahydrofuran, trifluoroacetic acid and water (3:1:0.4:1), 358.4 mg (378 μmol) of the compound (X) was dissolved. The solution was reacted at room temperature for 16 hours while stirring, and the reaction mixture was extracted with ethyl acetate (3×10 mL). The. organic layers were combined, washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel flash chromatography (dichloromethane methanol=10:1→dichloromethane:methanol:water=65:25:4) (yield: 138.1 mg (229 μmol), recovery: 62.7%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH:19]=[O:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].[CH3:21][Mg]Cl>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:1]([C:3]1([CH2:18][CH:19]([OH:20])[CH3:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: C[Mg]Cl
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC=O)OCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(C)O)OCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of compound 8 (275 mg, 1.01 mmol) in dry THF (4 mL) was added dropwise over five minutes to a stirred solution of 1M MeMgCl in THF (1.52 mL, 1.52 mmol, 1.5 eq) at 0° C. under argon and allowed to warm slowly to room temperature. After stirring for two hours, another equivalent of 3M MeMgCl in THF (337 μL, 1.01 mmol, 1.0 eq) was added, and the mixture was stirred for an additional hour. The mixture was then diluted with saturated NaHCO3 and extracted three times with EtOAc. The combined organic phases were dried with Na2SO4, concentrated, and purified by column chromatography using 20:80:EtOAc:Hexane to give a yellow solid (280 mg, 96%): mp 103-104° C. 1HNMR (CDCl3, δ TMS) shows a 2:1 mixture of diastereomers. MS−: m/z 322 (MCl−), 286 ([M−H]−). Anal. (C18H25NO2): C, H, N. The product was carried on to the next step as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([CH2:10][C:11]([O:13]CC)=[O:12])[N:4]=1)[CH3:2].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([CH2:10][C:11]([OH:13])=[O:12])[N:4]=1)[CH3:2]
Reactant: CCOC(=O)Cn1nc(CC)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(CC)n(CC(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
Ethyl 3,5-diethyl-1H-pyrazole-1-acetate (2.79 g, 13.3 mmol) (i.e. the product of Example 15, Step B) in tetrahydrofuran (10 mL) was treated with sodium hydroxide (1.0 g) in water (7.5 mL) The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether. The resulting aqueous layer was acidified with concentrated hydrochloric acid to give a white precipitate. The precipitate was filtered and dried in air to give 690 mg of the title compound.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]([CH:26]1[C:35]2[N:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28][CH2:27]1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]([CH2:15][C:7]2[NH:6][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH:26]2[C:35]3[N:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:29][CH2:28][CH2:27]2)=[CH:19][CH:20]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 24.8 %

Procedure:
Isobutyraldehyde (0.1 mL, 1.1 mmol) was condensed with N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (152 mg, 0.382 mmol) in dry CH3OH (5 mL) for 17 h and the resultant imine was reduced with NaBH4 (81 mg, 2.14 mmol) for 1 h (see General Procedures A and B). Purification of the crude product by radial chromatography (2 mm TLC plate, 50:1:1 CH2Cl2/CH3OH/NH4OH) gave the free amine (43 mg, 25%).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31](=[O:33])[NH2:32])[CH:20]=[C:19]1[CH:34]1[CH2:36][CH2:35]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN[C@H](C(N)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:31]([NH2:32])=[O:33])[CH:20]=[C:19]1[CH:34]1[CH2:35][CH2:36]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-4-cyclopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 268, 1.47 g, 2.81 mmol) following the procedure described for Intermediate 21. The desired product was obtained as a light yellow foam (0.95 g, 80%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([C:14]1[CH:19]=[C:18]([C:20]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:24][CH2:23][CH2:22][O:21]2)[CH:17]=[CH:16][C:15]=1[NH:32][C:33](=[O:35])[CH3:34])=O>COCCOC>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]2([C:18]3[CH:19]=[C:14]4[C:15](=[CH:16][CH:17]=3)[NH:32][C:33](=[O:35])[CH:34]=[C:12]4[C:11]3[CH:36]=[CH:37][CH:38]=[C:9]([O:8][CH3:7])[CH:10]=3)[O:21][CH2:22][CH2:23][O:24]2)=[CH:30][CH:29]=1
Reactant: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2NC(C)=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cccc(-c2cc(=O)[nH]c3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Yield: 123 %

Procedure:
Potassium tert-butoxide (33 g) was added portionwise at room temperature to a solution of interm. (5-d) (36.4 g) in 1,2-dimethoxyethane (350 ml) and the mixture was stirred at room temperature overnight. The mixture was hydrolized and extracted with DCM. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The product was used without further purification, yielding 43 g of 6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-4-(3-methoxyphenyl)-2(1H)-quinolinone (interm. 5-e).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3c(Cl)cccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3c(Cl)cccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 75.5 %

Procedure:
A mixture of 2.01 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.95 g of 2-(dimethylamino)ethyl chloride hydrochloride, 2.49 g of powdered potassium carbonate, 60 ml of acetone and 0.6 ml of water is refluxed for 23 hours. After the reaction is completed, insoluble materials are removed by filtration. The filtrate is evaporated to remove solvent. The residue is digested with isopropyl ether and the resultant crystals are collected by filtration and recrystallized from ethyl acetate. 1.84 g of (±)-cis-2-(4-methoxypheny)-3-hydroxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained. Yield: 75.4%
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:11]([C@@H:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)=[O:12])[CH2:24]2)[CH:18]=1
Reactant: COC(=O)c1cccc(C2CCCNC2)c1
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc([C@H]2CCCN(C(=O)[C@H]3COc4ccccc4O3)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (240 mg, 1.21 mmol) in DCM (5 ml) was added to an ice-cold mixture of 3-(piperidin-3-yl)benzoic acid methyl ester (267 mg, 1.21 mmol), triethylamine (59 mg, 0.58 mmol) and DCM (10 ml). After stirring for 2 h at RT, the mixture was washed with 1 M HCl (10 ml) and 1 M Na2CO3. The organic phase was dried over Na2SO4 and evaporated to dryness and the residue was purified by flash chromatography using heptane/EtOAc as eluent. The first eluting diastereomer was collected to afford 98 mg of the title compound.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][N:9]=1>O.CS(C)=O>[CH3:16][N:13]1[CH2:14][CH2:15][N:10]([C:5]2[C:4](=[O:1])[NH:9][CH:8]=[CH:7][N:6]=2)[CH2:11][CH2:12]1
Reactant: [OH-]
Reactant: CN1CCN(c2nccnc2Cl)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2ncc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of NaOH (5.4 g, 125 mmol) in a mixture of water/DMSO (1:1; 15 mL) at 80° C. was added 1-(3-chloro-2-pyrazinyl)-4-methylpiperazine (obtained in Step 1 above; 2.5 g, 12 mmol). After being stirred for 2 h, the dark red solution was cooled to room temperature, extracted with EtOAc overnight to give, after drying and solvent removal in vacuo, 0.96 g (43%) of the title compound as an off-white solid. HPLC purity: 88%. MS m/z 195 (M+H)+. HRMS m/z calcd for C9H14N4O (M)+ 194.1168, found 194.1159.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:16][NH3+:17]>C(O)C>[CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[N:17][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1=Cc1ccccc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Product: ON=C1CCCCC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.8 %

Procedure:
A mixture of 2-benzylidenecyclohexanone (3.5 g, 18.8 mmol, J. Chem. Soc. 1949, 2957), hydroxylammonium chloride (3.9 g, 56 mmol) and ethanol (50 ml) was stirred at ambient temperature for 3 days. The solvent was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate (200 ml) and water (50 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic extracts were washed with water and dried (MgSO4). The solvent was evaporated in vacuo to give 3.7 g of 2-benzylidenecyclohexanone oxime as a solid. M.p. 114°-115° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8])([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 120 h

Procedure:
A mixture of 3,4-dinitro-benzoylchloride (24 g, 93.7 mmol) in 80 mL THF was added to a stirred mixture of aniline (10.4 mL, 112 mmol) and TEA (15.6 mL, 112 mmol) in 300 mL THF under nitrogen. After stirring for 5 days, the mixture was filtrated, washed with THF and evaporated to dryness. The residue was taken up in diethyl ether, filtrated and dried at 55° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)O1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]([C:27]2([C:30]3[CH:40]=[CH:39][C:33]4[O:34][C:35]([F:38])([F:37])[O:36][C:32]=4[CH:31]=3)[CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:20][C:19]=1[CH3:41]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:38][C:35]1([F:37])[O:34][C:33]2[CH:39]=[CH:40][C:30]([C:27]3([C:25]([NH:24][C:22]4[CH:21]=[CH:20][C:19]([CH3:41])=[C:18]([C:9]5[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=5)[N:23]=4)=[O:26])[CH2:29][CH2:28]3)=[CH:31][C:32]=2[O:36]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(O)c1
Temperature: 120 °C
Yield: 78.2 %

Procedure:
To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (132 mg, 0.600 mmol) and N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (183 mg, 0.500 mmol) in DME (3 mL) and 2 M Na2CO3 (0.5 mL) was added Pd(PPh3)4 (29 mg, 0.025 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(3-hydroxyphenyl)-5-methylpyridin-2-yl)cyclopropanecarboxamide (166 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 7.18-7.15 (m, 2H), 6.91-6.88 (m, 2H), 6.79-6.78 (m, 1H), 6.73-6.69 (m, 2H), 2.29 (s, 3H), 1.75 (q, J=3.6 Hz, 2H), 1.15 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 426.2.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:11]([C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2C(N[C:22](=[O:23])[C:17]=12)=O)(OCC)=[O:12].Cl>C([O-])([O-])=O.[Na+].[Na+].O>[CH:25]1[CH:26]=[C:16]2[C:11]([N:1]([C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:22](=[O:23])[C:17]2=[CH:18][CH:24]=1)=[O:12]
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O

Procedure:
In a solution of Na2CO3 (51.5 g) in water (350 ml) at 5° C. was dissolved L-glutamic acid (29.4 g). Carboethoxy phthalimide (59.6 g) was added to the solution and suspended therein and thereafter reacted at 350° C. for 30-40 minutes. Then the solution was freed from insoluble matter, adjusted to pH 2.5 with 6N-HCl, and allowed to stand at 0° C. The resulting precipitate was filtered, and recrystallized from water to give N,N-phthaloylglutamic acid, yield 35.7 g, 64.4%; specific rotation [α]D25 =-48.6°(C=1, dioxane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[Mn+2]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CO)ccc21
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a solution of N-tert-butoxycarbonylindol-5-yl methanol (2.56 g, 10.35 mmol) in dry methylene chloride (60 mL) was added manganese oxide (9 g, 103.5 mmol). The reaction mixture was stirred for 3 h at room temperature and then heated at reflux. After 3 h, the heterogeneous slurry was filtered through Celite and concentrated to afford N-tert-butoxycarbonyl-5-formylindole (2.5 g).