Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[O:20])=[CH:13][CH:12]=2)=[N:9][N:10]=1)C.C(=O)([O-])O.[Na+].Cl>C(O)C.O>[CH3:27][C:23]1[CH:22]=[C:21]([C:19](=[O:20])[CH2:18][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3[O:7][C:6]([CH2:5][C:4]([OH:35])=[O:3])=[N:10][N:9]=3)=[CH:12][CH:13]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:26]=[CH:25][N:24]=1
Reactant: CCOC(=O)Cc1nnc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)CC(c2ccc(-c3nnc(CC(=O)O)o3)cc2)c2ccccc2C)ccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (5-{4-[(−)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-[1,3,4]oxadiazol-2-yl)-acetic acid ethyl ester (146 mg) in a mixture of ethanol (5 mL) and water (1.25 mL) was added sodium hydrogencarbonate (104 mg) and the reaction mixture stirred at room temperature for 4 h. The solution was adjusted to approximately pH 3 by using 1 M aqueous hydrochloric acid and then extracted over a sat. solution of brine (50 mL) with ethyl acetate (3×50 mL). The combined organic phases were dried over sodium sulfate and the crude reaction product purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Light yellow solid. MS (ESI+): m/z=442.4 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH2:17]([N:19]([CH2:36][CH3:37])[C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(O)[C:27]#[CH:28])=[CH:22][CH:21]=1)[CH3:18]>C1(C)C=CC=CC=1>[CH2:36]([N:19]([CH2:17][CH3:18])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:12][C:5]3[C:6]4[C:11]([C:2]([OH:1])=[C:3]([C:13]([O:15][CH3:16])=[O:14])[C:4]=3[CH:28]=[CH:27]2)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:22][CH:21]=1)[CH3:37]
Reactant: COC(=O)c1cc(O)c2ccccc2c1O
Reactant: C#CC(O)(c1ccccc1)c1ccc(N(CC)CC)cc1
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(C2(c3ccccc3)C=Cc3c(C(=O)OC)c(O)c4ccccc4c3O2)cc1
Yield: 55.7 %

Procedure:
Methyl 1,4-dihydroxynaphthalene-2-carboxylate (4.00 g, 18.3 mmol), 1-(4-diethylaminophenyl)-1-phenyl-prop-2-yn-1-ol (4.67 g, 18.3 mmol) and Al2O3 (4.5 g) in toluene (150 mL) was refluxed for 3 hrs, filtered whilst hot and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM (20% hexane) as eluent followed by a second filtration through silica using DCM as eluent. The residue was crystallised from acetone-MeOH and the product isolated as a yellow solid (4.89 g, 56%)
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[F:19][C:20]1[CH:26]=[CH:25][C:23](N)=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(F)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(F)cc4)c3c2s1
Yield: 92 %

Procedure:
Prepared from VII and 4-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 92%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3049, 2840, 2226, 1722, 1643, 1610, 1581, 1557, 1502, 1377, 1355, 1305, 1269, 1227, 1208, 1166, 1130, 1090, 981, 846, 829, 818; 19F NMR (282 MHz, DMSO-d6) δ −120.31; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.16 (s, 1H), 7.76 (d, 1H, J=9.0 Hz), 7.26-7.08 (m, 4H); HRMS calcd for C16H9N5SF (M+H+): 322.0563, found 322.0551.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([NH:18][C:19]3[C:24]([N+:25]([O-])=O)=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O1CCOCC1.[Fe]>[NH2:25][C:24]1[C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:10](=[O:11])[NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:13]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)c1cccc(Nc2ncccc2[N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Nc1cccnc1Nc1cccc(C(=O)Nc2cc(Cl)cc(Cl)c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
A mixture of 2-[3-(3,5-dichlorophenylcarbamoyl)phenylamino]-3-nitropyridine (565 mg) and iron powder (0.4 g) in acetic acid (5 ml) and 1,4-dioxane (5 ml) was stirred at 80° C. for 3 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-amino-2-[3-(3,5-dichlorophenylcarbamoyl)phenylamino]pyridine (284 mg).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26](Cl)=O.O=P(Cl)(Cl)Cl>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1ccc(CCC(=O)Cl)c(OC)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)c(OC)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol), TEA (0.153 ml; 1.1 mmol), 2,4-dimethoxyphenylpropionylchloride (228 mg, 1.1 mmol) and POCl3 (0.5 ml; 5.5 mmol) as described in method 1; yield: 0.013 mg (3.7%); MS m/z: 351.3[M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 2.97-3.00 (m, 2H); 3.11-3.13 (m, 2H); 3.71 (s, 6H); 6.41-6.43 (m, 1H); 6.51 (br s, 1H); 7.06-7.08 (m, 1H); 7.75-7.77 (m, 1H); 7.81-7.83 (m, 1H); 8.15 (br s, 1H); 8.43 (s, 1H); HPLC (METHOD [A]): rt 12.06 min (100%)
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:17][NH:18][CH3:19].[BH3-]C#N.[Na+].Cl>CO>[CH3:17][N:18]([CH3:19])[CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CNC
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)C1CCN(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-oxo-piperidin-1-yl)-benzonitrile (100 mg, 0.5 mmol, reference example 116) dimethylamine hydrochloride (408 mg, 5 mmol) and NaCNBH3 (25 mg, 0.4 mmol) was dissolved in MeOH (7 mL) and stirred at room temperature overnight. After 24 h, additional NaCNBH3 (24 mg, 0.38 mmol) was added and the mixture was stirred overnight at room temperature. The pH of the mixture was adjusted to pH 2 with concentrated HCl and extracted with Et2O (3×). The aqueous phase was adjusted to pH 10 with KOH pellets, and extracted (3×) with Et2O. The latter combined organic phases were washed with brine, dried with Na2SO4, filtered and evaporated. The crude material was taken into the next step without further purification. 1H NMR (CDCl3): δ 7.44 (d, 2H), 6.83 (d, 2H), 3.86 (m, 2H), 2.86 (dt, 2H), 2.32-2.38 (m, 1H), 2.28 (s, 6H), 1.92 m(m, 2H), 1.54 (dq, 2H). MS (EI) m/z 229 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:11]([O-])=O)[CH:5]=[CH:4][CH:3]=1>[Pd]>[NH2:11][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Agent: [Pd]
Product: Cc1cccc(N)c1C(=O)O
Yield: 127.2 %

Procedure:
To a methanolic solution (150 ml) of 6-methyl-2-nitrobenzoic acid (14.25 g) was added palladium-on-carbon (1.40 g) and the hydrogenation reaction was conducted at atmospheric temperature and pressure (hydrogen consumption 5.3 1). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to provide the title compound as light-yellow solid (15.12 g; yield 100%). 1H-NMR (CDCl3) δ: 2.47(3H,s), 6.50(2H,t,J=8.1Hz), 7.00-7.07(4H,m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])=[CH:7][CH:6]=1.[CH3:33][N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39](O)=[O:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[C:39]([C@@H:35]2[CH2:36][CH2:37][CH2:38][N:34]2[CH3:33])=[O:40])=[CH:7][CH:6]=1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccc(CC(=O)OC)cc3)c2n1
Reactant: CN1CCCC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3ccc(CC(=O)OC)cc3)C(=O)[C@@H]3CCCN3C)c2n1

Procedure:
The product of example 1, step (ix) (0.43 g), 1-methyl-pyrrolidine-2-carboxylic acid (0.13 g) and HATU (0.37 g) were stirred in DCM (5 ml) at rt for 7 days. The reaction mixture was purified by SCX and RPHPLC, to give the title compound. Yield 24 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].S(Cl)([Cl:20])=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][Cl:20])=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)oc2ccc(Br)c(OC(C)C)c12
Solvent: ClCCl
Product: Cc1c(CCl)oc2ccc(Br)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-yl) methanol (0.3 g, 1 mmole) in 10 mL dichloromethane was added 0.73 mL of thionyl chloride and the reaction was stirred at room temperature for 2 hours. The solvent was concentrated in vacuo, the residue was added toluene to provide 0.33 g of 5-bromo-4-isopropoxy-3-methyl-2-chloromethyl-1-benzofuran.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[C:20]([OH:22])[C:19](S(O)(=O)=O)=[CH:18][C:3]=1[C:4]([C:6]1[CH:11]=[C:10](S(O)(=O)=O)[C:9](O)=[CH:8][C:7]=1O)=[O:5].[Na][Na]>>[OH:1][C:2]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1cc(S(=O)(=O)O)c(O)cc1O)c1cc(S(=O)(=O)O)c(O)cc1O
Agent: [Na][Na]
Product: O=C(c1ccccc1)c1ccc(O)cc1O

Procedure:
2,2′,4,4′-tetrahydroxy-5,5′-disulfobenzophenone, disodium salt;
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8].[NH:14]([CH2:16]C(O)=O)[CH3:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]12[CH2:3][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:10][CH:11]1[N:14]([CH3:16])[CH2:15][CH2:13]2
Reactant: CNCC(=O)O
Reactant: C=C(Cl)CN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2N(C)CCC2(Cl)C1

Procedure:
10.3 g (50 mmol) of ethyl N-(2-chloroallyl)-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 4.5 g (50 mmol) of sarcosine in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].C([O:20][N:21]=O)CCC>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[N:21][OH:20])[C:6]2=[O:15]
Reactant: CCCCON=O
Reactant: COc1cc2c(c(Cl)c1OC)CCC2=O
Product: COc1cc2c(c(Cl)c1OC)CC(=NO)C2=O

Procedure:
Similar procedure as described in example 9B was used, starting from 4-Chloro-5,6-dimethoxy-indan-1-one and n-butylnitrite to give 4-Chloro-5,6-dimethoxy-indan-1,2-dione 2-oxime. LC-MS: m/e 256 (MH+).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:18]([Cl:20])[CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:18]([Cl:20])[CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1cnc(NC(=O)OC(C)(C)C)c(Cl)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(Cc1cnc(NC(=O)OC(C)(C)C)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
A solution of KOH (0.44 g, 6.72 mmol, 85%) in ethanol (5 ml) was added to a solution of 2-(6-tert-butoxycarbonylamino-5-chloro-pyridin-3-ylmethyl)-malonic acid diethyl ester (2.45 g, 6.11 mmol) in ethanol (25 ml) and methylene chloride (10 ml) at 0° C. The mixture was stirred for 18 h at room temperature. The solvent was evaporated in vacuo and the residue dissolved in water. The aqueous layer was washed with ether, acidified to pH 4 by 1 M HCl and extracted with methylene chloride and ethyl acetate. The combined organic layers were washed with water and brine and dried. Filtration and concentration under reduced pressure gave the crude product which was purified by flash chromatography (10% MeOH in CH2Cl2) giving 2-(6-tert-butoxycarbonylamino-5-chloro-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.41 g, 62%) as a yellow-white glassy foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([O:16][C:17]2[C:22](/[CH:23]=C/C)=[CH:21][C:20]([F:26])=[CH:19][C:18]=2[Br:27])[CH:14]=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH:14]=[CH:23][C:22]3[C:17](=[C:18]([Br:27])[CH:19]=[C:20]([F:26])[CH:21]=3)[O:16]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=CC(COS(=O)(=O)c1ccc(C)cc1)Oc1c(Br)cc(F)cc1/C=C/C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2C=Cc3cc(F)cc(Br)c3O2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 95.8 %

Procedure:
To a solution of 2-{2-bromo-4-fluoro-6-[(1E)-prop-1-enyl]phenoxy}but-3-enyl 4-methylbenzenesulfonate (10.95 g, 0.024 mol) in dry dichloromethane (300 mL) at room temperature under nitrogen was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (1.97 g, 2.4 mmol) and the reaction mixture stirred at room temperature for 5 days. The reaction mixture was then concentrated under reduced pressure to a small volume and directly pre-adsorbed onto silica gel. Purification by flash chromatography using a solvent gradient of 5 to 30% ethyl acetate in hexane gave 9.5 g (96%) of (8-bromo-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate as a grey solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[C:26](F)[C:25]([CH3:29])=[CH:24][C:23]=1[N+:30]([O-:32])=[O:31]>>[Cl:21][C:22]1[C:23]([N+:30]([O-:32])=[O:31])=[CH:24][C:25]([CH3:29])=[C:26]([CH:27]=1)[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[N:9]=[C:10]([CH3:18])[C:11]=12
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Product: COc1ccc(Cn2nc(C)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4C)ccnc32)cc1
Yield: 75.3 %

Procedure:
Prepared from 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150 g, 0.557 mmol; prepared as in Example 5, Step B) and 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (0.106 g, 0.557 mmol), according to the procedure of Example 13, Step A. Purified by Biotage 40S column eluting with 3:1 hexane/EtOAc then EtOAc to obtain the product (184 mg, 75%) as an off white solid. 1H NMR (CDCl3, 400 MHz) δ 8.36 (d, J=5.1 Hz, 1H), 7.95 (s, 1H), 7.35 (d, J=9.0 Hz, 1H), 7.21 (s, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.23 (d, J=5.1 Hz, 1H), 5.58 (s, 1H), 3.77 (s, 3H), 2.63 (s, 3H), 2.31 (s, 3H). LRMS (APCI pos) m/e 439 (M+1).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@:9]1([C:21]([O:23][CH3:24])=[O:22])[CH2:19][C@@H:18]([OH:20])[C@@H:12]2[O:13][C:14]([CH3:17])([CH3:16])[O:15][C@@H:11]2[CH2:10]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[OH:8][C@:9]1([C:21]([O:23][CH3:24])=[O:22])[CH2:19][C@@H:18]([O:20][S:26]([CH3:25])(=[O:28])=[O:27])[C@@H:12]2[O:13][C:14]([CH3:16])([CH3:17])[O:15][C@@H:11]2[CH2:10]1
Reactant: COC(=O)[C@@]1(O)C[C@@H](O)[C@@H]2OC(C)(C)O[C@@H]2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@]1(O)C[C@H]2OC(C)(C)O[C@H]2[C@H](OS(C)(=O)=O)C1
Reaction time: 8 h

Procedure:
Triethylamine (5.0 mL, 35.9 mmol) was added dropwise to a 0° C. solution of Example 13B (4.4 g, 17.9 mmol) and methanesulfonyl chloride (1.38 mL, 17.9 mmol) in dichloromethane (60 mL). After stirring overnight, the reaction mixture was washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and concentrated to afford the crude desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C@H:11]([CH3:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[C:6]([C:20]([F:23])([F:22])[F:21])[N:5]=[CH:4][CH:3]=1.[CH:24](=O)[C:25]1[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[CH:29][CH:30]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:24]1[NH:1][C:2]2[CH:3]=[CH:4][N:5]=[C:6]([C:20]([F:23])([F:21])[F:22])[C:7]=2[C:8](=[O:9])[N:10]1[C@H:11]([CH3:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1C=O
Reactant: C[C@H](Cc1ccccc1)NC(=O)c1c(N)ccnc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccccc1C1Nc2ccnc(C(F)(F)F)c2C(=O)N1[C@H](C)Cc1ccccc1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
(R)-4-amino-N-(1-phenylpropan-2-yl)-2-(trifluoromethyl)nicotinamide (16.23 g, 50.2 mmol) and ortho-anisaldehyde (8.2 g, 60.2 mmol) were combined along with a catalytic amount of 4-toluenesulfonic acid (0.174 g, 1.0 mmol) in anhydrous toluene (550 mL). This mixture was heated at reflux overnight in a round bottom flask fitted with a Dean-Stark trap. The resultant dark solution was cooled to room temperature, then concentrated in vacuo to a dark brown paste. This paste was suspended in ethyl acetate, and the resultant solids were collected by filtration to provide the product (6.94 g). The filtrate was concentrated in vacuo then purified by silica gel column chromatography using 40-60% ethyl acetate/hexanes as eluant to give 12.1 g of additional product diastereomers (84% total yield). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, 1H), 7.1-7.3 (m, 7H), 6.9 (d, 1H), 6.8 (t, 1H), 6.5 (d, 1H), 5.95 (d, 1H), 5.7 (d, 1H), 4.8 (m, 1H), 3.95 (s, 3H), 3.0 (dd, 1H), 2.4 (dd, 1H), 1.3 (d, 3H). MS m/z 442.4 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C)C=O>C(Cl)(Cl)Cl>[OH:17][CH:3]([CH2:2][N:27]1[CH2:28][CH2:29][N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][CH2:26]1)[CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1CCc2ccc(OCC(O)CCl)cc2N1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1CCc2ccc(OCC(O)CN3CCN(c4ccccc4)CC3)cc2N1

Procedure:
5.1 Grams of 7-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril and 8 g of 4-phenylpiperazine are mixed with 50 ml of dimethylformamide and reacted at 50°-60° C. for 5 hours under stirring conditions. The reaction mixture is concentrated under a reduced pressure to dryness and the residue thus obtained is dissolved in 80 ml of chloroform, then the chloroform layer is washed 3 times with 5% of sodium hydrogencarbonate aqueous solution and washed 3 times with water and dried with anhydrous sodium sulfate. Chloroform is removed by distillation under a reduced pressure and the residue thus obtained is purified by a silica gel-chromatography [silica gel: Wako C-200, extracting solvent:chloroform:methanol=30:1 (v/v)]. Then the extracted product is converted into its hydrochloride by using ethanol containing hydrogen chloride and ethanol is removed by distillation under a reduced pressure. The thus obtained residue is recrystallized from water to obtain 5.6 g of 7-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.monohydrochloride.1/2 hydrate in the form of colorless crystals with a melting point of 122° C. (decomp.).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH2:17][CH2:18][CH3:19])=[CH:11]2.CN(C)[CH:22]=[O:23]>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH2:17][CH2:18][CH3:19])=[C:11]2[CH:22]=[O:23]
Reactant: CCCc1cc2cc(OC)ccc2[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1[nH]c2ccc(OC)cc2c1C=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Dimethylformamide (2 mL) was cooled to 0° C. Phosphorus oxychloride (0.5 mL) was added and the reaction mixture was stirred for 10 minutes. A solution of 5-methoxy-2-propylindole (325 mg, 1.7 mmol) in dimethylformamide (3 mL) was added to the reaction mixture dropwise over 10 minutes. The solution was stirred for an additional 40 minutes. The reaction mixture was added to ice cold 1 N NaOH (50 mL) and stirred for 10 minutes. The precipitate was collected and dried overnight in an oil driven vacuum pump equipped to a vacuum desiccator set at 40° C. yielding a white solid (318 mg, 86%): TLC Rf 0.67 in 4:1 ethyl acetate/hexanes. Melting point=166-168° C. 1H NMR (600 MHz, CDCl3) δ 10.16 (s, 1H), 8.31 (s, 1H), 7.79 (d, 1H, J=2.46 Hz), 7.23-7.22 (d, 1H, J=8.82 Hz), 6.89-6.87 (dd, 1H, J1=2.54, J2=8.76 Hz), 3.89 (s, 3H), 3.06-3.04 (t, 2H, J=7.5 Hz), 1.84-1.80 (m, 2H) 1.05-1.03 (t, 3H, J=7.32 Hz); 13C NMR (150 MHz, CDCl3) δ 184.4, 156.5, 151.4401, 129.6, 126.7, 114.7, 113.5, 111.5, 103.0, 55.8, 28.3, 23.5, 13.8. Elemental analysis calculated for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.92; H, 6.97; N, 6.34.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>CCOCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:22](=[O:25])[CH:23]=[CH2:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2ccccc2N1
Reactant: C=CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N1c2ccccc2CC1C(=O)OCC
Yield: 78.3 %

Procedure:
To a chilled and stirred mixture of 2,3-dihydroindole-2-carboxylic acid ethyl ester (14.34 g.), triethylamine (7.65 g.) and anhydrous ether (600 ml.) was added dropwise acryloyl chloride (7.1 g.) dissolved in a small amount of ether. The ice bath was removed, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was chilled in ice, then a precipitate was removed by filtration. The filter residue was washed with ether. The combined filtrate and washing were washed with water, then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure on a rotary evaporator gave the titled compound (14.4 g.) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].[NH4+].[Cl-].O>CN(C=O)C>[N:2]1[NH:15][N:16]=[N:17][C:1]=1[C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)COc1ccc(C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(-c2nn[nH]n2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution methyl 2-(4-cyanophenoxy)acetate in DMF was treated with NaN3 and NH4Cl and stirred in an oil bath at 80° C. for 18 hours. Then, the mixture was poured into H2O and extracted with Et2O. The aqueous layer was acidified to pH 2-3 with HCl and the precipitate was collected to give methyl 2-(4-(2H-tetrazol-5-yl)phenoxy)acetate.