Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O)C.[Cl:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:7]=1[N+:15]([O-])=O.[OH-].[Na+]>O>[Cl:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:15]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc(N)c1Cl

Procedure:
A solution of 1 ml. of concentrated hydrochloric acid in 5 ml. of 5% ethanol is slowly added to a refluxing mixture of 10.1 g. of 1-chloro-2,6-dinitrobenzene, electrolytically reduced iron and 20 ml. of 50% ethanol. The mixture is heated at reflux for two hours. The mixture is allowed to cool slightly and the pH is adjusted to 8 with sodium hydroxide solution. The iron products are removed by filtration. The solvent is removed from the filtrate to leave a solid which is dissolved in water and extracted with methylene chloride. Removal of the solvents leaves an oily solid which upon recrystallization of from Skellysolve B gives off-white crystals of 2-chloro-1,3-diaminobenzene having a melting point of 82°-83.5° C.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:43][CH3:44])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:49])([F:51])[F:50])[CH:47]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:43][CH3:44])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CCCCCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoate (250 mg) is dissolved in ethanol (4 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethylamino]-heptanoic acid (131 mg). The resulting 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoic acid (131 mg) is dissolved in ethanol (1 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (178 μl), and concentrated under reduced pressure to give 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-heptanoic acid sodium salt (133 mg). MS (m/z): 734 [M−Na]−
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:25]1[C:30]([Cl:31])=[N:29][C:28]([Cl:32])=[CH:27][C:26]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[Cl:32][C:28]1[CH:27]=[C:26]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])[CH:25]=[C:30]([Cl:31])[N:29]=1
Reactant: O=C=Nc1cc(Cl)nc(Cl)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Cl)nc(Cl)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2,6-dichloropyridin-4-isocyanate (230 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 287 mg (81.1%) of the desired product as a solid.
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Cl:32][C:33]1[C:34]([N:61]2[CH2:66][CH2:65][N:64]([CH2:67][C:68]3[CH:69]=[N:70][CH:71]=[CH:72][CH:73]=3)[CH2:63][CH2:62]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:47]=[CH:46][C:45]([N:48]4[CH2:53][CH2:52][N:51](C(OC(C)(C)C)=O)[CH2:50][CH2:49]4)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:32][C:33]1[C:34]([N:61]2[CH2:62][CH2:63][N:64]([CH2:67][C:68]3[CH:69]=[N:70][CH:71]=[CH:72][CH:73]=3)[CH2:65][CH2:66]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:43]=[CH:44][C:45]([N:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[CH:46][CH:47]=3)[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Cl)cnc4[nH]3)cc2)CC1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cnc2[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Yield: 48.4 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 4-(4-(6-chloro-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate (10 mg, 0.0169 mmol), TFA (0.25 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (4 mg, 49%) as a pale yellow solid;
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](Br)[CH:9]=1)(=[O:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[CH3:23][C:24]1([CH3:39])[CH2:29][CH2:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH2:25]1>C1(C)C=CC=CC=1.CCO.CCOC(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>[CH3:1][N:2]([CH3:16])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:27]2[CH2:28][CH2:29][C:24]([CH3:39])([CH3:23])[CH2:25][CH:26]=2)[CH:9]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)CCc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Temperature: 80 °C
Yield: 41.2 %

Procedure:
A solution of 477 mg (1.55 mmol) of 2-(4-amino-3-bromo-phenyl)-ethanesulfonic acid dimethylamide (as prepared in Example 28, step (c)) in toluene (13 mL) and EtOH (6.5 mL) was treated with 6.21 mL (12.4 mmol) of 2.0 M aqueous Na2CO3 and 403 mg (1.71 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. The mixture was degassed via sonication, placed under Ar, treated with 179 mg (0.155 mmol) of Pd(PPh3)4 and heated to 80° C. for 18 h. The mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (1×50 mL). The aqueous layer was extracted with EtOAc (1×50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 215 mg (41%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C18H28N2O2S, 337.2 (M+H). found 337.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[CH2:11]([C:13]1[NH:17][N:16]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[C:28]([F:31])([F:30])[F:29])[CH:14]=1)[CH3:12].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:17]1[C:13]([CH2:11][CH3:12])=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[C:28]([F:29])([F:30])[F:31])=[N:16]1)=[O:10]
Reactant: CN=C=O
Reactant: CCc1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)nn1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Potassium carbonate (0.83 g, 6.0 mmol) and methyl isocyanate (0.29 g, 5.0 mmol) were added to a solution of 5-ethyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (1.81 g, 6.0 mmol) in ethyl acetate (15 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a yellow solid of N-methyl-5-ethyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (1.42 g, yield: 79.3%). mp: 97-100° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.30 (t, J=7.5 Hz, 3H), 2.95 (d, J=5.0 Hz, 3H), 3.12 (q, J=7.5H, 2H), 5.93 (s, 1H), 6.75-7.00 (m, 1H), 7.45 (d, J=9.2 Hz, 1H), 8.41 (dd, J=2.7 and 9.2 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:15][CH2:16][CH3:17])=[N:8][C:9](S(C)=O)=[N:10][CH:11]=1)=[O:5])[CH3:2].CCCCCC.C(OCC)(=O)C.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:15][CH2:16][CH3:17])=[N:8][C:9]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCNc1nc(S(C)=O)ncc1C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCNc1nc(Nc2ccccc2)ncc1C(=O)OCC
Temperature: 25 °C
Yield: 33 %

Procedure:
A solution of 4-ethylamino-2-methanesulfinyl-pyrimidine-5-carboxylic acid ethyl ester (5.38 g, 20.9 mmol) in 4 mL of aniline was heated at 130° C. for 1 hour. The solution was cooled to room temperature, and 20 mL of 1:1 hexane:ethyl acetate was added. The resultant white solid was collected by filtration to give 1.96 g (33%) of the title product. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 3:1 hexane:ethyl acetate to provide an additional 257 mg (4%) of pure 4-ethylamino-2-phenylamino-pyrimidine-5-carboxylic acid ethyl ester, mp 145-147° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccccc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.068 mMol) benzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:18][N:19]=3)[N:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)[O:46][N:47]1[C:51]2[N:52]=[CH:53][CH:54]=[CH:55][C:50]=2[N:49]=N1.C(N(CC)C(C)C)(C)C.OC(C(F)(F)F)=O.CC1ON=C([C@@H](N)C)N=1>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:18][N:19]=3)[N:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:49][C@H:50]([C:51]1[N:52]=[C:53]([CH3:54])[O:46][N:47]=1)[CH3:55])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1Cl
Agent: Cc1nc([C@H](C)N)no1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc([C@H](C)NC(=O)c2ccc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cc2Cl)no1
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoic acid (50 mg, 0.1 mmol, Example 2, Step 4) in N,N-dimethylformamide (2 mL, 20 mmol) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (68 mg, 0.18 mmol) (Aldrich, Cat. #226084) and N,N-diisopropylethylamine (42 μL, 0.24 mmol). After stirring the solution for 15 min, (1S)-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethanamine TFA salt (18 mg, 0.14 mmol, Step 5) was added and stirred overnight. The mixture was purified by RP-HPLC (pH=10) to give the desired product which was further purified by RP-HPLC (pH=2) to afford the desired pure product as the TFA salt. LCMS (M+H)+: m/z=525.0/427.0. 1H-NMR (500 MHz, DMSO-d6): 9.22 (s, 1H), 8.98 (dd, J=5.0, 1.5 Hz, 1H), 9.15 (d, J=8.0 Hz, 1H), 8.56 (d, J=8.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 8.14 (dd, J=8.0, 1.5 Hz, 1H), 8.06 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 8.02 (s, 1H), 7.90 (dd, J=9.0, 2.0 Hz, 1H), 7.68 (dd, J=8.5, 5.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 5.24 (m, 1H), 4.66 (s, 2H), 2.60 (s, 3H), 1.51 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:34][C:33]4[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.14 mmol) was reacted with 4-nitrobenzaldehyde to provide 36 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:17]2[N:16]=[CH:15][C:14]3[N:13]([CH3:18])[CH:12]=[C:11]([C:19]([O:21]CC)=[O:20])[C:10](=[O:24])[C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[N:25]1[CH2:30][CH2:29][C:28]([OH:41])([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:27][CH2:26]1.C(O)(=O)C>C(O)C.O>[F:3][C:4]1[C:17]2[N:16]=[CH:15][C:14]3[N:13]([CH3:18])[CH:12]=[C:11]([C:19]([OH:21])=[O:20])[C:10](=[O:24])[C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[N:25]1[CH2:30][CH2:29][C:28]([OH:41])([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cn(C)c2cnc3c(F)c(N4CCC(O)(c5cccc(C(F)(F)F)c5)CC4)ccc3c2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2c3ccc(N4CCC(O)(c5cccc(C(F)(F)F)c5)CC4)c(F)c3ncc21
Temperature: 80 °C
Yield: 67.6 %

Procedure:
0.86 cm3 of 1 N aqueous potassium hydroxide was added, with stirring, to a suspension of 0.39 g of ethyl 7-fluoro-8-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate in 4.5 cm3 of ethanol and 3.5 cm3 of water. The mixture was heated at about 80° C. for 3 hours, and then after cooling, 20 cm3 of water were added and then the medium was acidified with 0.05 cm3 of acetic acid. The precipitate was filtered off, dewatered, washed with 2 cm3 of isopropanol and then washed twice with 2 cm3 of diisopropyl ether and dried. 0.25 g of 7-fluoro-8-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylic acid was obtained in the form of a yellow solid, which melted above 260° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:18][C:19]1([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:11][C:6]1[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=[C:2]([NH:18][C:19]2([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]2)[C:7]=1[CH2:8][CH2:9][OH:10]
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)C1
Reactant: OCCc1c(Cl)nc(N2CCOCC2)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(Nc2nc(N3CCOCC3)nc(Cl)c2CCO)CCN(C(=O)OC(C)(C)C)C1
Temperature: 130 °C
Reaction time: 30 h
Yield: 80 %

Procedure:
To a solution of 2-[4,6-dichloro-2-(morpholin-4-yl)pyrimidin-5-yl]ethanol (Preparation 1)(3.47 g, 12.5 mmol) and tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate (racemic from a commercial source or Preparation 3 for a chirally pure enantiomer) (5.00 g, 24.97 mmol) in NMP (40 mL) was added DIPEA (8.07 g, 62.44 mmol) at 10° C. The resulting mixture was stirred at 130° C. for 30 h. The mixture was diluted with EtOAc (30 mL) and washed with brine (20 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography, eluting with petroleum ether/EtOAc (1:1) to give the title compound (4.40 g, 80%) as a light yellow gum. 1H NMR (400 MHz, 80° C., DMSO-d6) δ 6.48 (s, 1 H), 4.76 (t, J=5.0 Hz, 1 H), 3.76 (d, J=11.1 Hz, 1 H), 3.68-3.53 (m, 10 H), 3.45-3.28 (m, 3 H), 2.69 (t, J=6.24 Hz, 2 H), 2.35-2.26 (m, 1 H), 2.01-1.92 (m, 1 H), 1.49 (s, 3 H), 1.40 (s, 9 H). m/z (APCI+) for C20H32ClN5O4 442.2 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[N:8]=[N:7][C:6]([CH2:9][CH2:10][OH:11])=[N:5]1)([CH3:3])[CH3:2].[CH:12]([N:15]1[C:19]([CH2:20][CH2:21][OH:22])=[N:18][N:17]=[N:16]1)([CH3:14])[CH3:13].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[CH:1]([N:4]1[N:8]=[N:7][C:6]([CH2:9][CH2:10][O:11][S:24]([CH3:23])(=[O:26])=[O:25])=[N:5]1)([CH3:3])[CH3:2].[CH:12]([N:15]1[C:19]([CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[N:18][N:17]=[N:16]1)([CH3:14])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1nnnc1CCO
Reactant: CC(C)n1nnc(CCO)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1nnc(CCOS(C)(=O)=O)n1
Product: CC(C)n1nnnc1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 17 %
Yield: 4 %

Procedure:
To a mixture of 2-(2-isopropyl-2H-tetrazol-5-yl)-ethanol and 2-(1-isopropyl-1H-tetrazol-5-yl)-ethanol (1.5 g, 9.6 mmol) in methylene chloride (40 mL) was added methanesulfonyl chloride (0.82 mL, 11 mmol) and triethylamine (2.67 mL, 19.2 mmol). The solution was stirred at room temperature for 6 h, loaded on to a silica gel column, and eluted using methylene chloride/heptane followed by ethyl acetate/methylene chloride to provide methanesulfonic acid 2-(2-isopropyl-2H-tetrazol-5-yl)-ethyl ester (370 mg, 17% yield) and methanesulfonic acid 2-(1-isopropyl-1H-tetrazol-5-yl)-ethyl ester (80 mg, 4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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:23][C:24]1[CH:29]=[C:28]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])[CH:16]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2cccc(Cl)c2)c1
Yield: 66.6 %

Procedure:
3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.048 g (66%) of 3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O>>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:5]1[CH2:4][CH2:3][CH2:2][C:1]1[O:9][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)CCCC(=O)O
Product: c1ccc2oc(CCCc3nc4ccccc4o3)nc2c1

Procedure:
1 Mol of glutaric acid is reacted with 2 mols of aminophenol to produce 1,3-bis-(bezoxazole-2-yl)-propane.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([O-:38])=[O:37]>C(Cl)(Cl)Cl>[C:22]([CH2:21][N:15]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:20][CH2:19][N:18]([CH2:43][C:42]2[CH:45]=[CH:46][C:39]([N+:36]([O-:38])=[O:37])=[CH:40][CH:41]=2)[CH2:17][CH2:16]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
To a solution of compound (20) (1.85 g, 4.62 mmol) in dry CHCl3 (50 ml) were added triethylamine (1.93 ml, 1.40 g, 13.86 mmol) and 4-nitrobenzylbromide (0.99 g, 4.62 mmol). After stirring the mixture at an ambient temperature for 10 hours, the solvent was removed under reduced pressure, and the residue was purified via alumina (basic) column chromatography. Extraction with ethyl acetate/methanol (10:2) gave a solidified clear oily compound (21) (1.98 g, 80% yield).