Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.N1C=CC=CC=1.[C:52](Cl)(=[O:56])[O:53][CH2:54][CH3:55]>C(Cl)Cl>[F:43][C:40]([F:41])([F:42])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:52]([O:53][CH2:54][CH3:55])=[O:56])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCNc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N(CC)C(=O)OCC)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg) and pyridine (371 μl) are dissolved in methylene chloride (5 ml), and thereto is added ethyl chlorocarbonate (293 μl) under ice-cooling. The reaction solution is stirred at room temperature overnight and the organic solvent is concentrated under reduced pressure. To the residue are added ethyl acetate and an aqueous citric acid solution, and the mixture is separated. 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 (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (176 mg). MS (m/z): 725 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.O=[C:9]([CH2:15][CH2:16][C:17](OC)=[O:18])[CH2:10][C:11]([O:13][CH3:14])=[O:12]>>[CH3:7][C:5]1[N:6]=[C:2]2[NH:1][C:15]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:16][C:17](=[O:18])[N:3]2[N:4]=1
Reactant: Cc1nc(N)n[nH]1
Reactant: COC(=O)CCC(=O)CC(=O)OC
Product: COC(=O)CCc1cc(=O)n2nc(C)nc2[nH]1
Temperature: 160 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
3-Amino-5-methyl-1H-s-triazole (19.8 g) (about 0.12 mol) (about 70%) and 30 g (0.16 mol) of dimethyl 3-oxo-adipate are melted together while gassing with argon for 1 hour in a bath heated at 160° C. In so doing, the volatile products are removed in a water-jet vacuum. After cooling the solid residue is dissolved in dichloromethane/methanol (1:1 v/v). The turbid yellowish solution is filtered and concentrated. The crystals which thereby result are filtered off under suction and washed with ethanol, subsequently with diethyl ether. There are obtained 20 g of methyl 4,7-dihydro-2-methyl-7-oxo-s-triazolo[1,5-a]pyrimidine-5-propionate as a white crystals of melting point 222°-225° C.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([C:4]1[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)CCCOc1ccc(C(C)=O)cc1OC
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 4-(4-acetyl-2-methoxyphenoxy)butyrate (10 g) was added to cold 70% nitric acid (140 cm3) and the resulting orange solution was stirred for 2 h and then poured into a beaker containing ice-water (1 dm3). The slurry warmed with stirring overnight to give a yellow solid which was collected and recrystallised from methanol to give methyl 4-(4-acetyl-2-methoxy-5-nitrophenoxy)butyrate as a pale yellow solid (8.5 g). 1H NMR (CDCl3) δ 2.21 (2H, m, J=6.6 Hz, CCH2C), 2.50 (3H, s, MeCO), 2.57 (2H, t, J=7.1 Hz, CH2CO), 3.7 (3H, s, OMe), 3.99 (3H, s, OMe), 4.16 (2H, t, J=6.2 Hz, CH2O), 6.75 (1H, s, aromatic) and 7.62 (1H, s, aromatic).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][C:11]=3[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27]Cl)[CH2:22][CH2:21]1>>[OH:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[O:9][C:8](=[O:19])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[C:16]2[O:17][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: O=c1oc2c(O)cccc2c(O)c1-c1ccccc1
Reactant: ClCCN1CCOCC1
Product: O=c1oc2c(O)cccc2c(OCCN2CCOCC2)c1-c1ccccc1
Yield: 60.2 %

Procedure:
Prepared as described in Example 30 from 45.9 g. (0.18 mol) of 3-phenyl-4,8-dihydroxy-coumarin and 31.5 g. (0.21 mol) of 2-morpholino-1-chloroethane. After recrystallisation from ethane, 39.8 g. of a white substance are obtained; M.P. 190°-191° C. Yield 60.2% (theoretical yield 66 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]1[CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:7]1=[C:6]([C:26]([OH:28])=[O:27])[C:5]2=[O:29].C(=O)(O)[O-].[K+].Br[CH2:36][C:37]1[O:38][C:39](=[O:43])[O:40][C:41]=1[CH3:42]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:36][C:37]3[O:38][C:39](=[O:43])[O:40][C:41]=3[CH3:42])[CH2:14][CH2:13]1)[N:8]1[CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:7]1=[C:6]([C:26]([OH:28])=[O:27])[C:5]2=[O:29]
Reactant: O=C(O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)C(c1ccccc1)S2
Reactant: Cc1oc(=O)oc1CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2n3C(c3ccccc3)S2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
6-Fluoro-4-oxo-1-phenyl-7-(1-piperazinyl)-4H-[1,3]-thiazeto-[3,2-a]quinoline-3-carboxylic acid (3.0 g) and 0.88 g of potassium bicarbonate were suspended in 50 ml of N,N-dimethylformamide, 1.69 g of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one was dropped thereinto with ice cooling, and the mixture was stirred for 3 hours. After the reaction, the mixture was poured into ice water, the crystals separated out therefrom was collected by filtration, washed with water, dried in vacuo, and the resulting crude crystals were recrystallized from chloroform-ethanol to give 1.3 g of desired product, m.p.201°-202° C. (decompn.).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14](=[O:19])[NH:15][CH:16]1[CH2:18][CH2:17]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([NH:15][C:14]([C@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]2)=[O:19])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)NC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CC1)[C@H]1C[C@@H](O)CN1
Yield: 95.3 %

Procedure:
(2R,4R)-2-Cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g) was deprotected using 50 mL of 30% TFA in DCM at rt for 2 hours to give 3 g of (2R,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide as a light yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:33][NH:34][CH:35]([CH2:37][CH3:38])[CH3:36]>C(Cl)(Cl)Cl>[CH3:33][N:34]([CH:35]([CH3:36])[CH2:37][CH3:38])[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18]
Reactant: CCC(C)NC
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2)n1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(C)N(C)C(=O)c1cc2ccccc2c(-c2ccccc2)n1
Yield: 63.5 %

Procedure:
Operations are carried out as for Example 7, starting with 2.96 g of 1-phenyl isoquinoline 3-carboxylic acid, 1.33 g of triethylamine, 1.49 g of ethyl chloroformate and 1.34 g of N-methyl 2-butanamine in 120 ml of chloroform. 2.4 g of N-methyl N(1-methyl propyl) 1-phenyl isoquinoline 3-carboxamide melting at 95°-96° C., are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].[CH:19]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH2:20]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:20][CH2:19][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: C=CS(C)(=O)=O
Reactant: CCOc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 79.4 %

Procedure:
To 1-[3-(ethyloxy)-4-nitrophenyl]piperazine (0.5 g, 1.99 mmol) in 10 mL of dioxane was added, methyl vinyl sulfone (0.53 g, 4.97 mmol). The mixture was heated to 120° C. for 2 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step B (0.565 g, 1.58 mmol, 79%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.83 (d, J=9.34 Hz, 1H), 6.57 (dd, J=9.43, 2.47 Hz, 1H), 6.51 (d, J=2.38 Hz, 1H), 4.16 (q, J=6.96 Hz, 2H), 3.36-3.41 (m, 4H), 3.30-3.34 (m, 2H), 3.01 (s, 3H), 2.73 (t, J=6.87 Hz, 2H), 2.49-2.55 (m, 4H), 1.32 (t, J=6.96 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[C:10]([NH2:18])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:43]([O:47][C:48]([NH:50][CH2:51][CH2:52][CH:53]([C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=1)[C:54](O)=[O:55])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:54](=[O:55])[CH:53]([C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=3)[CH2:52][CH2:51][NH:50][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[CH:14][CH:15]=2)[C:10]([NH2:18])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(C(=O)Nc1ccc2c(c1)c(N)nn2C(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a stirred solution of 3,5-diamino-indazole-1-carboxylic acid tert-butylester (2.17 g, 8.75 mmol), PyBroP (4.1 g, 8.75 mmol) and 4-tert-butoxycarbonylamino-2-(3,4-dichloro-phenyl)-butyric acid (3 g, 8.75 mmol) in dichloromethane (100 mL) was added diisopropylethylamine (3.0 mL, 17.5 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature over 4 hours then was concentrated and the residue partitioned between EtOAc and ammonium chloride (saturated, aqueous). The organic phase was separated and washed with sodium bicarbonate (saturated, aqueous), then dried (sodium sulfate) and concentrated to a brown foam. Purification by column chromatography (silica, 20% petroleum ether-EtOAc gave the title compound as a light brown solid (2.92 g, 58%); 1H NMR (400 MHz, DMSO) 1.36 (9H, s), 1.56 (9H, s), 1.80–1.90 (1H, m), 2.10–2.20 (1H, m), 2.89 (2H, m), 6.29 (2H, brs), 6.87 (1H, t), 7.38 (1H, d), 7.45 (1H, d), 7.61–7.65 (2H, m), 7.90 (1H, m), 8.19 (1H, s), 10.30 (1H, s); MS (ES+) m/e=578.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]([CH3:28])[CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:38][C:39]4[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=4[N:41]=3)[CH2:14][C@H:13]2[NH:25][CH:26]([CH3:27])[CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(C)C)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC(C)C)C3)sc12
Yield: 33.2 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(isopropylamino)piperidine-1-carboxylate obtained in Example (211a) (24.0 mg, 0.058 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (18 mg, 0.064 mmol) and sodium carbonate (61 mg, 0.580 mmol), to obtain 10 mg of the title compound (33%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:20]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:57][CH2:58]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NC2CCOCC2)s1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) in DMF (1.5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (88 mg, 0.28 mmol), N,N-diisopropyl ethyl amine (214 μL, 1.25 mmol) and 4-aminotetrahydropyran (28 mg, 0.28 mmol). The resulting reaction mixture was stirred for 1 h. The reaction mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (68 mg, 66%) as a white solid. MS: m/e=415.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:38]([F:41])([F:40])[F:39])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]=3[C:38]([F:40])([F:39])[F:41])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1ccc(Cl)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-chloro-2-trifluoromethyl-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 571.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(OC)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-methoxy-phenylboronic acid (49 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound. Yield: 13 mg, 12%; LC/MS tr 1.48 min; MS(ES+) m/z 366 (M+H)
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[I-].[Na+].C(O[CH2:25][CH3:26])(=O)C>CN(C=O)C>[C:25]1([CH2:26][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[C:14]2[C:6](=[CH:5][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:12][CH:11]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: CCOC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc3ccccc23)CCCC1=O
Reaction time: 0.08 h
Yield: 41 %

Procedure:
40% Methanolic Triton B (1.6 mL, 3.6 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (870 mg, 3.6 mM) in 30 mL of DMF at 25° C. After 5 minutes, 1-chloromethyl naphthylene (642 mg, 3.6 mM) and sodium iodide (450 mg, 3.0 mM) were added and the resultant mixture stirred at room temperature for 25 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HCl, H2O, sat NaHCO3, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 560 mg (41%) of the 9-[(1-naphthyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a yellow solid. 1H NMR (CDCl3) δ 8.0 (d, 1H, J=8 Hz), 7.9 (d, 1H, J=8 Hz), 7.7 (d, 1H, J=8 Hz), 7.6 (t, 1H, J=8 Hz), 7.55 (t, 1H, J=8 Hz), 7.35 (d, 1H, J=8 Hz), 7.15-7.05 (m, 3H), 6.4 (d, 1H, J=8 Hz), 5.8 (s, 2H), 4.05 (s, 3H), 2.8 (t, 2H, J=6 Hz), 2.55 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1721, 1646, 1464, 1448, 1438, 1285, 1122, 796, and 761. MS (ES) m/e 382, 384.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:15][CH3:16])[CH:8]=2)[N:3]=1.Cl.[CH3:18][O:19][NH2:20].C(O)C>>[CH3:18][O:19][N:20]=[CH:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:14][CH2:15][CH3:16])=[CH:6][CH:5]=2
Reactant: CON
Reactant: CCOc1ccc2nc(Cl)c(C=O)cc2c1
Agent: Cl
Solvent: CCO
Product: CCOc1ccc2nc(Cl)c(C=NOC)cc2c1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-6-ethoxyquinoline-3-carbaldehyde (0.235 g, 1.0 mmol) in ethanol O-methylhydroxylamine hydrochloride (0.10 g, 1.1 mmol) was added. The reaction mixture was heated to reflux for 0.5 hours. After cooling to room temperature the precipitated compound was filtered and dried. Yield 180 mg. M.p. 142-4° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[N:30]=[N:31][C:32]([CH:34]=O)=[CH:33][C:26]=2[NH:25]1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:22])[N:11]2[CH2:10][CH2:9][N:5]2[CH2:6][C@@H:7]([OH:8])[C@@H:3]([CH2:2][NH:1][CH2:34][C:32]3[N:31]=[N:30][C:27]4[S:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[CH:33]=3)[CH2:4]2)=[CH:16][CH:17]=1
Reactant: O=Cc1cc2c(nn1)SCC(=O)N2
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1CSc2nnc(CNC[C@H]3CN(CCn4c(=O)ccc5ccc(F)cc54)C[C@H]3O)cc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (100 mg; 0.33 mmol) and 6-oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine-3-carbaldehyde (for a synthesis see WO2004058144, Example 58) (65 mg, 0.33 mmol) in methanol (2 mL), DCM (4 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (210 mg; 1.0 mmol) was added and the mixture was stirred at room temperature for 4 h. The reaction was evaporated and chromatographed on silica gel, eluting with 0-10% methanol-DCM-1% NH4OH to give 42 mg of the title compound as an oil which solidified to an off-white powder upon standing.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)(=[O:35])=[O:34])[C:27]=2[F:41])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:26]2[C:27]([F:41])=[C:28]([NH:32][S:33]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)(=[O:34])=[O:35])[CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(N)n3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(-c2sc(C3CCNCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-1-piperidinecarboxylate (46 mg, 0.077 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to give 22 mg of the title compound. MS (ESI): 501.1 [M+1]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19]1>O>[OH:17][CH:18]1[CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:20]([C:23]([OH:25])=[O:24])[CH2:19]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C1CC(O)CN1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
10 g (70.9 mmol) of 4-fluoronitrobenzene, 11.75 g (85 mmol) of potassium carbonate and 9.3 g (70.8 mmol) of trans-4-hydroxyproline were stirred in 100 ml of distilled water. The mixture was refluxed for 16 hours and was then cooled to room temperature. The product was extracted with ethyl acetate. The organic phases were washed with a saturated solution, dried over sodium sulphate and concentrated under reduced pressure. The oil obtained was crystallized from an ethyl acetate/heptane mixture. A yellow powder was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[N:23]([CH2:26][C:27](O)=[O:28])=[N+:24]=[N-:25].C([O-])(O)=O.[Na+].C(Cl)CCl>CN(C=O)C>[N:23]([CH2:26][C:27](=[O:28])[NH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=NCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stir bar, rubber septum, and argon inlet containing tert-butyl 3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propylcarbamate (amine, 160 mg, 0.5 mmol), 2-azidoacetic acid (56 mg, 0.55 mmol, in 50% DCM solution), NaHCO3 (168 mg, 2 mmol), and 1 mL DMF was added EDC (115 mg, 0.6 mmol). The mixture was stirred at rt for 3 h and concentrated in vacuo. The crude product was purified by silica chromatography (gradient 5% to 90% EtOAc in hexane) to afford compound 141 as a clear oil (130 mg, 65%). MS (ESI) m/z 426 (M+Na+).