Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].[CH3:10][O:11][N:12]=[C:13]([C:17](=O)[CH:18](Br)Br)[C:14]([OH:16])=[O:15]>O1CCCC1.O>[NH2:1][C:2]1[S:3][CH:18]=[C:17]([C:13](=[N:12][O:11][CH3:10])[C:14]([OH:16])=[O:15])[N:4]=1
Reactant: CON=C(C(=O)O)C(=O)C(Br)Br
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)O)c1csc(N)n1
Temperature: 30 °C
Reaction time: 4 h
Yield: 40.6 %

Procedure:
Thiourea (377 mg) and sodium acetate (406 mg) were added to a solution of 2-methoxyimino-3-oxo-4,4-dibromobutyric acid (syn isomer, 500 mg) in tetrahydrofuran (5 ml) and water (5 ml), and the solution was stirred at 30° C. for 4 hours. The solution was adjusted to pH 3.5, concentrated under reduced pressure and allowed to stand at 0° C. overnight. The precipitates were collected by filtration, washed with water and dried to give 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 135 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10]>[Pd]>[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Product: CCOC(=O)C=Cc1ccccc1
Yield: 66.4 %

Procedure:
The procedure described in Example 9 is repeated, but using 2.79 ml (25 mmols) of iodobenzene and 2.98 ml (27.5 mmols) of ethyl acrylate. After a reaction time of 4.5 hours at 130° C., 2.92 g (16.6 mmols) of ethyl cinnamate are obtained, corresponding to a yield of 66% of theory (conversion figure 6600; Pd content 0.01 mol %).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18](CCC(OC)=O)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[O-].[Na+].C1C(=O)N([Cl:37])C(=O)C1>C1COCC1>[Si:1]([O:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([Cl:37])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CCS(=O)(=O)c1ccc2c(c1)CCC2O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCc2cc(S(=O)(=O)Cl)ccc21
Reaction time: 0.33 h

Procedure:
To a solution of methyl 3-[(1-{[tert-butyl(dimethyl)silyl]oxy}-2,3-dihydro-1H-inden-5-yl)sulfonyl]propanoate (140 mg, 0.35 mmol) in THF (1 mL) was added sodium methoxide (0.70 mL, 0.5 M, 0.35 mmol). The reaction mixture was stirred for 20 minutes, then the solvents were removed under reduced pressure and the residue was stripped down from heptanes to generate a white foam. This foam was suspended in DCM (2 mL) at 0° C. and then NCS (47 mg, 0.35 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction was quenched by the addition of brine (2 mL) and the phases were separated using a phase separator. The aqueous layer washed with DCM, and the combined organic layers were concentrated under reduced pressure. The crude concentrate was purified on silica gel eluting with hexanes and ethyl acetate to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncccc2-c2nc(C)nc(N)n2)cc1F
Temperature: 75 °C

Procedure:
4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (232 mg, 0.409 mmol) was treated with TFA (8.0 mL) (Aldrich) and heated at 75° C. with a reflux condenser for 17 h. The TFA was removed in vacuo and the crude product was treated with 2 M NH3 in MeOH resulting in a suspension that was filtered and washed with water to give the desired product in ca. 80% purity. It was then resuspended in MeOH and filtered and washed with 1 N NaOH (aq), MeOH and hexanes and dried to give an olive-colored amorphous solid. It was further purified on the ISCO (12 g column, 1-25% MeOH in DCM) to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (68.6 mg, 0.210 mmol, 51.3% yield) as a fibrous, yellow amorphous solid. m/z (ESI, +ve ion) 328.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.95 (1H, s); 8.80 (1H, dd, J=7.8, 2.0 Hz); 8.42 (1H, d, J=2.3 Hz); 8.33-8.40 (2H, m); 7.91 (1H, br. s.); 7.77 (1H, br. s.); 6.94 (1H, dd, J=7.8, 4.7 Hz); 3.94 (3H, s); 2.43 (3H, s).
Reaction SMILES: Br[CH2:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH3:11])[CH2:7][CH2:6]1)=O.[C:12]([O:16][C:17](=[O:32])[CH2:18][CH2:19][N:20]([CH2:24][C:25]1[S:26][C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=1)[C:21]([NH2:23])=[S:22])([CH3:15])([CH3:14])[CH3:13]>CO>[C:12]([O:16][C:17](=[O:32])[CH2:18][CH2:19][N:20]([C:21]1[S:22][CH:2]=[C:3]([C@H:5]2[CH2:10][CH2:9][C@H:8]([CH3:11])[CH2:7][CH2:6]2)[N:23]=1)[CH2:24][C:25]1[S:26][C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: C[C@H]1CC[C@H](C(=O)CBr)CC1
Reactant: CCc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Solvent: CO
Product: CCc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc([C@H]3CC[C@H](C)CC3)cs2)s1
Temperature: 60 °C

Procedure:
2-Bromo-1-(trans-4-methyl-cyclohexyl)-ethanone (61 mg, 0.277 mmol) was added to a methanol (about 4 mL) solution of 3-[1-(5-ethyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (100 mg, 0.304 mmol) and the reaction was heated at 60° C. overnight to obtain the 3-[[4-(trans-4-methyl-cyclohexyl)-thiazol-2-yl]-(5-ethyl-thiophen-2-ylmethyl)-amino]-propionic acid tert-butyl ester product following a method analogous to General Procedure C. The solvent was removed at reduced pressure and the residue was dissolved in aqueous saturated sodium bicarbonate solution and ethyl acetate. The aq portion was extracted two times with EtOAc, and the combined organic portion was dried over sodium sulfate. Solvent removal under reduced pressure gave the crude product which was purified by silica gel chromatography (eluent: hexanes→19:1 hexanes:EtOAc→9:1 hexanes:EtOAc) to give the aminothiazole derivative (52 mg).
Reaction SMILES: [Cl:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19](OC(C)(C)C)=O)[CH2:3]1.Cl.O1CCOCC1.BrC1[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=2)[CH2:3]1
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2Cl)nc1Cl
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](Cl)C2)nc1C
Yield: 40.4 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-3-chloro-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (198b) (101 mg, 0.258 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (71.0 mg, 0.284 mmol) and sodium carbonate (547 mg, 5.16 mmol), to obtain 48 mg of the title compound (40%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]([O:19]C)=[O:18])=[CH:15][C:14]3[O:21][CH:22]=[CH:23][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[I-].[Li+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]3[O:21][CH:22]=[CH:23][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cc2occc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1cc2occc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
Methyl 4-(3,4-dichlorobenzenesulfonyl)furo[3,2-b]pyrrole-5-carboxylate (1.15 g) and lithium iodide (4.0 g) were dissolved in pyridine (50 ml) and heated at reflux for 5 hours, cooled, then concentrated in vacuo. The residue was partitioned between 2N HCl and ether. Combined organic extracts were dried (MgSO4), concentrated, and the residue triturated with ether to give the product as a white crystalline solid which was filtered and dried (0.58 g, 52%), NMR d(DMSO) 7.02 (1H, d), 7.27 (1H, s), 7.88 (2H, s), 8.03 (1H, d), 8.22 (1H, s); M/z (−) 360 (M+), 314, 252, 250, 227, 225, 209, 170. Analysis for C13H7Cl2NO5S found C, 43.2%; H, 2.1%; N, 3.8%; theory C, 41.4%; H, 2.0%; N, 3.9%.
Reaction SMILES: CO[C:3]1[C:6](=[O:7])[C:5](=[O:8])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:13]=[CH:14][C:15]=1[CH3:16].[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]([CH2:26][NH:25][C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:18]([NH:17][C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[C:10]([NH:9][C:4]3[C:5](=[O:8])[C:6](=[O:7])[C:3]=3[NH:41][CH2:40][CH2:39][O:38][CH3:37])[CH:11]=2)=[O:19])=[CH:28][CH:29]=1
Reactant: COc1c(Nc2cc(NC(=O)c3sccc3NCc3ccnc4ccccc34)ccc2C)c(=O)c1=O
Reactant: COCCN
Product: COCCNc1c(Nc2cc(NC(=O)c3sccc3NCc3ccnc4ccccc34)ccc2C)c(=O)c1=O

Procedure:
EXAMPLE 46 was prepared according to the procedure described in EXAMPLE 3 using N-{3-[(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino]-4-chlorophenyl}-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide (EXAMPLE 44) and 2-methoxyethylamine instead of dimethylamine. MS (ES+): m/z 541.9 [M+1]
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9](C(O)=O)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.[Br:19]NC(=O)CCC(N)=O>CN(C)C=O.C(OCC)(=O)C>[Br:19][C:9]1[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:12][N:11]2[CH2:13][CH2:14][CH2:15][C:10]=12
Reactant: Cc1cccc(-c2nn3c(c2C(=O)O)CCC3)n1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nn3c(c2Br)CCC3)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (1.4 g, 5.8 mmol) in N,N-dimethylformamide (20 mL) is treated with N-bromosuccinamide (1 g, 5.6 mmol) and stirred at room temperature for 16 h. The mixture is diluted with ethyl acetate and washed three times with water, once with brine, dried (sodium sulfate), filtered, and concentrated in vacuo to yield the title compound, 1.5 g (94%), as light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(#N)C>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cn1
Temperature: 25 °C
Yield: 41 %

Procedure:
A 250-mL three-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-nitro-5-bromopyridine (5.00 g, 24.6 mmol), piperazine (5.66 g, 65.7 mmol) and acetonitrile (70 mL). The reaction mixture was heated at reflux for 20 h. After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was titrated with hexane/ethyl acetate (1:1, 30 mL) to afford 217a in 41% yield (2.10 g) as a yellow solid: mp 113-115° C.; 1H NMR (500 MHz, DMSO-d6) d 8.23 (d, 1H, J=3.5 Hz), 8.13 (d, 1H, J=9.0 Hz), 7.44 (dd, 1H, J=9.0, 3.5 Hz), 3.41 (t, 4H, J=5.0 Hz), 2.82 (t, 4H, J=5.0 Hz), 1.90 (s, 1H); MS (ESI+) m/z 209.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[C:13]([S:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][N:8]=[CH:9]2)([O-])=O.[Sn](Cl)Cl.Cl>>[NH2:1][C:4]1[C:13]([S:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][N:8]=[CH:9]2
Reactant: CSc1ccc2cnncc2c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Product: CSc1ccc2cnncc2c1N

Procedure:
5-Nitro-6-methylthiophthalazine, prepared as described by Sturrock et al., Can. J. Chem., 49, 3047 (1971) and Hirsch & Orphanos, J. Heterocyclic Chem., 2, 206 (1965), was reduced with tin (II ) chloride and HCl to yield 5-amino-6-methylthiophthalazine. This material was coupled with commercially available oleoyl chloride to yield the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[ClH:5].[F:6][C:7]([F:11])([F:10])[CH2:8][NH2:9].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[ClH:5].[F:6][C:7]([F:11])([F:10])[CH2:8][NH:9][CH:2]([CH3:4])[CH3:1]
Reactant: NCC(F)(F)F
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)NCC(F)(F)F
Yield: 65.1 %

Procedure:
After briskly stirring a mixture of acetone (1.10 ml; 15 mmol), 2,2,2-trifluoroethylamine hydrochloride (1 g; 7.4 mmol), AcOH (2 ml) and 3 Å molecular sieves (5 g) in 30 ml of CH2Cl2 for 2 hour at room temperature, sodium triacetoxyborohydride (3.20 g; 15 mmol) was added. After stirring 18 hours at room temperature, the reaction mixture was filtered through celite and 5 ml of ethereal HCl were added. After removing the volatiles in vacuo the residue was partitioned between ether (100 ml) and 1N NaOH (100 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and filtered. Ethereal HCl (5 ml) was added and the volatiles were removed in vacuo to afford 855 mg (65%) of the title compound of this step as a white powder. mp (melting point)=80°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=4)[CH:29]=[CH:30][C:31]=3[O:32][CH3:33])=[O:25])[C:17](=[O:22])N(OC)C)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:44][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:38][CH:39]=4)[CH:29]=[CH:30][C:31]=3[O:32][CH3:33])=[O:25])[C:17](=[O:22])[CH3:44])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)N(C)OC
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(C)=O
Reaction time: 6 h

Procedure:
To a solution of 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(methoxy-methyl-carbamoyl)-ethyl]-amide (0.1 g, 0.162 mmol) in anhydrous THF (2 mL) was added methyl magnesium bromide [0.35 ml, 1.4M solution in Toluene/THF (75:25)] at 0° C. and allowed to come to room temperature and stirred for 6 h. Reaction was quenched with aq NH4Cl and extracted with EtOAc. Organic layer was washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and the residue was purified by silicagel column chromatography to get pure 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [1-(R)-(3′-chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-oxo-propyl]-amide (0.055 g)
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1>>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][C:16]=2[C:22]([F:24])([F:23])[F:25])[N:3]=1
Reactant: O=Cc1ccc2[nH]nc(Br)c2c1
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Product: O=Cc1ccc2c(c1)c(Br)nn2Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
3-Bromo-1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazole-5-carbaldehyde was prepared from 3-bromo-1H-indazole-5-carbaldehyde and 4-chloro-2-(trifluoromethyl)benzyl bromide following General Procedure A.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].[OH-].[K+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13](=[N:16][OH:17])[NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(-c2ccc(C#N)o2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2ccc(C(N)=NO)o2)cc1

Procedure:
A mixture of 9.0 g (0.050 mole) of 5-(p-methylphenyl)-2-furonitrile, 3.75 g (0.054 mole) of hydroxylamine hydrochloride, 3.5 g (0.054 mole) of potassium hydroxide and 125 ml of absolute ethanol was refluxed for 2 hours and then cooled in an ice bath. The insoluble material was filtered and discarded. The filtrate was added to a mixture of ice/H2O and the resulting solid was filtered and stirred in 150 ml of refluxing hexane. The mixture was filtered hot and the solid was air dried to yield 7 g (65%). An analytical sample was prepared by recrystallizing a sample form hexane/Darco and drying in the vacuum pistol at the temperature of refluxing CHCl3, m.p. 139°-141°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18]Br.[OH-].[Na+].[CH2:22]([OH:26])[CH2:23][C:24]#[CH:25]>C1(C)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[I-].O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][O:26][CH2:22][CH2:23][C:24]#[CH:25]
Reactant: C#CCCO
Reactant: CCc1ccc(Cc2cc(Br)c(CBr)cc2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of 1-bromo-2-(bromomethyl)-4-chloro-5-(4-ethylbenzyl)benzene (200 mg, 0.497 mmol) in toluene (2 mL) was added NaOH (60 mg, 1.5 mmol), but-3-yn-1-ol (53 mg, 1.17 mmol) and TBAI (8.5 mg, 0.023 mmol) successively. After stirring overnight at 70° C., the solution was diluted with water. The solution was extracted with ethyl acetate and the extracts were washed with a saturated solution of NH4Cl, followed by drying over Na2SO4. The solution was concentrated and the resulting residue was purified by preparative TLC to afford 96 mg of title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][C:12]1[O:16][C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)([O-])=O.[Sn](Cl)Cl>>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][C:12]1[O:16][C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O)CCc1ccc(CNc2ccncc2[N+](=O)[O-])o1
Agent: Cl[Sn]Cl
Product: Nc1cnccc1NCc1ccc(CCC(=O)O)o1

Procedure:
The desired compound was prepared by reduction of 5-[N-(3-nitropyrid-4-yl)aminomethyl]-2-carboxyethylfuran, prepared as in step 5, with tin(II) chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([OH:8])=O)[CH3:2].[F:11][C:12]([F:20])([C:16]([F:19])([F:18])[F:17])[CH2:13][CH2:14][NH2:15]>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([NH:15][CH2:14][CH2:13][C:12]([F:20])([F:11])[C:16]([F:19])([F:18])[F:17])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)O
Reactant: NCCC(F)(F)C(F)(F)F
Product: CCOC(=O)C(C)C(=O)NCCC(F)(F)C(F)(F)F

Procedure:
2-Methyl-malonic acid monoethyl ester was coupled with 3,3,4,4,4-pentafluoro-butylamine in analogy to the description in example 73 to yield 2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid ethyl ester as colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1.C(N(CC)CC)C.Cl[C:31](=[O:42])[CH:32]([P:34](=[O:41])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[F:33]>CN(C=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:31](=[O:42])[CH:32]([P:34](=[O:41])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[F:33])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: CCOP(=O)(OCC)C(F)C(=O)Cl
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)C(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-amino-4-(3-chloro-4-fluorophenylamino)-7-methoxy-quinazoline (1.0 eq.) and triethylamine (1.5 eq.) were dissolved in DMF (10 ml), and the mixture was stirred at 0° C. for 30 min. A solution of diethyl (2-chloro-1-fluoro-2-oxoethyl)phosphonate (1.5 eq.) in DMF (5 ml) was added dropwise slowly into the mixture mentioned above, and stirred overnight at room temperature. After the reaction finished, the mixture was quenched with saturated NaHCO3, extracted with EtOAc, and the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, then the crude product was purified by column chromatography (mobile phase 40:1 DCM/MeOH) and a light yellow solid of diethyl (2-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxy-quinazolin-6-yl)amino)-1-fluoro-2-oxoethyl)phosphonate was given. (50% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:20]2)[CH2:13][CH2:14][N:15]([CH:17]=[O:18])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(#N)C>[C:35]([O:16][N:15]([CH2:14][CH2:13][C@@H:12]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:20]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH:17]=[O:18])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cc([C@@H](CCN(O)C=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CCN(C=O)OC(C)=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a solution of (1R)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (300 mg, 0.64 mmol) in acetonitrile (6 mL) was added acetic anhydride (0.1 mL, 1 mmol) at room temperature. After 4 h, the solvent was removed in vacuo and the residue was purified by chromatography (Silica Gel) to give (1R)—N-{2-[3-(N-acetoxy-N-formyl-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide as a white solid (0.21 g, 64% yield): mp: 72-74° C. 1H NMR (DMSO-d6) δ 1.17 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.19 (s, 3H, CH3), 2.32-2.50 (m, 2H, CH2), 2.59-2.68 (m, 1H, CH), 3.60-3.67 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.99-4.09 (m, 3H, NCHH, CH2), 4.56 (d, J=17 Hz, 1H, NCHH), 5.30-5.38 (m, 1H, NCH), 6.88-6.93 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 8.11 (s, 1H, CH), 8.29 (d, J=8 Hz, 1H, Ar), 10.47 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.69, 18.01, 19.16, 28.87, 35.94, 45.87, 46.13, 51.18, 55.45, 63.80, 111.96, 112.32, 116.55, 117.55, 119.76, 131.30, 132.79, 137.14, 142.32, 147.99, 148.59, 157.50, 163.00, 167.31, 168.57, 174.94; Anal Calcd for C27H33N3O7+0.2 H2O: C, 62.95; H, 6.53; N, 8.16; H2O, 0.70. Found: C, 62.81; H, 6.63; N, 7.92; H2O, 0.59.