Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(Cl)([Cl:13])=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:8]([Cl:13])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1nc(C)c(C(=O)O)s1
Solvent: Cc1ccccc1C
Product: Cc1nc(C)c(C(=O)Cl)s1

Procedure:
In a 300-ml three-neck flask, 7.9 g (0.5) mole) of 2,4-dimethylthiazole-5carboxylic acid were suspended in 200 ml of xylene and under heating and reflux, phosgene was blown at a flow rate of 340 ml/hr for 12 hours (0.18 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 8.2 g of 2,4-dimethylthiazole-5-carboxylic acid chloride. Its purity and yield were 95.0% and 98.0%, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].CC(C)([O-])C.[K+].Cl.Cl[CH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH3:32]>CC(N(C)C)=O>[CH3:32][N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][CH2:25][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CN1CCCC1CCCl
Reactant: Cc1ccccc1CCc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1CCc1ccccc1OCCC1CCCN1C
Yield: 23 %

Procedure:
Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(2-methylphenyl)ethyl]phenol (prepared as described in Preparation 24), 1.59 g of potassium t-butoxide and 1.73 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 350 mg (yield 23%) of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>>[OH:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:11]([OH:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(N)cc1O
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(O)c3)n2)cc1O

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methoxylaniline were reacted to yield N2,N4-bis(3-hydroxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.82 (d, 1H J=4 Hz), 7.18 (m, 2H), 6.95 (m, 2H), 6.83 (m, 2H) 3.93 (s, 6H); LCMS: ret. time: 16.63 min.; purity: 97%; MS (m/e): 373 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][C@@H:14]([CH3:28])[C@@H:15]([CH3:27])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].C[O-].[Na+].[N+:32]([C:35]1[N:36]=[CH:37][NH:38][CH:39]=1)([O-:34])=[O:33]>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([CH2:16][C@H:15]([CH3:27])[C@H:14]([CH3:28])[CH2:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH2:3][CH2:2][N:38]3[CH:39]=[C:35]([N+:32]([O-:34])=[O:33])[N:36]=[CH:37]3)[CH:6]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCBr)c2)cc1OC
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCn3cnc([N+](=O)[O-])c3)c2)cc1OC
Yield: 61.2 %

Procedure:
The Standard Procedure 2 was followed by use of 5a (58.2 mg, 0.129 mmol, 1.0 equiv), sodium methoxide (15.4 mg, 0.285 mmol, 2.2 equiv), and 4-nitroimidazole (6a, 29.3 mg, 0.259 mmol, 2.0 equiv). After workup and purification with column chromatography (80% EtOAc in hexanes as eluant), 7a (38.1 mg, 0.0789 mmol) was obtained in 61% yield as white solids: mp (recrystallized from methanol) 80.4-81.0° C.; 1H NMR (CDCl3, 400 MHz) δ 0.79 (d, J=6.8 Hz, 3H, CH3), 0.83 (d, J=6.4 Hz, 3H, CH3), 1.59-1.76 (m, 2H, 2×CH), 2.17-2.35 (m, 2H, 2×ArCH), 2.67-2.71 (m, 2H, 2×ArCH), 3.82 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.18-4.22 (m, 2H, CH2N), 4.36 (t, J=4.6 Hz, 2H, CH2O), 6.51 (s, 1H, ArH), 6.65-6.68 (m, 2H, 2×ArH), 6.73-6.78 (m, 3H, 3×ArH), 7.60 (s, 1H, nitroimidazole C5-H), 8.12 (s, 1H, nitroimidazole C2-H); 13C NMR (CDCl3, 100 MHz) δ 16.06, 16.20, 38.25, 38.95, 39.04, 39.06, 47.92, 55.77, 55.81, 55.92, 68.08, 111.17, 111.66, 112.45, 115.50, 120.60, 120.90, 123.10, 134.34, 134.58, 136.56, 146.66, 146.99, 147.82, 148.03, 148.60; IR (neat) 2957 (s), 2933 (s), 1589 (w), 1543 (s), 1516 (s), 1455 (w), 1337 (s), 1261 (s), 1236 (s), 1029 (s) cm−1; HRMS (FAB) m/z calcd for C26H34N3O6 (M+H)+: 484.2448. found: 484.2444.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:30]=O)=[O:27])([CH3:24])([CH3:23])[CH3:22].C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][NH:11][CH2:30][CH:29]([NH:28][C:26]([O:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:27])[CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)COCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC(CNC[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
The product from Example 17B (0.35 g, 1.25 mmol) and the product from Example 17A (0.36 g, 1.29 mmol) in absolute ethanol (12 mL) were treated with sodium cyanoborohydride (94 mg, 1.50 mmol) and a catalytic amount of acetic acid. The resulting mixture was stirred at ambient temperature overnight. The mixture was partitioned between water (40 mL) and ethyl acetate (3×40 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexanes:ethyl acetate, 1:1) to provide the title compound (0.15 g, 22%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[C:3]=1[Cl:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH3:20])=[O:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:18]2[CH2:20][O:19]2)=[C:4]([Cl:9])[C:3]=1[Cl:10]
Reactant: CC(C)=O
Reactant: Oc1ccc(Br)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1c(Br)ccc(OCC2CO2)c1Cl
Yield: 71 %

Procedure:
A solution of the crude 4-bromo-2,3-dichlorophenol (7.96 g) and (2R)-glycidyl 3-nitrobenzenesulfonate (8.52 g) in dry acetone (250 mL) was treated with potassium carbonate (13.61 g) and refluxed under nitrogen for 12 h. The reaction was cooled, filtered and filtrate was concentrated in vacuo and the residue was flash chromatographed (20% ethyl acetate/hexanes) to yield the desired product (6.94 g) in 71% yield. 1H-NMR (400 MHz, CDCl3) δ: 7.48 and 6.82 (d, 2H), 4.37 and 4.34 (dd, 1H), 4.06 and 4.03 (dd, 1H), 3.42-3.39 (m, 1H), 2.96-2.94 (m, 1H), 2.85-2.83 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[H][H]>[Pt]=O.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/C1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Yield: 37.5 %

Procedure:
2.00 g of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene was added to a mixed solvent of 30 ml of ethanol and 5 ml of acetic acid, and then 0.20 g of platinum oxide was added thereto. Thereafter, the mixture was stirred in a hydrogen stream at room temperature for 7.5 hours. After the reaction, the catalyst was removed by filtration, and the filtrate was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.69 g of the title compound as pale yellow crystal.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:16])[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[C:7]2=[C:8]([CH3:16])[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Temperature: 70 °C
Yield: 100 %

Procedure:
To a mixture of ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (24 mg, 0.10 mmol, preparation: See, U.S. Pat. No. 6,670,357, especially example 61, the disclosure of which is hererin incorporated by reference), 2-fluoro-4-nitrophenol (20 mg, 0.125 mmol) and K2CO3 (28 mg, 0.20 mmol) was added DMF (0.5 mL). The reaction was heated at 70° C. for 20 minutes, cooled to room temperature and 2 mL of water was added. The mixture was filtered, the solid was washed with water, and dried to give the title compound (36 mg, 100%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCC)cc1

Procedure:
In a manner according to Example 1, ethyl p-aminohydrocinnamate is alkylated with 1-bromohexadecane and potassium carbonate in hexamethylphosphoramide, providing ethyl 4-(hexadecylamino)hydrocinnamate.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C@H:21]([C@H:111]([OH:129])/[CH:112]=[CH:113]/[CH2:114][CH2:115][CH2:116][CH2:117][CH2:118][CH2:119][CH2:120][CH2:121][CH2:122][CH2:123][CH2:124][CH2:125][CH2:126]CC)[CH2:22][O:23][CH:24]1[O:29][CH:28]([CH2:30][OH:31])[CH:27]([O:32][CH:33]2[O:38][CH:37]([CH2:39][OH:40])[CH:36]([O:41][CH:42]3[O:47][CH:46]([CH2:48][OH:49])[CH:45]([OH:50])[CH:44]([O:51][CH:52]4[O:57][CH:56]([CH2:58][OH:59])[CH:55]([O:60]C5(C([O-])=O)OC([C@@H](O)[C@@H](O)CO)[C@H](NC(C)=O)C(O)C5)[CH:54]([OH:81])[CH:53]4[OH:82])[CH:43]3[NH:83][C:84]([CH3:86])=[O:85])[CH:35]([O:87]C3(C([O-])=O)OC([C@@H](O)[C@@H](O)CO)[C@H](NC(C)=O)C(O)C3)[CH:34]2[OH:108])[CH:26]([OH:109])[CH:25]1[OH:110])=[O:19].[Na+].[Na+].C([O-])(=O)C.O>C(Cl)(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH:21]([CH:111]([OH:129])/[CH:112]=[CH:113]/[CH2:114][CH2:115][CH2:116][CH2:117][CH2:118][CH2:119][CH2:120][CH2:121][CH2:122][CH2:123][CH2:124][CH2:125][CH3:126])[CH2:22][O:23][CH:24]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:27]([O:32][C@@H:33]2[O:38][C@H:37]([CH2:39][OH:40])[C@H:36]([O:41][C@@H:42]3[O:47][C@H:46]([CH2:48][OH:49])[C@H:45]([OH:50])[C@H:44]([O:51][C@@H:52]4[O:57][C@H:56]([CH2:58][OH:59])[C@H:55]([OH:60])[C@H:54]([OH:81])[C@H:53]4[OH:82])[C@H:43]3[NH:83][C:84]([CH3:86])=[O:85])[C@H:35]([OH:87])[C@H:34]2[OH:108])[C@H:26]([OH:109])[C@H:25]1[OH:110])=[O:19]
Reactant: CCCCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](COC1OC(CO)C(OC2OC(CO)C(OC3OC(CO)C(O)C(OC4OC(CO)C(OC5(C(=O)[O-])CC(O)[C@@H](NC(C)=O)C([C@@H](O)[C@@H](O)CO)O5)C(O)C4O)C3NC(C)=O)C(OC3(C(=O)[O-])CC(O)[C@@H](NC(C)=O)C([C@@H](O)[C@@H](O)CO)O3)C2O)C(O)C1O)NC(=O)CCCCCCCCCCCCCCCCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCC/C=C/C(O)C(COC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC

Procedure:
A 1 ml quantity of 0.5% ganglioside GDla solution, 1 ml of 40 mM acetate buffer (pH 5.0) and 1 ml of sterilized water were mixed together, and to the mixture was added 1 ml of aqueous solution of Isozyme L (8 U/ml). The mixture was allowed to react at 37° C. for 1 hour, and 1/10 part by volume of chloroform was added thereto to stop the enzyme reaction. Asialo GM1 was extracted from the reaction solution with use of a mixture of chloroform and methanol (2:1) and then lyophilized, giving 2.0 mg of asialo GM1 as a white powder.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 100 °C
Yield: 52.1 %

Procedure:
To a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (5 g, 26 mmol,) in DMSO (50 ml) was added tert-butyl 4-aminopiperidine-1-carboxylate (5.3 g, 26.5 mmol, 1 eq.) and potassium carbonate (7.3 g, 52.8 mmol, 2 eq.). The resulting solution was stirred with heating overnight at 100° C. (oil bath). The resulting solution was diluted with of ethyl acetate (300 ml) and washed with sodium chloride (sat., 300 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with ethyl acetate to afford tert-butyl 4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate as a white powder (5 g, 51%). (ES, m/z):[M+H]+ 370.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cccc(F)c3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg) and commercially available 3-fluorophenol (0.20 ml) were mixed and stirred at 180° C. for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate and then with chloroform to obtain 125 mg of the title compound (yield: 94%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[N:31]1([CH2:36][CH2:37][NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[O:30]=[C:4]1[C:3](=[CH:2][NH:46][C:43]2[CH:44]=[CH:45][C:40]([CH2:39][NH:38][CH2:37][CH2:36][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:41][CH:42]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CNCCN2CCCC2)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CNCCN4CCCC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 30.5 %

Procedure:
small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 200 mg, 0.498 mmol) and THF (4 mL). To the resulting solution was added 4-[(2-Pyrrolidin-1-yl-ethylamino)-methyl]-phenylamine (prepared below; 109.2 mg, 0.498 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜5 mL of EtOAc. Hexanes were added causing a yellow precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 31% (0.092 g, 0.152 mmol) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([CH3:14])[C:10]=2[NH2:15])=[CH:5][CH:4]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][N:12]=[C:11]([CH3:14])[C:10]=2[NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1
Reactant: O=C(Cl)c1ccccc1
Product: COc1ccc(-c2[nH]nc(C)c2NC(=O)c2ccccc2)cc1

Procedure:
The preparation took place in analogy with Example 15a), starting with 500 mg of 5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (50) and 315 μl of benzoyl chloride. The following was obtained: 51 C18H17N3O2 (307.36) MS (ESI) 308 (M+H)
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:38])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[CH:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:38])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CCNCC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product of step i) (170 mg) in methanol (5 mL) was added 4M HCl in 1,4-dioxane (5 mL). The solution was stirred at room temperature for 2 hours. The volatiles were removed under vacuum and the residue was purified by HPLC to yield the title compound as a solid (25 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][CH2:4][N:5]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([N+:26]([O-])=O)=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:13]=1)=[O:7]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:26][C:11]1[CH:10]=[CH:9][C:8]([C:6]([N:5]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:4][CH2:3][CH:2]([CH3:34])[CH3:1])=[O:7])=[CH:13][C:12]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Tert-butyl 3-[(5-{[bis(3-methylbutyl)amino]carbonyl}-2-nitrophenyl)amino]propylcarbamate (1.65 g) in solution in a mixture of ethyl acetate/ethanol 2:1 (130 ml), and 10% palladium on carbon (165 mg) are introduced into an autoclave. After stirring for 3 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (1.35 g; 89% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[C:26](=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH3:22])[C:19]([O:21][CH3:26])=[O:20])=[CH:10][C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(C)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Yield: 74 %

Procedure:
A mixture of α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid (0.5 g.), methanol (5 ml.) and concentrated sulphuric acid (4 drops) was heated under reflux for six hours. The mixture was then poured into water (10 ml.), and the resulting mixture was neutralised with sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3×5 ml.) and the combined extracts were washed successively with sodium bicarbonate solution (5 ml.) and water (5 ml.), and then dried with sodium sulphate. The solvent was evaporated in vacuo and the residue crystallised from cyclohexane to give methyl α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionate m.p. 90°-92.5° C., in 74% yield.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])(=O)[CH3:2].Cl.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([O:28][NH2:29])[CH:25]=[CH:26][CH:27]=1.CC([O-])=O.[Na+]>CCO>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:4]([C:1](=[N:29][O:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:30])[CH:23]=2)[CH3:2])[CH:9]=1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOc1cccc(C(F)(F)F)c1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 90.6 %

Procedure:
A solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (310 mg, 1.03 mmol), O-(3-trifluoromethylphenyl)hydroxylamine hydrochloride (220 mg, 1.03 mmol) and anhydrous NaOAc (93 mg, 1.13 mmol) in EtOH (18 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:5) afforded N-{4-chloro-2-[1-(3-trifluoromethylphenoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 134 (430 mg, 91%), as a pale yellow solid. M.p. 63-64° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.00, br S, 1H, 7.71, d, J=9.0 Hz, 1H, 7.60, d, J=2.2 Hz, 1H, 7.56-7.35, m, 5H, 2.58, s, 3H. O-(3-Trifluoromethylphenyl)hydroxylamine hydrochloride was prepared in two steps by the procedure of Petrassi, M. H.; Sharpless, K. B.; Kelly, J. W. Org. Lett., 2001, 3, 139-142.