Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH2:13][CH2:14][CH3:15])[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:13]([C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[CH:12][N:11]=1)[CH2:14][CH3:15]
Reactant: CCCc1nc(C=NNC(=O)OCC)c[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCc1ncc2cn[nH]c(=O)n12

Procedure:
An 8.75 gm. portion of 3-(2-n-propyl-4-imidazolylmethylene)carbazic acid ethyl ester is 50 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 159°-162.5° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO.C([O-])(=O)C.[Na+].[F:17][C:18]([F:25])([F:24])[C:19]([F:23])([F:22])[C:20]#[N:21]>O>[C:3]([C:2](=[C:20]([NH2:21])[C:19]([F:23])([F:22])[C:18]([F:25])([F:24])[F:17])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#CC(F)(F)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)C(F)(F)F
Yield: 29.1 %

Procedure:
To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoroethyl-5-thiazolecarboxylate, nD25 =1.4460.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[NH:4].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=O>N1C=CC=CC=1.C(OCC)C>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]1[O:1][N:2]=[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[N:4]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3ccccc3Cl)n2)CC1

Procedure:
tert-Butyl 4-(N-hydroxyamidino)-piperazine-1-carboxylate (290 mg) prepared in Example 36 was dissolved in 2 ml of pyridine, 0.20 ml of 2-chlorobenzoyl chloride was added thereto and the mixture was heated to reflux for 1 hour. The reaction solution was diluted with diethyl ether, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution and dried over anhydrous magnesium sulfate. The residue prepared by evaporation of the solvent was purified by a preparative thin-layer silica gel chromatography (hexane:ethyl acetate=7:3) to give 64.0 mg of the title compound as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8]N1C(=O)CCC1=O.[NH2:16][C:17]1[CH:43]=[CH:42][C:20]([C:21]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:26][C:25]=2[Cl:41])=[O:22])=[CH:19][CH:18]=1>O>[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:23][C:24]2[C:25]([Cl:41])=[CH:26][C:27]([C:31]([F:40])([C:36]([F:37])([F:38])[F:39])[C:32]([F:33])([F:34])[F:35])=[CH:28][C:29]=2[Cl:30])=[O:22])=[CH:42][C:43]=1[Cl:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 67.3 %

Procedure:
To the toluene (30 ml) solution in which 4-amino-N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoro propan-2-yl)phenyl]benzamide (2.80 g) is dissolved, N-chlorosuccinimide (0.87 g) was added. The reaction solution was stirred for 6 hours at 80° C. under heating. The solution was cooled to room temperature, diluted with water and extracted twice with ethyl acetate. The organic phases were combined, and then dried over magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to give 4-amino-3-chloro-N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl] benzamide (2.03 g, yield 67.3%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)=[O:4].[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:23]([N+:33]([O-:35])=[O:34])[CH:22]=1>C(#N)C>[Cl:12][C:10]1[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:37])([F:19])[F:36])=[CH:22][C:23]=3[N+:33]([O-:35])=[O:34])[CH2:28][CH2:29]2)[CH:11]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCNCC1
Reactant: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CC#N
Product: O=C(CN1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (100 mg) was dissolved in acetonitrile (5 ml) and (4-trifluromethyl-2-nitrophenyl)piperazine (253 mg) added. The solution was stirred overnight at room temperature. After this time the solvent was removed in vacuo. Purification by flash chromatography on silica gel eluting with a mixture of dichloromethane and methanol (98:2, then 93:7 v/v) afforded the title compound. m/z (ES+) 521 (MH)+
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:9]([NH:10][C:11]([CH3:16])([CH2:14][OH:15])[CH2:12][OH:13])=[N:8][C:7]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])=[N:6][C:5]=2[N:27]=1.[OH-:28].[K+].O.[CH3:31]O>>[F:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:17][C:7]1[N:8]=[C:9]([NH:10][C:11]([CH3:16])([CH2:14][OH:15])[CH2:12][OH:13])[C:4]2[S:3][C:2]([O:28][CH3:31])=[N:27][C:5]=2[N:6]=1
Reactant: CC(CO)(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(Cl)sc12
Reactant: [OH-]
Reactant: CO
Agent: [K+]
Solvent: O
Product: COc1nc2nc(SCc3cccc(F)c3F)nc(NC(C)(CO)CO)c2s1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
The product from step (f) (0.339 g) was suspended in methanol (32 ml). Potasium hydroxide (0.088 g) added and mixture stirred at 50° C. for 20 minutes. Neutralised with 2N HCl and solvents removed in vacuo to give an orange residue. Water added to remove inorganics and the yellow solid was collected by filtration to give 0.3 g of desired product. 90% yield.
Reaction SMILES: C1[C:17]2=[C:18]3[C:8]([C:9]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]3=CC=1.[C:19](=[O:21])=[O:20].[OH2:22]>CC(O)=O.CO>[O:10]=[C:9]1[C:8]2[C:7]([C:19]([OH:21])=[O:20])=[CH:6][CH:5]=[CH:4][C:18]=2[C:17](=[O:22])[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: O
Reactant: O=C1c2ccccc2-c2cccc3cccc1c23
Reactant: O=C=O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Yield: 46 %

Procedure:
The purified benzanthrone (63.7 g, 0.277 mol) was dissolved in 1500 mL of glacial HOAc at 90° and stirred with a mechanical stirrer. After cooling to 80° solid CrO3 (Mallinckrodt, Co., 2nd and Mallinckrodt St., St. Louis, MO, 63147, 200 g, 2 mol) was added in ~5 g portions over about 4 h. The exothermic reaction maintained the mixture at ~80° during this time and CO2 was evolved. After CO2 evolution ceased and the reaction temperature fell, the heating mantle was reapplied and the reaction stirred at 75° for an additional 6 h. The reaction was cooled to RT and stirred overnight. H2O (1.5 L) was then added to the dark-green solution. The reaction was then filtered to give a deep brown solid which was washed with CH3OH (200 mL) until the washings were colorless. The resulting solid was dissolved 2 L of hot methoxyethanol and filtered through Celite (Trade Mark of Johns-Manville Co., Denver, CO, 80110) to remove a black solid residue. The volume of the solution was reduced to ~75 mL (some solid formed) and diluted with 100 mL CH3OH to give the product. This material was filtered to give 32.0 g (46%) of golden brown 9,10-dihydro-9,10-dioxo-1-anthracenecarboxylic acid mp 287°-289 °, (C, H,), (lit. mp 293°-294°, Chemistry of Carbon Compounds IIIb, edited by E. H. Rodd, 1419 (1956), Elsevier, N.Y.).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH2:18].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[F:1][C:2]1[N:7]=[C:6]([C:8]([NH:18][NH:17][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1cccc(F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)c1cccc(F)n1
Reaction time: 2 h

Procedure:
6-Fluoro-2-pyridinecarboxylic acid (2.83 g, 20.06 mmol, CAS[402-69-7], commercially available e.g. from Sigma-Aldrich or Apollo Scientific) was dissolved in Dichloromethane (DCM) (100 mL) at 0° C. Oxalyl chloride (2.107 mL, 24.07 mmol) and a drop of N,N-dimethylformamide (DMF) was added and the mixture was stirred for 2 hours. The solvents were removed in vacuo and azeotroped with toluene (3×20 ml). The residue was dissolved in dichloromethane (DCM) (100 ml) whereupon 1,1-dimethylethyl hydrazinecarboxylate (2.92 g, 22.06 mmol) and N,N-diisopropylethylamine (DIPEA) (7.71 mL, 44.1 mmol) were added. The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and saturated sodium bicarbonate solution (50 ml). The aqueous phase was extracted with ethyl acetate (3×100 ml), the combined organic extracts were washed with brine (50 ml), were dried over anhydrous sodium sulphate and were concentrated in vacuo. The residue was purified by flash chromatography (Biotage SP4, 40+M, 0-100% ethyl acetate/iso-hexane) to afford 1,1-dimethylethyl 2-[(6-fluoro-2-pyridinyl)carbonyl]hydrazinecarboxylate (5.04 g, 19.75 mmol).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@H:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[C:21]=1[NH2:27])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=[CH:30]1.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>CN(C)C=O>[CH3:35][Si:34]([CH3:36])([C:37]([CH3:40])([CH3:39])[CH3:38])[O:28][C@@H:17]([CH2:16][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:18][O:19][C:20]1[C:21]2[NH:27][CH:30]=[N:26][C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(OC[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)c1N
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H](COc1cccc2nc[nH]c12)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
(S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-2,3-diaminobenzene (1 g, 2.7 mmol) was dissolved in N,N Dimethylformamide (10 mL) and imidazole (0.27 g, 4.0 mmol) and tert-butyldimethylsilyl chloride (0.6 g, 4.0 mmol) were added The solution was stirred at ambient temperature for 18 hours and then was partitioned between chloroform and water The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give the desired benzimidazole 1.3 g (96%). NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=2[OH:18])=[CH:3][N:2]=1.[C:19](=O)([O-:21])[O-:20].[K+].[K+].C(OC(=O)[N:31]([S:37]([C:40]1[CH:45]=[C:44]([Cl:46])[C:43](F)=[CH:42][C:41]=1[F:48])(=[O:39])=[O:38])[C:32]1[N:33]=[CH:34][S:35][CH:36]=1)(C)(C)C>CS(C)=O.O>[F:17][C:14]([F:15])([F:16])[C:19]([OH:21])=[O:20].[Cl:46][C:44]1[C:43]([O:18][C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14]([F:16])([F:17])[F:15])=[CH:12][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[CH:42][C:41]([F:48])=[C:40]([S:37]([NH:31][C:32]2[N:33]=[CH:34][S:35][CH:36]=2)(=[O:38])=[O:39])[CH:45]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1-c1ccnnc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 118.4 %

Procedure:
2-Pyridazin-4-yl-4-(trifluoromethoxy)phenol (Preparation 30, 88 mg, 0.34 mmol) was dissolved in dimethylsulfoxide (4 mL). Potassium carbonate (90 mg, 0.65 mmol) was added, followed by tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 4, 141 mg, 0.34 mmol). The reaction mixture was stirred for 18 hours at ambient temperature then diluted with water and extracted with ethyl ether (×3). The combined organic phase was concentrated in vacuo and purified by silica gel column chromatography (hexanes to ethyl acetate gradient elution). The residue was dissolved in saturated hydrogen chloride in methanol and stirred for 18 hours at ambient temperature. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to afford the title compound as an off-white powder (133 mg).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.CN1CCOCC1.[O:42]1[C:46](=[O:47])[CH2:45][CH2:44][C:43]1=[O:48]>C1COCC1>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][C:46](=[O:47])[CH2:45][CH2:44][C:43]([OH:48])=[O:42])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCC(=O)O)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 96 h

Procedure:
A mixture of 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 230 mg, 0.50 mmol) and 4-methyl-morpholine (300 mg, 30.0 mmol) in THF (3 mL) was treated with dihydro-furan-2,5-dione (250 mg, 2.50 mmol) and heated at 120° C. under microwave irradiation for 4 hrs and then thermally at 60° C. for four days. The crude reaction mixture was purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM. The fractions containing product were concentrated in vacuo affording the title compound as a colorless glass which solidified in a white solid by standing (182 mg).
Reaction SMILES: [CH2:1]([O:4][CH3:5])[C:2]#[CH:3].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1I>C1COCC1.C(N(CC)CC)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:3]#[C:2][CH2:1][O:4][CH3:5]
Reactant: C#CCOC
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC#Cc1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl propargyl ether (Fluka; 68898; 1.27 mL; 15 mmol; 1.50 eq.) was added dropwise to a suspension of 4-chloro-3-iodobenzoic acid (ABCR; TWC2211-D1; 2 824.60 mg; 10 mmol; 1 eq.), dichlorobis(triphenylphosphine)palladium(II) (701.91 mg; 1 mmol; 0.10 eq.) and cuprous iodide (190.45 mg; 1 mmol; 0.10 eq.) in a mixture of THF (20 mL) and triethylamine (10 mL). The reaction was stirred at RT for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl, and extracted twice with EtOAc. The combined extract were evaporated under vacuo to afford an orange solid. The latter was dissolved in EtOAc and extracted 4 times with NaOH 0.1M. Then the aqueous layer was filtered, acidified to pH=3-4 with HCl 1M, and extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a slightly orange powder. 1H NMR (DMSO-d6, 300 MHz) δ 13.42 (br. s., 1H), 8.03 (d, J=2.07 Hz, 1H), 7.92 (dd, J=2.17, 8.38 Hz, 1H), 7.71 (d, J=8.48 Hz, 1H), 4.41 (s, 2H), 3.19-3.37 (m, 3H). LC/MS (Method B): 223.0 (M−H)−. HPLC (Method A) Rt 3.51 min (Purity: 98.8%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][CH2:2][CH2:3][CH:4]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCC(CCN)Cc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCC(CCNS(=O)(=O)c1ccc(Cl)cc1)Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 8-amino-6-(3-pyridylmethyl)-octanoate (0.5 g) is dissolved in 50 ml of methylene chloride and 3 ml of triethylamine is added. To this solution is added dropwise a solution of 0.5 g of p-chlorophenylsulfonyl chloride in 10 ml of methylene chloride. The reaction mixture is stirred at room temperature for 1 h, the solvent is evaporated and the residue thus obtained purified by chromatography over silica gel, using methylene chloride as eluent to obtain methyl 8-(p-chlorophenylsulfonamido)-6-(3-pyridylmethyl)-octanoate as an oil.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](F)=O.[N:7]1([CH:13]=[CH:14][C:15]([O:17]C)=[O:16])CCCC[CH2:8]1.C([N:21](CC)CC)C.CNN.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:6])[C:3]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:7]([CH3:8])[N:21]=1
Reactant: CCN(CC)CC
Reactant: O=C(F)C(F)F
Reactant: COC(=O)C=CN1CCCCC1
Agent: CNN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)O)c(C(F)F)n1
Temperature: -30 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
At −30° C., difluoroacetyl fluoride (18.7 g, 0.187 mol; 98%) was introduced into a solution of methyl 3-piperidin-1-ylacrylate (99%, 29.05 g, 0.17 mol) and triethylamine (25.8 g, 0.255 mol) in toluene (250 ml). The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (250 ml). After separation of the phases, the aqueous phase was extracted once with toluene (200 ml). The toluene phases were combined and, under reduced pressure, concentrated to about 350 ml. The reaction solution obtained in this manner was, at −50° C., added dropwise to a solution of methylhydrazine (8.78 g, 0.187 mol) in toluene (150 ml). The reaction mixture was stirred at −50° C. for 2 h and then, over a period of 1 hour, warmed to room temperature. Aqueous sodium hydroxide solution (10%, 105.3 g, 0.263 mol) was then added, and the reaction mixture was heated under reflux conditions for 2 h. After cooling to room temperature, the phases were separated. The toluene phase was extracted with aqueous sodium hydroxide solution (10% strength, 100 ml). The aqueous phases were combined, adjusted to a pH of 1 using hydrochloric acid (conc.) and cooled to 0° C. The precipitated solid was filtered off, washed with cyclohexane and dried at 60° C. under reduced pressure. This gave 3-difluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid in an amount of 21.1 g (65% yield) in a purity of 91% (according to quant. HPLC). 1H-NMR (CDCl3): δ=3.85 (s, 2H), 3.95 (s, 3H), 7.12 (t, 1H), 7.9 ppm (s, 1H).
Reaction SMILES: [ClH:1].FC1C=CC=C(F)C=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4C=NC=CC=4)=[CH:23][C:16]=23)=[C:10]([F:30])[CH:9]=1)=[O:6].Cl.FC1C=C(NC(=O)[CH2:66][C:67]([NH:69][C:70]2[CH:75]=[CH:74][C:73]([F:76])=[CH:72][CH:71]=2)=[O:68])C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:1].[F:30][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:66][C:67]([NH:69][C:70]2[CH:75]=[CH:74][C:73]([F:76])=[CH:72][CH:71]=2)=[O:68])[CH:13]=[CH:12][C:11]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][C:22]([CH3:24])=[CH:23][C:16]=12
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1c(F)cccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a mixture of 3-fluoro-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (20 mg, 0.078 mmol, Compound E of Example 292), 3-(4-fluorophenylamino)-3-oxopropanoic acid (20 mg, 1 mmol, Compound A of Example 25), and HATU (44 mg, 0.12 mmol) in DMF (0.5 mL) was added DIPEA (0.1 mL). The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired product (HCl salt, 12.5 mg, 34%) as a white solid. 1H NMR (CD3OD) δ 8.05 (d, 1H, J=7.2 Hz), 7.79 (dd, 1H, J=12.7, 2.8 Hz), 7.50-7.53 (m, 2H), 7.27-7.36 (m, 2H), 6.97 (m, 2H), 6.70 (d, 1H, J=6.6 Hz), 6.20 (s, 1H), 3.47 (s, 2H), 2.40 (s, 3H); LC/MS(ESI+) m/z 437 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>[Ni].CO.C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cl)c2cccnc12
Yield: 98 %

Procedure:
In the similar fashion using route 6 general procedure 14, 5-chloro-8-nitroquinoline (Intermediate 25) (500 mg, 2.40 mmol), Raney nickel (100 mg, 20% wt), hydrazine hydrate (0.5 ml, 9.62 mmol) and MeOH/THF (10 ml, 4:1), gave the title compound (420 mg, 98%) which was used in the next step without purification.