Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[OH:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>C1COCC1.O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:20]=2)=[O:26])=[C:3]([OH:16])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1O
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(OCc2ccccc2)cc1O
Reaction time: 1.25 h

Procedure:
To a solution of 1.00 g (4.6 mMol) 2-amino-5-benzyloxy-phenol [preparation see: WO 03/045925; page 146] in 15 ml THF, a solution of 1.1 g (5.0 mMol) 4-chloro-3-trifluoromethyl-phenylisocyanate in 15 ml THF is added dropwise. After 75 min at rt, the reaction mixture is diluted in water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Trituration from hexane gives the crystalline title compound: m.p.: 182-184° C.; HPLC: tRet=17.5.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([C:12]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=1[C:14](O)=[O:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>>[CH2:1]([O:8][CH2:9][C:10]1[C:12]2[C:13](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:14](=[O:15])[NH:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)COCc2ccccc2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(COCc3ccccc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(2-benzyloxyacetyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [NH:1]=[N+:2]=[N-:3].[F:4][C:5]1[CH:6]=[C:7]([C:12](O)([CH3:14])[CH3:13])[CH:8]=[C:9]([F:11])[CH:10]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:1]([C:12]([C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:5]([F:4])[CH:6]=1)([CH3:14])[CH3:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N
Reactant: CC(C)(O)c1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N=[N+]=[N-])c1cc(F)cc(F)c1
Temperature: -5 °C
Reaction time: 20 h

Procedure:
Hydrogen azide (2M in toluene, 1.5 mol) was added to the solution of 2-(3,5-difluoro-phenyl)-propan-2-ol (Preparation 50, 145 g, 0.84 mol, 1 eq) in chloroform (1 L) and the content of the flask was cooled to −5° C. The mixture of TFA (2.5 mol, 2.98 eq) with chloroform (1:1) was added dropwise at such a rate to keep the internal temperature below −5° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirring was continued for 20 h. The reaction was poured into 2M sodium hydroxide and layers were separated. The aqueous phase was extracted two times with chloroform and combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the title compound was used in the next step without further purification (171 g, 0.87 mol, 100%).
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[NH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH3:27])[CH2:21]1>C1(C)C=CC=CC=1>[CH2:26]([N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([NH:19][CH:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:21]1)[CH3:27]
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CCN1CCCC(N)C1
Solvent: Cc1ccccc1
Product: CCN1CCCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
A solution of 4.0 g. of 9-acetoxyxanthene and 2.36 g. of 3-amino-1-ethylpiperidine in 175 ml. of dry toluene was refluxed for 24 hours. The cooled solution was then concentrated in vacuo. The residue was chromatographed on activated magnesium silicate, eluting with ether and acetone. Concentration of the acetone fraction in vacuo and then chromatographing on silica gel with acetone, then concentrating the eluate in vacuo gave N-(N-ethyl-3-piperidinyl)-9-xanthenylamine, m.p. 47.5°-48.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[C:28]1(B(O)O)[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: OB(O)C1=CCCCC1
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](F)CC1

Procedure:
Nitrogen was bubbled through a solution of 5-bromo-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (20 mg, 0.043 mmol) and cyclohexen-1-ylboronic acid (13 mg, 0.103 mmol) in 2M Na2CO3 (1.3 mL) and DME (2.6 mL) for 6 min. Pd(PPh3)4 (4.4 mg) was added and the mixture was refluxed for 1 h and 30 min. It was cooled, diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The crude was purified by chromatography over silica gel (hexane:EtOAc—9:1 and 4:1 as eluents) yielding pure 5-cyclohex-1-enyl-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (10 mg, 50%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]([CH2:11][CH2:12]O)=[CH2:10]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:8][C:9]1[CH2:10][C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:12][CH:11]=1
Reactant: C=C(C)CCO
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=CCOC2(CCCCC2)C1
Temperature: 115 °C
Yield: 79.4 %

Procedure:
A mixture of p-TSA (20 g, 0.105 mol) and toluene (2 L) was heated to 115° C. To this mixture were added cyclohexanone (980 g, 10 mols) and isoprenol (946 g, 11 mols) and heated further for 3-6 h. Water was removed from the reaction azeotropically. The reaction mixture was then cooled to room temperature. The organic phase was washed with a 5% Na2CO3 solution, washed with water dried and concentrated and distilled further to provide 4-methyl-1-oxaspiro [5.5] undec-3-ene (1.32 kg) having a purity of 98% (sum of the isomers) for a total yield of 80%.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[H-].[Na+].Cl[C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=1.O>CN(C)C=O>[Cl:23][C:22]1[C:17]([N:6]2[C:2]([CH3:1])=[C:3]([C:7]([F:13])([F:12])[C:8]([F:10])([F:9])[F:11])[N:4]=[CH:5]2)=[N:18][CH:19]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:21]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cc1[nH]cnc1C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(F)(F)C(F)(F)F)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of 0.6 g (3 m mol) of 5-methyl-4-pentafluoroethylimidazole in 5 ml of N,N-dimethyl formamide was added slowly 120 mg (3 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 10 minutes. After the reaction was completed, to the reaction mixture was added dropwise 0.65 g (3 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 9 hours. After the reaction was completed, the reaction mixture was poured into water, and extracted with ethyl acetate. Further, then the residue was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.5 g of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-methyl-4-pentafluoroethylimidazole.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:32][CH2:28][CH2:29][CH2:30][CH3:31])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CCCCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCCNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), butan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 333 (M+, 2), 290 (6), 87 (7), 86 (bp), 85 (4), 70 (7).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 64.5 %

Procedure:
o-Phenylenediamine 7.79 g (72 mmole), 4-bromobenzaldehyde 16 g (87 mmole), and 2.8 g of PTSA (14 mmole) was stirred in 150 ml of Toluene, the reaction mixture was then heated to reflux for 16 hours, after cooling, the reaction mixture was extracted with water, and then the organic layer was evaporated to dry, the residue was then recrystallized with acetone to get 12.69 g of product (yield=64.54%).
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[O:19]>O1CCCC1>[Cl:10][C:2]1([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[O:19]1
Reactant: O=Cc1ccccn1
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1(Cl)OC1c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 ml of tert.-butyl dichloroacetate in 15 ml of tetrahydrofuran and 2.6 ml of picolinaldehyde were mixed together and cooled to -20° C. to -25° C. Over 15 minutes at this temperature, 28 ml of potassium tert.-butylate in tetrahydrofuran at 0.9M/l were introduced and the mixture was allowed to warm up to ambient temperature. After 1 hour and 25 minutes, 25 ml of water were added, and extraction was effected with tetrahydrofuran. The organic phase was washed with water saturated with sodium chloride and then dried. The resulting solution containing 1,1-dimethylethyl 2-chloro-3-(2-pyridyl)oxirane carboxylate was held at -25° C. and used for the following step of the synthesis.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C=O.[CH3:10][CH:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]1[CH3:19].N[CH2:21]C(OC)=O>C(O)(=O)C.O>[CH3:18][C:13]1([CH2:21][NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:12]([CH3:19])=[C:11]([CH3:10])[C:15]([CH3:16])=[C:14]1[CH3:17]
Reactant: COC(=O)CN
Reactant: CC1=C(C)C(C)C(C)=C1C
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CNCC1(C)C(C)=C(C)C(C)=C1C
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a stirred mixture of methyl glycinate hydrochloride (6.28 g, 0.05 mole) in 30 mL of glacial acetic acid and 37% aqueous formaldehyde (4.1 g, 1.5 g real, 0.05 mole) is added pentamethylcyclopentadiene (6.81 g, 0.05 mole) after all of the solid methyl glycinate has dissolved. A light brown solution is initially obtained. The temperature is kept at 35° C. for five minutes with ice-bath cooling to control the exotherm. The color of the solution changes to light purple and the temperature is then kept at 33° C. for about 6 hours. This reaction mixture is combined with 100 mL of water and the aqueous phase is extracted with two×20 mL portions of methylene chloride. The clear aqueous phase is then treated with 50% sodium hydroxide, with cooling to maintain a temperature of 35° C., to pH 12. The basic aqueous phase is extracted with two×30 mL portions of methylene chloride. The organic layer is concentrated in vacuo to give approximately 5.0 g of the title compound. Yield is 40%, about 80% purity, of the product which is identified by proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance and electron impact mass spectral analyses.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:12]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][C:15]([CH2:18][N:3]2[C:2](=[O:1])[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4]2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(Cc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
A mixture of methyl 6-hydroxynicotinate (3 g), 4-biphenylylmethyl bromide (5.8 g), potassium carbonate (8.2 g), and DMF (30 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially and concentrated. The resulting crystals were washed with diisopropylether and recrystallized from ethyl acetate/hexane to obtain the titled compound (5.1 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:16][CH2:17][C:18]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30]C)([CH3:22])[CH3:21])[N:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:37]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:16][CH2:17][C:18]([OH:36])([C:32]([F:34])([F:33])[F:35])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[OH:30])([CH3:21])[CH3:22])[N:7]=1)=[O:5])[CH3:38]
Reactant: CCN(CC)C(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3O)C(F)(F)F)cccc2n1
Reaction time: 20 h
Yield: 27.5 %

Procedure:
210 mg (0.39 mmol) of 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylamino]quinoline-2-carboxylic acid diethylamide is mixed with 7.8 ml (7.8 mmol) of a 1 M boron tribromide solution in dichloromethane. After 20 hours at room temperature, the reaction is halted by adding water. It is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium bicarbonate solution, and it is dried on sodium sulfate. After the solvent is removed and after purification on silica gel with hexane-ethyl acetate (0–100%), 56 mg (28%) of the product is obtained.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:4]=[C:3]([CH3:5])[CH:2]([CH2:11][CH:10]=[CH2:9])[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCC(C(C)=O)C(=O)OC
Yield: 56.3 %

Procedure:
A mixture of methyl acetoacetate (11.6 g, 100 mmol), allyl bromide (12.1 g, 100 mmol) and potassium carbonate (13.8 g, 100 mmol) in acetone (70 mL) is heated under reflux for 18 hours. The mixture is filtered and the filtrate is evaporated. The residue is chromatographed on silica gel (15:1 hexane:ethyl acetate) to give methyl 3-oxo-2-(1-propen-3-yl)butanoate (8.8 g, 47%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 2.22 (s, 3H), 2.58 (t, 2H), 3.54 (t, 1H), 3.72 (s, 3H), 4.90-5.12(m, 2H), 5.60-5.82 (m, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:50])[CH2:19][CH2:20][N:21]([C:39]1([C:47](Cl)=[O:48])[CH2:45][CH:44]2[O:46][CH:41]([CH2:42][CH2:43]2)[CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16].Cl>ClCCl>[CH2:15]([O:17][C:18](=[O:50])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:39]1([C:47](=[O:48])[NH:2][OH:3])[CH2:45][CH:44]2[O:46][CH:41]([CH2:42][CH2:43]2)[CH2:40]1)[CH3:16]
Reactant: NO
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCN(C1(C(=O)NO)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0° C. is treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture is allowed to warm to ambient temperature overnight. This mixture is then cooled to 0° C. and treated with a solution of (15.1 mmol) of the product from Step F in 73 mL of dichloromethane causing an exotherm to about 8° C. This mixture is stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction is then treated with 50 mL of 2N aqueous hydrochloric acid and was stirred at ambient temperature for one hour. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of the title compound in dichloromethane is used in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[CH:9]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>C(Cl)Cl.CO>[Cl:18][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:19])=[CH:4][N:3]=[C:2]([NH:32][C:31]3[CH:30]=[CH:29][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[CH:34][CH:33]=3)[N:7]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc(Cl)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1cc(Cl)cc(C(F)(F)F)c1
Yield: 76 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-5-(trifluoromethyl)phenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 76% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.79 (d, 2H, J=7.8 Hz), 7.69 (s, 1H), 7.55 (d, 2H, J=8.2 Hz), 7.26 (d, 2H, J=8.6 Hz), 3.47 (s, 2H), 2.50 (bs, 8H), 2.31 (s, 3H), 2.25 (s, 3H); MS (ESI): 476.3 [M+H]+, 238.7 [M+2H]2+.
Reaction SMILES: [ClH:1].[Cl:2][CH:3]1[C:12]2[N:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.Cl.[NH3:15]>CO.CCOCC>[ClH:2].[ClH:1].[NH2:15][CH:3]1[C:12]2[N:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: N
Reactant: Cc1cnc2c(c1)CCCC2Cl
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1cnc2c(c1)CCCC2N

Procedure:
The 8-chloro product of Example 2 (17 g.) was dissolved in methanol saturated with ammonia (400 ml.) and heated at 80° in a stainless steel bomb for 24 hours. The solvent was removed in vacuo and the residual oil triturated with anhydrous ether (3 × 50 ml.) and the triturates discarded. The oily solid was dissolved in water and the pH adjusted to 9.0 with sodium carbonate and extracted with ether (3 × 150 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give a pale yellow oil (5.5 g.). A sample (500 mg.) was dissolved in anhydrous ether (25 ml.) and the solution treated with excess ethereal hydrogen chloride and the resultant solid recrystallised from methanol-ether to give 8-amino-3-methyl-5,6,7,8-tetrahydroquinoline dihydrochloride quarter hydrate as colourless needles m.p. 210° C. (Found: C,50.5;H,6.9; N,11.6. C10H14N2.2HC1. 1/4H2O requires: C,50.2; H, 7.1; N, 11.7%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccncc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccncc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and isonicotinic acid.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[NH2:26][C:27]1[CH:31]=[C:30]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)[NH:29][N:28]=1.NC1C=CNN=1>O1CCCC1>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]2=[CH:2][NH:26][C:27]1[CH:31]=[C:30]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)[NH:29][N:28]=1
Reactant: O=C1Nc2ccc(F)cc2/C1=C/O
Reactant: Nc1cc(-c2ccco2)[nH]n1
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=CNc1cc(-c2ccco2)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-5-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 3-amino-5-(2-furyl)-pyrazole for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-5-fluoro-1,3-dihydro-indol-2-one (0.050 gms.) is reacted with 0.085 gms. of 3-amino-5-(2-furyl)-pyrazole by refluxing in tetrahydrofuran (1.5 mL).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:13][C:12]([F:15])([F:14])[CH2:11][NH:10][C@@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:20][C:21]1[CH:28]=[C:27]([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)[CH:26]=[C:25]([CH3:35])[C:22]=1[C:23]#[N:24].CN(C)C=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:23]([C:22]1[C:25]([CH3:35])=[CH:26][C:27]([C:29]2[CH2:34][CH2:33][N:32]([C:16]([C@@H:9]3[C@@H:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:12]([F:14])([F:15])[CH2:11][NH:10]3)=[O:18])[CH2:31][CH:30]=2)=[CH:28][C:21]=1[CH3:20])#[N:24]
Reactant: CC(C)(C)OC(=O)[C@H]1CC(F)(F)CN[C@@H]1C(=O)O
Reactant: Cc1cc(C2=CCNCC2)cc(C)c1C#N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: Cc1cc(C2=CCN(C(=O)[C@H]3NCC(F)(F)C[C@@H]3C(=O)OC(C)(C)C)CC2)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2S,3S)-3-(tert-butoxycarbonyl)-5,5-difluoropiperidine-2-carboxylic acid (48 mg, 0.00018 mol) and 2,6-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride (84.7 mg, 0.000217 mol) TFA salt in N,N-dimethylformamide (0.406 mL, 0.00524 mol) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (96.0 mg, 0.000217 mol), followed by N,N-diisopropylethylamine (0.0756 mL, 0.000434 mol). The mixture was stirred at rt overnight, then quenched with aq. sodium bicarbonate. The mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried, and evaporated to dry. The residue was used directly in next step without further purification. LCMS (M+H) 460.2.