Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([O:29]C(=O)C)([C:14](=[O:28])[N:15]([CH3:27])[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>OS([O-])(=O)=O.[K+]>[CH3:27][N:15]([C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=1)[C:14]([C:11]1([OH:29])[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:28]
Reactant: CC(=O)OC1(C(=O)N(C)c2ccc(OC(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Product: CN(C(=O)C1(O)CCN(Cc2ccccc2)CC1)c1ccc(OC(F)(F)F)cc1
Temperature: 70 °C
Yield: 59.1 %

Procedure:
A mixture of 0.782 g (1.7 mmol) acetic acid 1-benzyl-4-[methyl-(4-trifluoromethoxy-phenyl)-carbamoyl]-piperidin-4-yl ester and excess KOH 5M was heated to 70° C. The mixture was diluted with KHSO4 1N aq. and extracted with ethyl acetate. the combined organic fractions were dried with MgSO4 and evaporated. The residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and HCOOH. The product containing fractions were evaporated to yield 0.41 g (58%) of the title compound. MS (m/e): 409.1 [(M+H)+].
Reaction SMILES: [NH:1]([C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:2]([C:24](ON1C(=O)CCC1=O)=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:53][C@H:54]([C:62]([O:64][CH3:65])=[O:63])[CH2:55][S:56][CH2:57][NH:58][C:59]([CH3:61])=[O:60]>C(Cl)(Cl)Cl>[NH:1]([C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C@H:2]([C:24]([NH:53][C@H:54]([C:62]([O:64][CH3:65])=[O:63])[CH2:55][S:56][CH2:57][NH:58][C:59]([CH3:61])=[O:60])=[O:25])[CH2:3][S:4][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(ON1C(=O)CCC1=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)CSCNC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CSCNC(C)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 20 h

Procedure:
7.0 g of Trt-Cys(Trt)-OSu and 2.0 g of H-Cys(Acm)-OMe in 50 ml of chloroform are left to stand for 20 hours at room temperature. The solution is then diluted with 100 ml of chloroform and washed with 1 N citric acid, 1 N sodium bicarbonate and water, dried over sodium sulphate and evaporated. The residue is recrystallised from ethyl acetate-ether. Melting point 197°-198°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)[C:5]#[N:6].[Sn].Cl>CO>[NH2:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl
Agent: [Sn]
Solvent: CO
Product: N#Cc1cc(N)cc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-nitrobenzonitrile (1 g, 4.4 mmol) in MeOH (50 mL) was added tin (5.23 g, 44 mmol) and 3N HCl (44 mL, 132 mmol). The reaction mixture was stirred at RT for 2 h, the filtered off and washed with MeOH. The filtrate was concentrated in vacuo, and the remaining water phase was basified to pH=12 by addition of 4N NaOH. The aqueous layer was extracted twice with EtOAc (100 mL), the combined organics were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a yellowish solid. MS (LC/MS): 197.0 [M+H]+; tR (HPLC conditions c): 4.30 min.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C.Cl.Cl.[CH2:59]([N:61]1[CH2:66][CH2:65][NH:64][C@@H:63]([CH3:67])[CH2:62]1)[CH3:60].Cl>O.C(O)C.CN(C=O)C>[CH2:59]([N:61]1[CH2:66][CH2:65][N:64]([C:20]([C:19]2[CH:23]=[CH:24][C:16]([N:13]3[C:14]([OH:15])=[C:10]([C:6]4[C:5]([CH3:25])=[CH:4][C:3]([C:1]#[N:2])=[C:8]([F:9])[CH:7]=4)[CH:11]=[N:12]3)=[N:17][CH:18]=2)=[O:22])[C@@H:63]([CH3:67])[CH2:62]1)[CH3:60]
Reactant: CCN1CCN[C@@H](C)C1
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4cc(F)c(C#N)cc4C)c3O)nc2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.6 %

Procedure:
Combined 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (100 mg, 0.296 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (47.9 mg, 0.355 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (68.0 mg, 0.355 mmol), DMF (Volume: 591 μl), and N-ethyl-N-isopropylpropan-2-amine (258 μl, 1.478 mmol). The orange solution was stirred at ambient temperature for 5 minutes then (S)-1-ethyl-3-methylpiperazine dihydrochloride (65.4 mg, 0.325 mmol) was added and the reaction was stirred at ambient temperature for 12 h. The reaction mixture was diluted with a pre-made solution of water:ethanol (1:1, 5 mL). The reaction was acidified to pH 5 using 1N HCl. The solution was left to stir slowly at ambient temperature overnight. The precipitate was filtered and the solids were washed with water:ethanol (1:1, 2 mL), then dried on the filter paper. The white solids were collected and dried further under vacuum. The dried solids were taken up in 10 volumes of water:ethanol (1:1) and stirred at reflux until the solution was almost completely translucent. The hot solution was filtered and then slowly cooled to ambient temperature and stirred slowly at ambient temperature overnight to give solids. The solids were filtered and washed with water:ethanol (1:1, 2 mL), partially dried on filter paper, then dried under vacuum to give the title compound (57.9 mg, 0.129 mmol, 43.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (t, J=7.20 Hz, 3 H) 1.30 (d, J=6.82 Hz, 3 H) 2.14-2.28 (m, 1 H) 2.31-2.45 (m, 4 H) 2.53-2.60 (m, 2 H) 2.81-3.06 (m, 2 H) 3.13-3.43 (m, 2 H) 4.08-4.62 (m, 1 H) 7.64 (d, J=7.33 Hz, 1 H) 7.96 (dd, J=8.84, 2.27 Hz, 1 H) 8.08 (s, 1 H) 8.19 (d, J=12.63 Hz, 1 H) 8.43-8.52 (m, 2 H). ESI-MS m/z [M+H]+ 449.3, ret time: 0.79 minutes.
Reaction SMILES: Br[CH2:2][P:3](=[O:12])([O:8][CH:9]([CH3:11])[CH3:10])[O:4][CH:5]([CH3:7])[CH3:6].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13](=[O:16])([S:15][CH2:2][P:3]([O:8][CH:9]([CH3:11])[CH3:10])([O:4][CH:5]([CH3:7])[CH3:6])=[O:12])[CH3:14]
Reactant: CC([O-])=S
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SCP(=O)(OC(C)C)OC(C)C
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of diisopropyl bromomethylphosphonate (5.00 g, 19.3 mmol) in N,N-dimethylformamide (15.4 mL) was added potassium thioacetate (3.75 g, 32.8 mmol) followed by tetrabutylammonium iodide (0.36 g, 0.97 mmol). The reaction mixture was stirred at 85° C. for 2.5 hours. The reaction mixture was cooled and partitioned between water and EtOAc (3×) and the layers were separated. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (24 g column, eluent: 0 to 90% EtOAc/hexanes) provided the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][CH:21]([CH2:23][C:24]([O:26]CC)=[O:25])[C:20]4[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=4[O:18][C:17]=3[CH:33]=2)[CH:3]=1.[OH-].[Na+].Cl>CCO>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][CH:21]([CH2:23][C:24]([OH:26])=[O:25])[C:20]4[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=4[O:18][C:17]=3[CH:33]=2)[CH:3]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3cc(C)ccn3)cc2Oc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc(NCCCOc2ccc3c(c2)Oc2ccccc2C(CC(=O)O)C3)c1
Reaction time: 20 h
Yield: 60.2 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-[3-(4-methylpyridin-2-ylamino)-1-propyloxy]dibenzo[b,f]oxepine-10-acetate (119 mg, 0.27 mmole) and 0.991 N NaOH (0.545 mL, 0.54 mmole) in absolute EtOH (2 mL) was warmed in an oil bath set at 45° C. After 20 hr, the reaction was concentrated on the rotavap, and the residue was dissolved in H2O (1.5 mL). The solution was filtered to remove insoluble material, and the filtrate was carefully neutralized by dropwise addition of 1.0 N HCl (0.54 mL, 0.54 mmole). The precipitate was collected and dried in high vacuum to afford the title compound (68 mg, 58%) as a white solid: MS (ES) m/e 418.9 (M+H)+. Anal. Calcd for C25H26N2O4. 0.45 HCl: C, 69.05; H, 6.13; N. 6.44. Found: C, 69.25; H, 6.27; N. 6.16.
Reaction SMILES: C(O)C.[Cl-].[NH4+].O1CCCC1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH2:19][N:18]([C:25](=[O:41])[C@@H:26]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N+:38]([O-])=O)[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:17][CH2:16]2>[Fe].O>[NH2:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH:31][C@@H:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]([N:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:19]1)=[O:41]
Reactant: COc1cc2c(cc1OC)CN(C(=O)[C@@H](Nc1ccccc1[N+](=O)[O-])C(C)(C)C)CC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OC)CN(C(=O)[C@@H](Nc1ccccc1N)C(C)(C)C)CC2
Temperature: 25 °C
Yield: 87.8 %

Procedure:
Ethanol (5 ml) and a saturated aqueous ammonium chloride solution (5 ml) were added to a tetrahydrofuran (5 ml) solution of (2S)-1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-3,3-dimethyl-2-((2-nitrophenyl)amino)butan-1-one (395 mg, 0.92 mmol) obtained in Example 24, and the mixture was stirred at room temperature. Water was added to the reaction solution until the insoluble matter was dissolved, powdery iron (6 g) was added, and the mixture was refluxed with heating for 2 hours. The reaction solution was cooled to room temperature, and the excessive iron and tinorganic salt were filtered off using Celite. The filtrate was diluted with ethyl acetate (150 ml), washed with a 1 N aqueous sodium hydroxide solution (50 ml×2), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:1) and then chloroform and methanol (20:1) as eluents to obtain the captioned compound (321 mg, 87%) as a colorless foamy substance.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=C(C)C2C(=[N:38][OH:39])CC(C3C=CC=CC=3C3C=CC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:38][OH:39])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1cccnc1)C2
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Product: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1cccnc1)C2

Procedure:
The title compound was prepared from 2-amino-4-methyl-7-(2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one from stage 1, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (example 5/a stage 2—method A).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[C:13](O)=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].Cl>C(OCC)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[CH2:13][OH:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(CO)Oc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 22.5 g (0.077 mol) of (±)-2-[4-(4-chlorophenoxy)-phenoxy]-propionic acid (CRL 40299) in 150 ml of anhydrous diethyl ether is run over the course of 1 hour 30 minutes into a suspension of 6.6 g (0.173 mol) of LiAlH4 in 50 ml of anhydrous diethyl ether. Thereafter the reflux is maintained for 1 hour 30 minutes, the excess hydride is neutralised with ethyl acetate and the complex is hydrolysed with dilute hydrochloric acid. The organic phase is decanted, washed with water and dilute sodium hydroxide solution and gives, after drying over dry sodium sulphate and evaporation of the solvent, 21.4 g of a crystalline white mass, which is insoluble in water.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCOC.[Na].[O:15]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[O:25][C:26](F)=[C:27]([F:32])[C:28]([F:31])([F:30])[F:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[O:15]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[O:25][C:26]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[C:27]([F:32])[C:28]([F:29])([F:30])[F:31])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(Oc1cccc(Oc2ccccc2)c1)=C(F)C(F)(F)F
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: O
Solvent: COCCOC
Product: FC(=C(Oc1cccc(Oc2ccccc2)c1)Sc1ccccc1)C(F)(F)F
Temperature: 75 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
Eleven g (0.1 mole) of thiophenol and 150 ml 1,2-dimethoxy ethane are placed into a flask and stirred under nitrogen while 2.3 g of metal sodium are added in portions. When this reaction is complete, 32 g of 1-(3-phenoxyphenoxy)perfluoropropene are added dropwise causing a slight exotherm. The mixture is stirred at 75° C. for six hours following this addition. After cooling, 150 ml of dilute base water solution is added and the mixture is stirred. The product layer is separated and washed with 150 ml water, separated, dried over sodium sulfate, filtered and distilled to produce the title compound as an oil in a yield of 38 percent. The oil has a pour point of -26° C. and a boiling range of 150° to 190° C. at 0.5 mm Hg.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21](=[N:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=4[O:35][CH3:36])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:39]=[C:40]([C:45]([O:47]C)=O)[C:41]([O:43][CH3:44])=[O:42]>O(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21]4[N:25]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=5[O:35][CH3:36])[C:45](=[O:47])[C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][C:22]=4[CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCCC(=NCc1ccc(OC)cc1OC)c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 24.6 %

Procedure:
A solution of 4 N-(1-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)butylidene)-1-(2,4-dimethoxyphenyl)methanamine (5.7 g, 11.2 mmol) and dimethyl 2-(methoxymethylene)malonate (2.55 g. 14.4 mmol) in Ph2O (10 mL) was heated at 220° C. for 30 min. The reaction mixture was then cooled to room temperature and loaded directly on silica gel eluting with hexanes/EtOAc (9:1) to afford the title compound as an orange foam (1.7 g, 25%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@@H:45]([N:48]3[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]3)[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([C@H:42]3[CH2:47][CH2:46][C@@H:45]([N:48]4[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]4)[CH2:44][CH2:43]3)=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1CCN([C@H]2CC[C@@H](c3ccc(N)c4c3CN(C)C4=O)CC2)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-2-methyl-4-[cis-4-(4-methylpiperazin-1-yl)cyclohexyl]-2,3-dihydro-1H-isoindol-1-one. 1H NMR (CD3OD, 400 MHz): δ=1.29 (t, J=7.07 Hz, 6 H), 1.72 (dd, J=12.76, 3.66 Hz, 2 H), 1.77-1.89 (m, 2 H), 1.92-2.04 (m, 2 H), 2.21 (d, J=12.13 Hz, 2 H), 2.81-2.91 (m, 2 H), 2.93 (s, 3 H), 3.19 (s, 3 H), 3.33-3.41 (m, 2 H), 3.45 (br. s., 3 H), 3.91 (s, 3 H), 4.05-4.15 (m, 4 H), 4.55 (s, 2 H), 6.99 (ddd, J=7.96, 2.40, 2.27 Hz, 1 H), 7.13 (t, J=2.02 Hz, 1 H), 7.45 (d, J=8.59 Hz, 1 H), 7.70 (d, J=8.08 Hz, 1 H), 8.36 (s, 1 H), 8.41 (br. s., 1 H). MS (ES+): m/z 760.30 [MH+]; HPLC: tR=1.18 minutes (UPLC TOF MS: polar—3 min).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.CO.C1(C)C=CC(S([CH2:24][N+:25]#[C-:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCCCCC>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7]2[O:8][CH:26]=[N:25][CH:24]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc(-c2cnco2)cc1
Yield: 97.7 %

Procedure:
To a 250 mL round-bottom flask was added 4-(trifluoromethyl)benzaldehyde (4.50 g, 25.84 mmol), methanol (100 mL), p-toluene sulfonylmethyl isocyanide (5.55 g, 28.42 mmol), followed by potassium carbonate (4.60 g, 33.33 mmol). The reaction mixture was stirred at reflux for about 1 hour and followed by TLC. The solvent was then evaporated and saturated aq.NaHCO3 was added. The resultant suspension was extracted with CH2Cl2 (3×20 mL). Combined organic layers were washed with brine, dried (anhydrous Na2SO4), and concentrated to leave a yellow solid. The product was purified by MPLC column chromatography (Biotage; Acetone/hexane as an eluent) to provide 5-(4-(trifluoromethyl)phenyl)oxazole 30 (5.38 g, 98% yield) as white solid. MS (ES) m/z 214 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].[OH-].[Na+]>>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:3]1[C:2]([NH2:1])=[N:7][C:6]([C:8]2[NH:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:5][CH:4]=1
Reactant: Nc1cccc(C(=O)O)n1
Reactant: Nc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(-c2nc3ccccc3[nH]2)ccc1-c1ccccn1
Temperature: 0 °C

Procedure:
A suspension of 6-aminopyridine-2-carboxylic acid (1.12 g, 8.2 mmol) with 1,2-diaminobenzene (1.77 mg,16.4 mmol) was heated in 8 mL of PPA at 180 degree for 2 h. The reaction mixture was poured into 250 mL of ice-water and neutralized with 2 N NaOH (chilled) while vigorously stirred. The resulting precipitate was filtered to collect an off-white solid, which was washed with 20 mL warm water, dried and purified by chromatography using a 9:1 mixture of CH2Cl2 to MeOH (MS, M++H=211).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br.ClCCl.O>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2cccc(C)c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 265.2 %

Procedure:
(4-Methoxyphenyl)(3-methylphenyl)methanone (603 mg) was dissolved in dichloromethane (3 ml) to prepare a solution. A boron tribromide-dichloromethane solution (1.0 M) (11 ml) was added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was poured into ice-cooled water, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane/ethyl acetate as a solvent to give (4-hydroxyphenyl)(3-methylphenyl)methanone (1.50 g, yield 56%).
Reaction SMILES: FC(F)(OC1C=CC(OC2C=CC(C[NH2:17])=CC=2)=CC=1)C(F)F.C(N(CC)CC)C.[Cl:30][C:31]1[C:32]([CH3:40])=[N:33][N:34]([CH3:39])[C:35]=1[C:36](Cl)=[O:37]>C1(C)C=CC=CC=1>[Cl:30][C:31]1[C:32]([CH3:40])=[N:33][N:34]([CH3:39])[C:35]=1[C:36]([NH2:17])=[O:37]
Reactant: NCc1ccc(Oc2ccc(OC(F)(F)C(F)F)cc2)cc1
Reactant: Cc1nn(C)c(C(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nn(C)c(C(N)=O)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 233.5 %

Procedure:
To a stirred mixture of 4-[4-(1,1,2,2-tetrafluoroethoxy)phenoxy]benzylamine (359 mg, 1.14 mM), triethylamine (136 mg, 1.35 mM) and toluene (20 ml) was added dropwise a solution (10 ml) of 4-chloro-1,3-dimethylpyrazole-5-carbonyl chloride (200 mg, 1.04 mM) in toluene at 0°-10° C., and the mixture was stirred for 3 h at room temperature. The mixture was poured into ice water, and the mixture was extracted with toluene. The extract was washed with saturated sodium hydrogen carbonate solution, saturated ammonium chloride solution and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give N-{4-[1,1,2,2,-tetrafluoroethoxy)phenoxy]benzyl}-4-chloro-1,3-dimethylpyrazole-5-carboxamide (420 mg, 86%) as colorless crystals, m.p. 101.3° C.
Reaction SMILES: [NH2:1][C:2]1[N:21]=[C:5]2[C:6]([C:10]3([OH:20])[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:22][C:23]1[N:27]=[C:26]([N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[S:25][N:24]=1.[BH4-].[Na+]>C(O)C>[CH3:22][C:23]1[N:27]=[C:26]([N:28]2[CH2:29][CH2:30][CH:31]([NH:1][C:2]3[N:21]=[C:5]4[C:6]([C:10]5([OH:20])[CH2:11][CH2:12][CH:13]([C:16]([F:17])([F:18])[F:19])[CH2:14][CH2:15]5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH2:32][CH2:33]2)[S:25][N:24]=1
Reactant: Nc1nc2c(C3(O)CCC(C(F)(F)F)CC3)cccn2n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nsc(N2CCC(Nc3nc4c(C5(O)CCC(C(F)(F)F)CC5)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 219f), starting from 1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-4-(trifluoromethyl)cyclohexanol and 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one. As a reducing agent 4 equivalent sodium borohydride in ethanol was used at 70° C. over night. The title compound was obtained after column chromatography on silica gel using ethyl acetate as eluent as a white solid (yield: 46%).