Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.CN(C(O[N:16]1N=N[C:22]2[C:17]1=[CH:18]C=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:32][C:33]1[CH:38]=[C:37]([S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48](O)=[O:49])(=[O:41])=[O:40])[CH:36]=[CH:35][C:34]=1[NH:51][C:52](=[O:60])[C@:53]([OH:59])([CH3:58])[C:54]([F:57])([F:56])[F:55].CC(N)C>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[C:37]([S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]([NH:16][CH:17]([CH3:22])[CH3:18])=[O:49])(=[O:40])=[O:41])[CH:36]=[CH:35][C:34]=1[NH:51][C:52](=[O:60])[C@:53]([OH:59])([CH3:58])[C:54]([F:56])([F:55])[F:57]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2C(=O)O)cc1Cl)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccccc1S(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
N-Methylmorpholine (1.22 ml) and o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.092 g) were added to a solution of (R)-N-[2-chloro-4-(2-carboxyphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 125) (0.10 g) and 2-propylamine (0.024 ml) in DCM (20 ml) at (0° C. The reaction mixture was stirred at this temperature for 30 minutes then allowed to warm to room temperature, stirred for a further 3 hours then evaporated to dryness. The residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 50% ethyl acetate/hexane then triturated with ether/hexane to give the title compound (0.05 g) as a solid. NMR (CDCl3): 1.3 (d, 6H), 1.6 (s, 3H), 4.2-4.32 (m, 1H), 5.8 (brd, 1H), 7.4 (d, 1H), 7.5-7.7 (m, 3H), 7.9 (dd, 1H), 8.05-8.13 (m, 2H), 8.6 (d, 1H), 9.3 (brs, 1H); MS (ESP−): 491.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:30]([C:26]2[N:27]=[CH:28][O:29][C:25]=2[CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:31])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(O)c1ncoc1C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ncoc2C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.8 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 0.30 g, 1.03 mmol), 5-cyclohexyl-1,3-oxazole-4-carboxylic acid (Reference Example 14, 0.22 g, 1.13 mmol), triethylamine (0.23 g, 2.26 mmol), EDCI (0.22 g, 1.13 mmol) and HOBt (0.17 g, 1.13 mmol) in acetonitrile (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 50:50) and the resulting white solid was triturated with hexane to give the title compound (0.15 g, 37%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:13][CH2:12][N:11]3[C:5]2=[C:6]([CH:25]=1)[C:7]([N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[N:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=13>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:13]=[CH:12][N:11]3[C:5]2=[C:6]([CH:25]=1)[C:7]([N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[N:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=13
Reactant: CN1CCN(C2=Nc3ccccc3N3CCc4cc(Cl)cc2c43)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3-n3ccc4cc(Cl)cc2c43)CC1
Yield: 63.7 %

Procedure:
To a solution of 4-chloro-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (6 g, 17 mmoles), in chloroform (150 ml) was added manganese dioxide (10.5 g). The mixture was heated under reflux for 24 hours. The mixture was cooled, filtered and the solid was washed with dichloromethane (200 ml). The filtrate was then concentrated to dryness. The residue was purified by flash chromatography over a silica gel column (150 g), eluted with 2% methanol in dichloromethane (4 l) and 3% methanol in dichloromethane (2 l). Evaporation of the eluent gave 3.8 g (63%) of product. Recrystallization from toluene (40 ml) yielded the analytical sample, mp 170°-172° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Li]CCCC.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>C1COCC1>[CH3:16][Si:15]([C:13]#[C:14][C:3]1([OH:7])[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)([CH3:18])[CH3:17]
Reactant: O=C1CCCOC1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1(O)CCCOC1
Reaction time: 3 h
Yield: 50.4 %

Procedure:
A solution of dihydro-2H-pyran-3(4H)-one (200 mg, 2 mmol) in THF was treated with n-BuLi (2 mL) at −78° C. for about 30 min. Ethynyltrimethylsilane (300 mg, 3 mmol) was then added and the reaction mixture was stirred for 3 hr. Purification by gel chromatography afforded the title compound (200 mg, 50%); 1H NMR (400 MHz, DMSO) delta 0.15 (s, 9H), 1.52-1.55 (m, 1H), 1.62-1.67 (m, 1H), 1.80-1.88 (m, 1H), 3.23-3.26 (m, 1H), 3.37-3.44 (m, 1H), 3.49-3.56 (m, 2H), 5.52 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-])=O)=[CH:5][C:3]=1[NH2:4]>[Ni]>[CH3:9][C:7]1[CH:8]=[C:2]([CH3:1])[C:3]([NH2:4])=[CH:5][C:6]=1[NH2:10]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Agent: [Ni]
Product: Cc1cc(C)c(N)cc1N

Procedure:
2,4-Dimethyl-5-nitroaniline was reduced in the presence of Raney nickel utilizing substantially the same conditions described in Example 2 to form 2,4-dimethyl-1,5-phenylenediamine and that compound was sulfonated under the conditions of Example 3. The resulting 5-amino-2,4-dimethyltrifluoromethanesulfonanilide (10.72 g., 40 mmole) was dissolved in 1,2-dichloroethane (60 ml.), and the solution was cooled to a temperature of 0° to 5° C. To this solution was slowly added chloroacetyl chloride (10.16 g., 90 mmole). The solution was then heated at its reflux temperature for 10 hours. Hexane (100 ml.) was added to the hot reaction mixture, the reaction mixture was then filtered while hot, and the solid product was collected upon crystallization, m.p. 170°-172° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:12]2[C:11]([CH:13]=[C:14]3[N:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]4=[N:16][C:15]3=[O:23])=[CH:10][S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>C(O)C.CO>[CH3:3][C:4]1[C:12]2[C:11]([CH2:13][CH:14]3[N:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]4=[N:16][C:15]3=[O:23])=[CH:10][S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc2scc(C=C3C(=O)N=C4C=CC=CN34)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Cc1cccc2scc(CC3C(=O)N=C4C=CC=CN43)c12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 121 mg (3.2 mmol) of sodium borohydride in 50 mL of ethanol is added a solution of 624 mg (2.1 mmol) of 3-(4-methyl-benzo[b]thiophen-3-ylmethylene)-imidazo[1,2-a]pyridin-2-one in 50 mL of methanol dropwise at −78° C. After stirring for 15 minutes at −78° C., the reaction mixture is quenched with saturated aqueous ammonium chloride solution at −78° C. The product is extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired compound.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18](=[O:20])[CH3:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Br-:21].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>C1COCC1>[Br:21][CH2:19][C:18]([C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)=[O:20]
Reactant: [Br-]
Reactant: COc1ccc(-c2c(C(C)=O)cnn2C(C)(C)C)cc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C(=O)CBr)cnn2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 32.1 %

Procedure:
To a solution of the compound (260 mg, 0.95 mmol) obtained in step 4 in THF (5 mL) was added dropwise a solution of trimethylphenylammonium tribromide (359 mg, 0.95 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 14 hr, and the precipitate was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 2→45% ethyl acetate/hexane) to give 2-bromo-1-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)ethanone (107 mg, 0.305 mmol, 31.9%) as a white powder.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]=3[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29].[OH-].[Na+]>ClCCl.CO>[NH:1]1[C:5]2[C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]=3[N:8]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1
Reactant: c1cnc2c(c1)NCCc1cn[nH]c1-2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ncccc32)cn1

Procedure:
To a solution of 2 mmol 1,4,5,6-tetrahydropyrazolo[3,4-d]pyrido[3,2-b]azepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 4.2 mmol of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. After stirring over the mixture is worked-up as described for Example 1 and the initial solid treated with 1N NaOH in methanol as described for Example 1 to give the product as a solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=[O:8])[N:3]=[CH:2]1.[CH2:10](I)[CH3:11]>>[S:1]1[CH:5]=[C:4]([CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])[N:3]=[CH:2]1
Reactant: O=C(O)Cc1cscn1
Reactant: CCI
Product: CCC(C(=O)O)c1cscn1

Procedure:
2-(1,3-Thiazol-4-yl)butanoic acid was prepared from commercially available 1,3-thiazol-4-ylacetic acid and ethyl iodide using a procedure analogous to that used to prepare
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[SH:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:9]2[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=[CH:32][C:8]=2[N:7]=1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([S:5][C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:9]2[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=[CH:32][C:8]=2[N:7]=1)[CH2:2][CH3:3]
Reactant: CCCI
Reactant: CCOC(=O)c1cccc2nc(S)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCSc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
Propyl iodide (0.37 g) was added to a solution of ethyl 2-mercapto-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.91 g) in ethanol (13 ml) containing 1N NaOH (4.0 ml) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was adjusted to about pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration and purified by column chromatography on silica gel. Recrystallization from ethyl acetate-hexane gave colorless prisms (0.4 g, 40%), m.p. 177–178° C. (decomp.).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>CCO>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2ccccc2)CC1
Agent: NN
Solvent: CCO
Product: NCCCCN1CCN(c2ccccc2)CC1

Procedure:
Compound 3b (7.70 g, 21.21 mmol) was reacted with NH2NH2 (3.0 g, 93.75 mmol) in EtOH (60 mL) to give 4b, 4.60 g (93%) (Procedure B). 1H NMR (CDCl3) 1.48-1.61 (m, 4H), 2.83-2.43 (t, J=7.2 Hz, 2H, NCH2), 2.61-2.63 (t, J=4.5 Hz, 4H, N(CH2)2), 2.72-2.76 (t, J=6.4 Hz, 2H, NCH2), 3.19-3.22 (t, J=4.6 Hz, 4H, N(CH2)2), 6.33-6.94 (m, 3H, Ar—H), 7.23-7.28 (m, 2H, Ar—H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][OH:21])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][O:21][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(N(CCCO)CC2CC2)cc1C(F)(F)F
Reactant: Oc1ccc(F)cc1
Product: N#Cc1ccc(N(CCCOc2ccc(F)cc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-fluorophenol: MS (APCI) m/z 393 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:50]=[CH:49][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH:25]=O)[C:22]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[N:38]=[C:39]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[O:40][C:41]=4[CH3:42])=[CH:31][CH:30]=3)=[N:21]2)=[CH:17][CH:16]=1.C(OP([CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])(OCC)=O)C.[H-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[C:23](/[CH:25]=[CH:59]/[C:60]([O:62][CH2:63][CH3:64])=[O:61])[C:22]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[N:38]=[C:39]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[O:40][C:41]=4[CH3:42])=[CH:31][CH:30]=3)=[N:21]2)=[CH:49][CH:50]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccccc5)oc4C)cc3)cc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a mixture of 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-carbaldehyde (25.20 g), ethyl diethylphosphonoacetate (9.50 g), and N,N-dimethylformamide (200 ml), sodium hydride (60%, oily, 1.68 g) was added at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice water, and the obtained crystals were collected by filtration, and ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]propenoate (25.58 g, yield: 92%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 148–149° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:14](=[O:39])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([O:22][CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:16]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:2].[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:14](=[O:39])[C:15]1[CH:16]=[C:17]([O:22][CH2:23][CH2:24][NH:25][C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCC1
Reaction time: 2 h

Procedure:
A solution of crude 4-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)ethoxy]-5-chloro-benzoyl}-cyclopentyl-amino)-butyric acid ethyl ester (0.020 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.005 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[S:7].Cl.C(=O)([O-])O.[Na+]>>[CH3:1][O:2][CH:3]1[S:7][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[N:5][CH2:4]1
Reactant: COC(CNC(=S)N1CCN(c2ccc(O)cc2)CC1)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC1CN=C(N2CCN(c3ccc(O)cc3)CC2)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 6 parts of N-(2,2-dimethoxyethyl)-4-(4-hydroxyphenyl)-1-piperazinecarbothioamide and 25 parts of a diluted hydrochloric acid solution is stirred overnight at room temperature. Upon the addition of sodium hydrogen carbonate, the product is allowed to crystallize. It is filtered off and recrystallized from ethanol, yielding 4.3 parts (73%) of 4-[4-(4,5-dihydro-5-methoxy-2-thiazolyl)-1-piperazinyl]phenol; mp. 165.6° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]([OH:23])=[O:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[N+:17]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[NH2:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.4 %

Procedure:
To a solution of [tert-butoxycarbonyl-(4-fluoro-2-nitro-benzyl)-amino]-acetic acid (5.11 g, 15.50 mmol) in absolute EtOH (30 mL), was added 10% Pd/C (1.02 g, 20% w/w). The reaction was stirred at r.t. for 5 h under hydrogen atmosphere. After completion of the reaction, as confirmed by TLC, the reaction mixture was filtered through celite bed and was washed with EtOAc (10 mL) and MeOH (10 mL). The solvents were removed in vacuo to afford 2-((2-amino-4-fluorobenzyl) (tert-butoxycarbonyl)amino) acetic acid (4.64 g, 99.9%), which was used as such far the next step without any further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][C@H:17]2[C:19]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:20]=3[O:21][C:22](=[O:23])[C@H:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:18][C@H:17]([C:19]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:20]=2[OH:21])[C@H:16]([CH2:22][OH:23])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc2c(c1)OC(=O)[C@H]1CN(Cc3ccccc3)C[C@@H]21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc([C@H]2CN(Cc3ccccc3)C[C@H]2CO)c(O)c1

Procedure:
To 230 mmol of lithium aluminum hydride in 800 ml of THF, under a nitrogen atmosphere, are added 180 mmol of cis-2-benzyl-7-methoxy-1,3,3a,9b-tetrahydrobenzopyrano [3,4-c]pyrrol-4-one, described in Preparation G, at +5° C. The reaction medium is maintained at +10° C. for one hour before being hydrolyzed, and is filtered on Celite. The organic phase is dried and, after evaporation, gives the expected product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].[C:13]([C:15]1[CH:20]=[C:19]([O:21][C:22]2[N:26]([CH3:27])[N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[N:18]=[C:17](OC2N(C)N=C(C(F)(F)F)C=2)[CH:16]=1)#[N:14]>S1(CCCC1)(=O)=O.CCCCC.C(OCC)(=O)C>[C:13]([C:15]1[CH:16]=[C:17]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:4]=2[F:3])[N:18]=[C:19]([O:21][C:22]2[N:26]([CH3:27])[N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:20]=1)#[N:14]
Reactant: OCc1ccc(F)cc1F
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(C#N)cc(Oc2cc(C(F)(F)F)nn2C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(C#N)cc(OCc2ccc(F)cc2F)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
Sodium hydride (0.1 g, 60%, 2.5 mmol) is added to a solution of 2,4-difluorobenzyl alcohol (0.28 ml, 2.5 mmol) in sulfolane (5 ml) at 50° C. After 1 hour at 50° C., 4-cyano-2,6-bis(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine (1 g, 2.3 mmol) (from Example 2) is added to the reaction mixture. The mixture is heated to 90° C. overnight. After cooling, the reaction mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed 6 times with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 8/2 v/v) and washing of the product with diisopropyl ether yields the title compound (0.2 g, 21% yield) of melting point 109° C.
Reaction SMILES: [C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=O)[CH:6]=1)([O:3][CH3:4])=[O:2].O=P(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:6]=[C:5]([C:1]([O:3][CH3:4])=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(=O)[nH]c2ccccc12
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)nc2ccccc12
Temperature: 25 °C

Procedure:
A stirred solution of 4-carbomethoxy quinolin-2-one (prepared as shown in Method D (1.76 g, 9 mmol), POCl3 (4.6 g, 30 mmol) in toluene (40 mL) was heated at reflux for 2 h then allowed to cool to room temperature and poured into ice water (50 mL). The mixture was extracted with ethyl acetate (3×50 mL). The organics were combined, washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford the desired 2-chloro-4-carbomethoxyquinoline lv (1.50 mg). 1H NMR (DMSO-d6) δ 8.54 (d, J=8 Hz, 1H), 8.03–8.06 (m, 1H), 7.89–7.94 (m, 2H), 7.75–7.77 (m, 1H), 3.98 (s, 3H); ESI-MS m/z 222.1 (100, M+H+).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26](=[O:29])[CH2:27][CH3:28].C(N(C(C)C)CC)(C)C>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:10]=1
Reactant: CCC(=O)Nc1ccc(Cl)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 6.2 %

Procedure:
(Step 3) A solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.88 g), N-[2-(aminomethyl)-4-chlorophenyl]propanamide hydrochloride obtained in Step 2 (1.99 g) and diisopropylethylamine (4.1 ml) in ethanol (15 ml) was stirred overnight at 70° C. The reaction solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate and 1N sodium hydroxide, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was further purified by HPLC. The obtained residue was extracted with ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, and 4N hydrogen chloride-ethyl acetate solution was added. The precipitated crystals were collected by filtration, and recrystallized from ethanol and ethyl acetate to give the title compound (100 mg).