Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[K+].[K+].COC1C=C(OC)C=CC=1C[N:25]1[C@H:28]([CH:29]=[N:30][O:31][CH3:32])[C@H:27]([NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[C:26]1=[O:44]>C(#N)C.O.C(OCC)(=O)C>[CH3:32][O:31][N:30]=[CH:29][C@H:28]1[NH:25][C:26](=[O:44])[C@H:27]1[NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]
Reactant: CON=C[C@@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CON=C[C@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Temperature: 78 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
11.9 g (44 mmol) of potassium peroxydisulphate and 9.6 g of dipotassium hydrogen phosphate are dispersed in 110 ml of acetonitrile and 350 ml of water. The mixture is heated to 78° C. and a solution of 11.8 g (27.6 mmol) of benzyl (3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(methoxyimino)methyl]-2-oxo-3-azetidinecarbamate (mixture of the E and Z isomers) in 300 ml of acetonitrile is added dropwise thereto. The pH of the solution is held at 7 by the addition of dipotassium hydrogen phosphate. After boiling for 6 hours, the mixture is cooled, the aqueous phase is discarded, the organic phase is diluted with ethyl acetate and washed successively with water, aqueous sodium bicarbonate solution and sodium chloride solution. After drying over sodium sulphate, the solvent is removed by evaporation and the crude mixture is chromatographed [230-400 mesh, ethyl acetate/n-hexane (8:2)], there being obtained 1.7 g (27%) of benzyl (3S,4S)-4-[(methoxyimino)methyl]-2-oxo-3-azetidinecarbamate (mixture of the E and Z isomers); melting point 170°-171° C.
Reaction SMILES: S([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]O)(C1C=CC(C)=CC=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O>[N:30]([CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:11])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCO)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCCOCCOCCOCCOCCO

Procedure:
To a solution of 2-[2-(2-{2-[2-(2-tosyloxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethanol (Loiseau, F. A.; Hii, K. K.; Hill, A. M. J. Org. Chem. 2004, 69, 639) (4.5 g) in dimethylformamide (30 mL), was added sodium azide (0.89 g). The solution was stirred at 70° C. for 18h and solvent was then removed in vacuo to a residue. Dichloromethane was added and the resulting precipitate was filtered off. The organic layer was concentrated in vacuo to give 2-[2-(2-{2-[2-(2-Azido-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethanol (3.1 g):
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[N:9][CH:10]=1.N1C=CN=C1.CN(C=O)C.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[Si:27]([O:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][N:9]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: COCOc1ccc(CO)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1ccc(CO[Si](C)(C)C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of (5-(methoxymethoxy)pyridin-2-yl)methanol (8.12 g), imidazole (4.90 g) and DMF (50 mL) was added tert-butyldimethylchlorosilane (8.68 g), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:10]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)C1

Procedure:
The title compound was prepared by following the similar procedure as described in intermediate-6, using 6-chloropyridin-3-ol and tert-butyl 3-hydroxypyrrolidine-1-carboxylate; MS: 299.0 (M+1)
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.FC(F)(F)OC1C=CC(N)=CC=1.C[O:38][C:39]1[CH:40]=[C:41]([C:45]2[C:46]3[CH2:59][CH2:58][N:57]([C:60]4[CH:65]=[CH:64][C:63]([O:66][C:67]([F:70])([F:69])[F:68])=[CH:62][CH:61]=4)[C:47]=3[N:48]=[C:49]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)[N:50]=2)[CH:42]=[CH:43][CH:44]=1>>[N:51]1([C:49]2[N:50]=[C:45]([C:41]3[CH:40]=[C:39]([OH:38])[CH:44]=[CH:43][CH:42]=3)[C:46]3[CH2:59][CH2:58][N:57]([C:60]4[CH:65]=[CH:64][C:63]([O:66][C:67]([F:70])([F:69])[F:68])=[CH:62][CH:61]=4)[C:47]=3[N:48]=2)[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(OC(F)(F)F)cc2)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Agent: Nc1ccc(OC(F)(F)F)cc1
Product: Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(OC(F)(F)F)cc2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 4-trifluoromethoxyaniline, 4-(3-methoxy-phenyl)-2-morpholin-4-yl-7-(4-trifluoromethoxy-phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[CH2:4]1.CC1C=C(N=C=O)C=CC=1.[C:27]1([CH:37]([N:39]=[C:40]=[O:41])[CH3:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[Cl:15])[CH2:8][N:5]1[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][C:40]([NH:39][CH:37]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH3:38])=[O:41])[CH2:4]1
Reactant: CC(N=C=O)c1cccc2ccccc12
Reactant: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Agent: Cc1cccc(N=C=O)c1
Product: CC(NC(=O)NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1)c1cccc2ccccc12

Procedure:
Proceeding as described above but substituting 3-(RS)-aminomethyl-1-(3,4-methylenedioxybenzyl)pyrrolidine with 3-aminomethyl-1-(3,4-dichlorobenzyl)-pyrrolidine and 3-methylphenylisocyanate with 1-(naphth-1-yl)ethylisocyanate gave 1-[1-(3,4-dichlorobenzyl)pyrrolidin-3-(RS)-ylmethyl]-3-[1-(naphth-1-yl)ethyl]urea.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CCN=C=NCCCN(C)C.O>ClCCl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:14]([C:11]2[CH2:10][CH2:9][N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH:12]=2)=[O:16])=[CH:26][CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)C2=CCN(c3ncccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3′-Chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylic acid (120 mg, 0.35 mmol), 4-tert-butylaniline (90.0 mg, 0.6 mmol), and EDCI (145 mg, 0.75 mmol) were combined in dichloromethane (3 mL) under N2 and stirred at room temperature overnight. The mixture was treated with water and the layers were separated. The organic layer was concentrated and the residue was purified via column chromatography (SiO2, ethyl acetate:hexanes, 1:4) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H), 7.61 (dd, 1H), 7.46 (d, 2H), 7.38 (s(br), 1H), 7.35 (d, 2H), 6.85 (dd, 1H), 6.75 (m, 1H), 4.10 (dd, 2H), 3.58 (dd, 2H), 2.68 (m, 2H), 1.30 (s, 9H); MS (ESI) 370 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][CH:6]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:11]1[CH:12]=[CH:13][C:8]([C:7]([C:4]2[S:5][CH:6]=[C:2]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[C:3]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:14])=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1c(Br)csc1C(=O)c1ccncc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccncc2)csc1C(=O)c1ccncc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
The mixture of ethyl 4-bromo-2-isonicotinoylthiophene-3-carboxylate (325 mg, 0.96 mmol), 4-pyridineboronic acid (177 mg, 1.44 mmol), Na2CO3 (254 mg, 2.4 mmol) and PdCl2(dppf) (63 mg, 0.077 mmol) was dissolved in 12 mL dioxane/H2O (3:1). The mixture was stirred at 100° C. for 2 h. After completion of the reaction the resulting mixture was concentrated under reduced pressure. The material was loaded onto a silica gel column and eluted with 20%-50% EtOAc/PE. Elution fractions containing the desired compounds were collected and the solvent was removed under reduced pressure to provide the title compound (260 mg, 80% yield) as an orange oil. LC-MS (Method A): m/z 339 (M+H)+, Rt: 1.77 min.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:19])[N:7](CC3C=NC=CC=3)[C:8]2=[O:11])=[CH:4][C:3]=1S(N)(=O)=O.ClC1C=C2C(=O)NC(=O)C2=CC=1S(=O)(=O)N.NCC1C=NC=CC=1>>[O:19]=[C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[C:8](=[O:11])[NH:7]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(Cc1cccnc1)C2=O
Agent: NCc1cccnc1
Agent: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Product: O=C1NC(=O)c2ccccc21
Yield: 73 %

Procedure:
6-Chloro-2,3-dihydro-1,3-dioxo-2-(3-pyridinylmethyl)-1H-isoindole-5-sulfonamide. Reaction of a mixture of 4-chloro-5-sulfamoylphthalimide and 3-(aminomethyl)pyridine according to the procedure of Example 1(a) afforded a 73% yield of the 1,3-dioxoisoindole intermediate. Crystallization of this material from dimethylformamide-methanol provided analytically pure 6-chloro-2,3-dihydro-1,3-dioxo-2-(3-pyridinylmethyl)-1H-isoindole-5-sulfonamide, m.p. 210°-212°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([OH:14])=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH2:32][NH2:33])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([NH:33][CH2:32][CH2:31][NH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)=[O:14]
Reactant: COc1ccc(NCCN)cc1
Reactant: O=C(O)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NCCNC(=O)[C@H](CC2CCCCC2)Nc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
A slurry of L-cyclohexylalanine (2.44 g, 14.3 mmol) and powdered NaOH (1.14 g, 28.6 mmol) in DMSO (20 mL) was heated to 100° C. for 20 min until the mixture viscosity decreased and stirring was enabled. 2-Chlorobenzoxazole (1.99 g, 13.0 mmol) was added, and the solution was stirred at 100° C. for 4 h. Upon cooling to room temperature, the solution was poured into 1 M HCl. The precipitate was filtered and dried to afford 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid was isolated as a white powder (1.69 g, 41%). Step B. To a stirring solution of 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid (288 mg, 1.0 mmol), N1-(4-methoxy-phenyl)-ethane-1,2-diamine.2HCl (239 mg, 1.0 mmol), and iPr2NEt (0.87 mL, 5.0 mmol) in dichloromethane (4 mL) was added HATU (418 mg, 1.1 mmol). The solution was stirred at room temperature for 4 hours and then evaporated to dryness. The crude material was chromatographed over silica gel (Hexanes/EtOAc) to afford the title compound as a white powder (243 mg, 56%). HPLC-MS calcd. for C25H32N4O3 (M+H+) 437.25. found 437.5.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][C:13]([F:17])=[CH:12][C:11]=2[F:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:16][C:15]1[CH:14]=[C:13]([F:17])[CH:12]=[C:11]([F:18])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Nc1ncccc1OCc1c(F)cc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1cc(F)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(F)c1

Procedure:
A mixture of 2-amino-3-(2,4,6-trifluorobenzyloxy)pyridine (2.29 g, 0.009 mol), 4chlorophenyl isothiocyanate (1.81 g, 0.01 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 3.03 g (79.5%), m.p.181°-183 ° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.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(C(C)C)C(C)C)C>O1CCCC1>[CH3:1][N:2]1[CH:3]=[C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]1=[O:8]
Reactant: C1COCCN1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N2CCOCC2)cc1
Yield: 105.6 %

Procedure:
A mixture 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (60 mg), morpholine (17 mg), benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (108 mg, BOP reagent) and N-ethyldiisopropylamine (62 mg) in tetrahydrofuran (0.6 ml) was stirred overnight at room temperature. The mixture was concentrated to dryness. The product was purified by chromatography (SiO2, dichloromethane/methanol 1:0 to 9:1) to give the title compound (75 mg) as a colorless foam, MS (ESI+): m/z=445.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][CH:38]([N:40]1[CH2:45][CH2:44][N:43]([C:46]2[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([O:53][CH3:54])[CH:47]=2)[CH2:42][CH2:41]1)[CH3:39].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:50][C:49]3[CH:51]=[CH:52][C:46]([N:43]4[CH2:44][CH2:45][N:40]([CH:38]([CH3:37])[CH3:39])[CH2:41][CH2:42]4)=[CH:47][C:48]=3[O:53][CH3:54])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(N4CCN(C(C)C)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 175 °C
Yield: 75 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.20 mmol) and 4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline (49 mg, 0.20 mmol) (Example 175, step B) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (99 μL, 0.40 mmol). The mixture was stirred and heated on a Biotage microwave at 175° C. for 35 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (110 mg, 0.15 mmol, 77%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 9.36 (br s, 1H), 8.45 (s, 1H), 8.20 (d, 1H, J=5.31 Hz), 8.05 (m, 1H), 7.74 (d, 1H, J=8.61 Hz), 7.69 (d, 1H, J=8.97 Hz), 7.35-7.47 (m, 3H), 7.27 (d, 1H, J=8.61 Hz), 7.19 (t, 2H, J=8.06 Hz), 6.95 (t, 1H, J=6.87 Hz), 6.67 (d, 1H, J=2.01 Hz), 6.53 (d, 1H, J=5.13 Hz), 6.47 (dd, 1H, J=2.11 and 8.70 Hz), 4.27 (q, 2H, J=6.78 Hz), 3.80 (s, 3H), 3.11-3.16 (m, 4H), 2.64-2.71 (m, 1H), 2.56-2.61 (m, 4H), 1.43 (t, 3H, J=6.78 Hz), 1.00 (d, 6H, J=6.41 Hz). MS (ESI): 719 [M+H]+.
Reaction SMILES: [C-:1]#[C-:2].[Li+].[Li+].[Na+].[I-].Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20].N#N>CS(C)=O>[CH2:19]([O:18][CH:17]([O:21][CH2:22][CH3:23])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:1]#[CH:2])[CH3:20]
Reactant: [C-]#[C-]
Reactant: CCOC(CCCCCCCCCCl)OCC
Agent: N#N
Agent: [I-]
Agent: [Li+]
Solvent: CS(C)=O
Product: C#CCCCCCCCCCC(OCC)OCC
Temperature: 30 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
To a dark solution of lithium acetylide, ethylenediamine complex (13.8 g, 134.90 mMol, (90%) Su: Aldrich) and NaI (0.78 g, 5.19 mMol, (99+%), Su: Acros) in DMSO (100 ml anhydrous (99.7%) Su: Acros) was charged 10-chloro-1,1-diethoxydecane 3 (27.48 g, 103.77 mMol Su: from step B) while maintaining reaction temperature around 30° C., under a blanket of N2. The addition funnel was rinsed with DMSO (15 ml, anhyrdrous, Su: Acros). The solution was monitored by GC for compound 3 consumption (compound 3<2.0 Area % by GC). After 4 hr stirring at 30° C., H2O (200 ml) were charged into the reaction mixture to quench the reaction. The aqueous layer was extracted with heptane (2×200 ml). The organic layer was filtered through a plug of Celite® 521 (15 g, Su: Sigma-Aldrich) one by one after phase separation. The combined filtrate was washed with a solution of H2O (100 ml) and brine (50 ml). The water in this organic solution was removed by azeotropic distillation under normal conditions by means of adding and removing heptane (repeat if necessary until KF=˜0.2%). The resultant solution was concentrated under reduced pressure (pot temperature ˜35° C.) to give 24.6 g of 12,12-diethoxydodec-1-yne 4 as an amber liquid (93% yield over steps A thru C, after C). This material was used without further purification. GC: column SP, Rt: 12.2 for 10-chloro-1,1-diethoxydecane 3, and Rt: 11.1 min for 12,12-diethoxydodec-1-yne 4 (<5 Area %). 1H NMR (CDCl3, 400 MHz): δ 4.48 (t, J=5.60, 1H), 3.6 (m, J=7.07 Hz, 2H), 3.5 (m, J=7.07 Hz, 2H), 2.18 (dt, J=7.10, 2.80 Hz, 2H), 1.94 (t, J=2.60 Hz, 1H), 1.6 (m, 2H), 1.52 (qn, J=7.2 Hz, 2H), 1.4 (m, 2H), 1.29 (br s, 10H), 1.20 (t, J=7.00 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.CC(C)([O-])C.[K+].[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][C:26]=1[O:33][CH:34]([F:36])[F:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(O)(C)(C)C>[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][C:2]2[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=2)=[CH:27][C:26]=1[O:33][CH:34]([F:35])[F:36])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc(C)c(Cl)c(N)n1
Reactant: FC(F)Oc1cc(CCl)ccc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)c(OC(F)F)c2)n1

Procedure:
In analogy to the method described in example A5, 3.8 g (22.7 mmol) of 4-amino-5-chloro-2,6-dimethylpyrimidine, 2.8 g (25 mmol) of potassium tert-butoxide and 6.8 g (22.7 mmol) of 4-benzyloxy-3-(1,1-difluoromethoxy)benzyl chloride are reacted in 15 ml of tert-butanol and 15 ml of toluene and the product is worked up. After chromatography on silica gel (mobile phase: toluene/dioxane=5:1), the title compound is obtained as a viscous, colorless oil. 1H NMR spectrum (CDCl3, δ ppm): 7.5-7.3 (m, 5H), 7.19 (m, 1H), 7.12 (dd, 1H), 6.58 (t, 1H, J=80 Hz), 5.58 (tb, NH), 5.13 (s, 2H), 4.63 (d, 2H), 2.51 (s, 3H), 2.43 (s, 3H)
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[N:4][N:5]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[N:18][CH:19]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.BrC1C=CC(C2N([C:40]3C=C[C:43]([S:46](N)(=O)=O)=[N:44][CH:45]=3)N=C(C(F)(F)F)C=2Cl)=CC=1>>[F:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[N:4][N:5]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[N:18][CH:19]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:45]2[N:44]=[CH:43][S:46][CH:40]=2)=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(F)c2-c2ccc(Br)cc2)cn1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(F)c2-c2ccc(-c3cscn3)cc2)cn1

Procedure:
The title compound was prepared according to the procedure of step 3 in the Example 4 using 5-[4-fluoro-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide, instead of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)=[O:24])[CH:8]([NH:13][CH:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15](O)=[O:16])[C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C@@H:32]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C@H:36]2[CH2:37][CH2:38][CH2:39][C@H:35]2[CH2:34][NH:33]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH:7]([NH:22][C:23]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)=[O:24])[CH:8]([NH:13][CH:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([N:33]2[CH2:34][C@@H:35]3[CH2:39][CH2:38][CH2:37][C@@H:36]3[C@H:32]2[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:16])[C:9]([F:10])([F:11])[F:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: CC(C)(C)C(NC(C(NC(=O)c1cnccn1)C1CCCCC1)C(F)(F)F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)C(NC(C(NC(=O)c1cnccn1)C1CCCCC1)C(F)(F)F)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The stereoisomer of 2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoic acid designated as 8A1-isomerA (crude product from above), (1S,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-1-carboxylate (9) (1 eq), N-methylmorpholine (0.106 mL, 2.5 eq) and O-(7-azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (101 mgm, 1 eq) in a mixture of N,N-dimethylformamide (1.2 mL) and tetrahydrofuran (0.2 mL) was stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate and washed successively with 1N hydrochloric acid, water, brine and then dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure gave crude product, which was purified by silica gel column chromatography. Elution with a solvent gradient from hexane to 20% ethyl acetate/hexane gave pure (1S,3aR,6aS)-ethyl 2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)octahydrocyclopenta-[c]pyrrole-1-carboxylate, designated as 10A1-isomer A.