Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])=[O:4].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]([Cl:16])=[O:8])=[O:4]
Reactant: CC(C)(NC(=O)C(F)(F)F)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(C)(NC(=O)C(F)(F)F)C(=O)Cl

Procedure:
0.54 g (2.71 mmol) 2-trifluoroacetylamino-isobutyric acid are combined with 1.8 ml (2.47 g, 20.8 mmol) thionyl chloride and refluxed for 2 hours with stirring. The mixture is then evaporated down i. vac. and any remaining thionyl chloride is eliminating by blowing dry nitrogen over it. The residue is taken up in diethyl ether and petroleum ether and evaporated down again by blowing dry nitrogen over it.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=O)[C:18](=[N:20][OH:21])[CH3:19])=[CH:13][CH:12]=2)[CH3:9])=[CH:4][CH:3]=1.Cl.[CH2:24]([O:26][NH2:27])[CH3:25]>N1C=CC=CC=1>[CH2:24]([O:26][N:27]=[C:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:9])=[CH:12][CH:13]=1)[C:18](=[N:20][OH:21])[CH3:19])[CH3:25]
Reactant: CCON
Reactant: CC(=NO)C(=O)c1ccc(OC(C)c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(C(C)=NO)c1ccc(OC(C)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 29.0 g of 1-(4-(1-{4-chlorophenyl}-ethoxy)-phenyl)-1,2-propanedione-2-oxime and 9.4 g of O-ethylhydroxylamine hydrochloride in 150 ml of pyridine is boiled at reflux for 1 hour. After cooling, the reaction mixture is concentrated by evaporation in vacuo. The residue is dissolved in ethyl acetate; the organic phase is washed twice with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The crude product is stirred together with hexane; filtration is carried out and the filter residue is dried, yielding the title product having a melting point of 132-134° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:10]2[CH:15]=[CH:14][C:13]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)cc1
Yield: 73 %

Procedure:
The same procedure described for 1 was used by employing 4-bromobenzonitrile (2 equiv.) and 1,4-phenylenebisboronic acid (1 equiv.) to furnish 17 as a white solid in 73% yield; mp 299-300° C. 1H NMR (DMSO-d6): δ 7.89 (dd, J=8.1, 2.1 Hz, 4H), 7.94-7.96 (m, 8H). MS (ESI) m/e (rel. int.): 280 (M+, 100). Anal. Calc. for C20H12N2: C %, 85.69; H %, 4.31. Found C %, 85.41; H %, 4.52.
Reaction SMILES: OC1C2C[S:17]C[C@@H](C(N)=O)NC(=O)CCCCOC(=O)C=2C(C)=C(OC)C=1.[CH3:28][Si:29]([CH3:63])([C:57]([CH3:62])([CH3:61])[CH:58]([CH3:60])[CH3:59])[O:30][C:31]1[C:48]2[CH2:47][S:46][CH2:45][C@@H:44]([C:49]([NH2:51])=O)[NH:43][C:42](=[O:52])[CH2:41][CH2:40][CH2:39][CH2:38][O:37][C:36](=[O:53])[C:35]=2[C:34]([CH3:54])=[C:33]([O:55][CH3:56])[CH:32]=1>C1(C)C=CC=CC=1>[CH3:63][Si:29]([CH3:28])([C:57]([CH3:61])([CH3:62])[CH:58]([CH3:60])[CH3:59])[O:30][C:31]1[C:48]2[CH2:47][S:46][CH2:45][C@H:44]([C:49](=[S:17])[NH2:51])[NH:43][C:42](=[O:52])[CH2:41][CH2:40][CH2:39][CH2:38][O:37][C:36](=[O:53])[C:35]=2[C:34]([CH3:54])=[C:33]([O:55][CH3:56])[CH:32]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OCCCCC(=O)N[C@H](C(N)=O)CSC2
Reactant: COc1cc(O)c2c(c1C)C(=O)OCCCCC(=O)N[C@H](C(N)=O)CSC2
Solvent: Cc1ccccc1
Product: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OCCCCC(=O)N[C@@H](C(N)=S)CSC2

Procedure:
The product of Example 68 was subjected in an analogous manner to the procedure described in Example 1(f) and the resulting (R)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-14-methoxy-13-methyl-6,12-dioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecine-4-carboxylic acid amide was reacted in toluene with an equimolar mount of 2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiaphosphetane at 60° C. for 30 min. The solvent was evaporated in vacuo, and the residue was chromatographed on silica gel using ethyl acetate/hexane (1:2, v/v) as eluent, to yield-(R)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-14-methoxy-13-methyl-6,12-dioxo-1,3,4,5,6,7,8,9,1 0, 12-decahydro-11,2,5-benzoxathiaazacyclotetradecine-4-thiocarboxylic acid amide as a white foam.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:40]1([NH2:46])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:46][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: NC1CCCCC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NC4CCCCC4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
Prepared from ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 19) and cyclohexylamine by the same method as Preparation 20. The title compound was obtained as a yellow foam.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:30])[CH2:26][CH2:27][O:28][CH3:29])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:33])[C:9]([C@@H:10]([CH3:31])[CH2:11]2)=[CH:8][C:7](=[O:32])[CH:6]=[CH:5]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:30])[CH2:26][CH2:27][O:28][CH3:29])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:33])[C:9](=[CH:8][C:7](=[O:32])[CH:6]=[CH:5]2)[C@@H:10]([CH3:31])[CH2:11]3)[CH2:14][CH2:15]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: COCCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Product: COCCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
2.0 g of 11β,21-dihydroxy-17-(3-methoxypropionyloxy)-6α-methyl-1,4-pregnadiene-3,20-dione is reacted analogously to Example 5(c) with acetic anhydride, worked up, and purified, thus isolating 1.36 g of 21-acetoxy-11β-hydroxy-17-(3-methoxypropionyloxy)-6α-methyl-1,4-pregnadiene-3,20-dione, mp 162° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[C:3]1=[O:31].Br[C:33]1[CH:43]=[CH:42][CH:41]=[C:40]([N:44]2[CH2:56][CH2:55][N:47]3[C:48]4[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=4[CH:54]=[C:46]3[C:45]2=[O:57])[C:34]=1[CH2:35][O:36][C:37](=[O:39])[CH3:38]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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][N:2]1[C:3](=[O:31])[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)=[CH:5][C:6]([C:33]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]3[CH2:56][CH2:55][N:47]4[C:48]5[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=5[CH:54]=[C:46]4[C:45]3=[O:57])[C:34]=2[CH2:35][O:36][C:37](=[O:39])[CH3:38])=[CH:7]1
Reactant: CN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CCCC3)C1=O
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
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 33.7 %

Procedure:
In a 10-mL glass vessel equipped with a magnetic stirring bar were placed 1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-1H-pyridin-2-one 197f (210 mg, 0.49 mmol), 113a (250 mg, 0.60 mmol), Pd(PPh3)4 (50 mg, 0.043 mmol) in 2 N Na2CO3 (2 mL) and 1,2-dimethoxyethane (5 mL). The vessel was sealed with a septum and placed into the microwave cavity. After the reaction mixture was stirred at 125° C. for 7 min., it was purified by flash chromatography (dichloromethane:methanol, 85:15) to give 34% (105 mg) of acetic acid 2-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-6-(1-oxo-3,4,6,7,8,9-hexahydro-1H-pyrazino[1,2-a]indol-2-yl)-benzyl ester 113b as solids.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][S:38][CH3:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH:20]([S:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:21][CH2:22][OH:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][S:38][CH3:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH:20]([S:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:21][CH2:22][OH:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Product: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12)c1csc(N)n1
Yield: 75.4 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-methylthiomethoxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 2.5 g) was treated with conc. hydrochloric acid (0.88 g) in a similar manner to that of Example 1-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-methylthiomethoxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 1.8 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[N:14]=[C:15]([CH3:22])[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.[CH:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH2:24].O>O1CCCC1>[Cl:3][C:4]1[C:13]2[N:14]=[C:15]([CH3:22])[N:16]([CH2:17][C:18]([CH3:19])([O:20][CH2:24][CH2:23][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:21])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: C=CS(C)(=O)=O
Reactant: Cc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 41 mg, 1.04 mmol) was added to a stirred solution of 1-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (prepared as described in U.S. Pat. No. 5,266,575 Comparative Example C1, 3.00 g, 10.4 mmol) and methyl vinyl sulfone (2.20 g, 20.7 mmol) in tetrahydrofuran (41 mL). The reaction mixture was stirred at room temperature for 17 hours. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with ethyl acetate) to yield 1.8 g of 4-chloro-2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C@@H:8]2[CH2:9][C:10]3[C:11]4[C:16]([NH:17][CH:18]=3)=[CH:15][CH:14]=[C:13]([O:19][CH3:20])[C:12]=4[C@@:7]2([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:6][CH2:5][C:4]1=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([N:3]1[C@@H:8]2[CH2:9][C:10]3[C:11]4[C:16]([NH:17][CH:18]=3)=[CH:15][CH:14]=[C:13]([O:19][CH3:20])[C:12]=4[C@@:7]2([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:6][CH:5]=[CH:4]1)[CH3:2]
Reactant: CCN1C(=O)CO[C@]2(c3ccccc3)c3c(OC)ccc4[nH]cc(c34)C[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCN1C=CO[C@]2(c3ccccc3)c3c(OC)ccc4[nH]cc(c34)C[C@@H]12
Yield: 11.7 %

Procedure:
Trans-7-ethyl-4,6,6a,8,9,10a-hexahydro-1-methoxy-10a-phenyl-7H-indolo[3,4-gh][1.4]benzoxazin-8-one (664 mg, 1.83 mmol) was reduced with LAH. The residue thus obtained was subjected to a silica gel column chromatography, eluting with n-hexane-ethyl acetate (3:1), to afford 74 mg (12%) of the title compound as a crude crystalline product (m.p.194-196 dec.)
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH:3]([CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:9]1)[CH2:4][C:5]#[N:6].Cl.[NH2:27][OH:28].CCN(C(C)C)C(C)C>CCO>[F:25][C:2]([F:1])([F:24])[CH:3]([CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[CH2:9]1)[CH2:4]/[C:5](=[N:27]/[OH:28])/[NH2:6]
Reactant: NO
Reactant: N#CCC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N/C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)=N\O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
In a 50 mL round-bottomed flask, 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanenitrile (200 mg, 549 μmol) and hydroxylamine hydrochloride (37.9 mg, 549 μmol) were combined with EtOH (2 ml) to give a colorless suspension. DIEA (106 mg, 144 μl, 823 μmol) was added and the resulting mixture was stirred at 100° C. for 6 hr. The crude reaction mixture was concentrated in vacuo to give (Z)-4,4,4-trifluoro-N′-hydroxy-3-((3-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)methyl)butanimidamide as a viscous oil. 85% pure by LC-MS. MH+=398.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[CH3:16][O-:17].[Na+].CO.O.Cl>CO>[CH3:16][O:17][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: COC(=O)c1ccc(CCl)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1ccc(C(=O)O)c([N+](=O)[O-])c1

Procedure:
A mixture of methyl 4-chloromethyl-2-nitrobenzoate (1.6 g), 28% sodium methoxide-methanol solution (2.5 ml) in methanol [16 ml) was stirred under reflux for 24 hours. To this mixture, water (5 ml) was added and the mixture was stirred for 2 hours, acidified with 1N hydrochloric acid, extracted with ethyl acetate. The combined organic extract was washed with water, dried over magnesium sulfate and evaporated to give 4-methoxymethyl-2-nitrobenzoic acid (0.84 g).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:28][CH:9]([NH2:8])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=1
Reactant: COc1ccc(CC(CCC(C)C)NC(=O)OC(C)(C)C)cc1OCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(N)CCC(C)C)cc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of N-t-butoxycarbonyl-1-(3-methylbutyl)-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine (89.69 g) in 156 ml of dichloromethane, 156 ml of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and washed with a saturated aqueous solution of sodium hydrogencarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (chloroform/methanol =30:1-20:1), to thereby obtain 59.65 g of 1-(3-methylbutyl)-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:19][C:20](=[O:34])[C:21]([NH:23][C:24]([CH3:33])([CH3:32])[CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:22])[CH:11]=[CH:12][C:13]=1[C:14]1[O:18][CH:17]=[N:16][CH:15]=1.C(N1CCOCC1)C>ClCCl.C(OCC)(=O)C>[CH3:1][S:2]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][C:24]([NH:23][C:21](=[O:22])[C:20]([NH:19][C:10]2[CH:11]=[CH:12][C:13]([C:14]3[O:18][CH:17]=[N:16][CH:15]=3)=[C:8]([O:7][CH3:6])[CH:9]=2)=[O:34])([CH3:33])[CH3:32])[CH2:27][CH2:28]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CC2CCNCC2)ccc1-c1cnco1
Agent: CCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CC2CCN(S(C)(=O)=O)CC2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
14 mg (0.12 mmol) of methanesulphonyl chloride were added to a solution of 40 mg (0.1 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl-N′-[1,1-dimethyl-2-(4-piperidinyl)ethyl]oxalamide in 1 ml of dichloromethane followed by 17 mg (0.15 mmol) of N-ethylmorpholine and the mixture stirred at room temperature for 4 hours. The resulting solution was diluted with ethyl acetate, washed with 2M hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate, evaporated to dryness and the residue triturated with diethyl ether. There was obtained 23 mg of N-[2-[1-(methanesulfonyl)-4-piperidinyl]-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as an off-white solid. MS m/e 479 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[CH3:13][N:14]=[C:15]=[O:16]>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:13][NH:14][C:15](=[O:16])[O:11][C:10]1[C:4]2[O:3][C:2]([CH3:12])([CH3:1])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)Oc2cccc(O)c2O1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)Oc1cccc2c1OC(C)(C)O2
Reaction time: 0.5 h
Yield: 85 %

Procedure:
2,2-Dimethyl-4-hydroxy-1,3-benzodioxole (14 parts) in benzene (25 parts) was treated with methyl isocyanate (6 parts) and a few drops of triethylamine with cooling. After standing for 30 minutes, the crystals of 2,2-dimethyl-1,3-benzodioxol-4-yl N-methylcarbamate which formed were filtered off and washed with benzene then with petroleum (boiling point below 40°C.) to yield the pure compound as a white solid, melting point 129°-130°C. (16 parts, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:28])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[C:37]([Si](C)(C)C)#[N:38]>ClCCl.O.[Zn+2].[I-].[I-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:28])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:29]2[CH:30]=[CH:31][C:32]([CH:33]([OH:34])[C:37]#[N:38])=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: N#CC(O)c1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Reaction time: 70 h

Procedure:
To a stirred solution of 4-(7-(4-chlorophenyl)-3-oxo-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)benzaldehyde (38.0 mg, 0.075 mmol) in dichloromethane (1 mL) at room temperature under argon was added cyanotrimethylsilane (9.3 mg, 0.093 mmol) and then ZnI2 (2.4 mg, 0.0075 mmol). After 70 h, the reaction mixture was diluted with water and extracted twice with dichloromethane. The organic extracts were combined, dried (MgSO4), filtered and evaporated. Purification by preparative reverse phase HPLC (methanol-water-trifluoroacetic acid), pooling the fractions, evaporating, redissolving the residuum in dichloromethane, washing with saturated aq. NaHCO3 solution, drying (MgSO4), filtering and evaporating provided the title compound as a light yellow solid, 10.4 mg, 26%. HPLC/MS: retention time=3.56 min, [M+H]+=536. 1H NMR (CDCl3): δ 8.71 (d, J=1.7 Hz, 1H), 7.85 (dd, J=1.6 Hz, 7.7 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.24 (d, J=6.5 Hz, 1H), 7.17 (d, J=8.3 Hz, 2H), 7.04 (d, J=8.3 Hz, 2H), 6.95 (d, J=6.6 Hz, 2H), 6.60 (d, J=7.2 Hz, 1H), 5.37 (s, 1H), 5.18 (s, 1H), 3.30 (br s, 1H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][CH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:50][CH2:49][C:48]3[CH:51]=[CH:52][C:45]([C:44]#[N:43])=[CH:46][CH:47]=3)=[O:31])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reactant: N#Cc1ccc(CN)cc1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc3c(C(=O)NCc4ccc(C#N)cc4)noc3c2Cl)C[C@H](C)O1

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and 4-(aminomethyl)benzonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCC(C(=O)O)c1ccc(N)cc1
Yield: 91.9 %

Procedure:
A solution of 2-(4'-nitrophenyl)butyric acid (6.99 g, 33.4 mmol) in 250 mL of EtOH and 0.5 g of 10% Pd-C was hydrogenated overnight at 55 psi. The solution was filtered and evaporated under vacuum to give 5.50 g (92%) of the desired product.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].I[C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]2)=[C:22]([C:32]([F:35])([F:34])[F:33])[CH:21]=1)=[O:18]>>[CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:37]2[CH:36]=[C:16]([CH:15]=[CH:14][C:38]=2[CH3:39])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([C:32]([F:33])([F:34])[F:35])[CH:21]=2)=[O:18])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(NC(C)C)nn1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(I)c3)cc2C(F)(F)F)cn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(C#Cc4ccc(NC(C)C)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl) benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp:141-143° C.; 1H NMR (300 MHz, CDCl3) δ: 9.82 (1 H, s), 8.34 (1 H, s), 8.20-8.23 (1 H, d, J=7.8 Hz), 7.96 (1 H, s), 7.84-7.86 (1 H, d, J=8.1 Hz), 7.54 (1 H, s), 7.29-7.31 (3 H, m), 6.81 (1 H, s), 6.63-6.66 (1 H, d, J=8.4 Hz), 5.11 (1 H, brs), 4.08 (1 H, m), 2.46 (3 H, s), 2.29 (3 H, s), 1.28-1.31 (6 H, d, J=6.3 Hz). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C28H26F3N6O: 519.2115. found: 519.2116.