Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH3:2]I.[N:4]1([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:11][N:10]=2)[CH:8]=[CH:7][N:6]=[CH:5]1.[Cl-].[NH4+]>CCOCC>[N:4]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([OH:23])[CH3:2])=[CH:11][N:10]=2)[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-n2ccnc2)nc1
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)(c1ccc(Cl)cc1)c1ccc(-n2ccnc2)nc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A Grignard reagent which is prepared by reacting 0.46 g of magnesium with 3 g of methyl iodide in 30 ml of ether is added to a suspension of 4.5 g of 2-(1-imidazolyl)-5-(4-chlorobenzoyl)pyridine in 50 ml of ether at -5° C. After the mixture is stirred at room temperature for an hour, the reaction mixture is poured into an aqueous ammonium chloride solution with caution. The precipitate is extracted with chloroform and the chloroform is distilled off. The residue is recrystallized from toluene to give 4.1 g of 1-[2-(1-imidazolyl)-5-pyridyl]-1-(4-chlorophenyl)ethanol in 90.3% yields as white crystals, melting at 140°-142° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].[CH:44]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH2:45]>C(O)(C)C>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:45][CH2:44][S:46]([CH3:49])(=[O:48])=[O:47])[CH2:23]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCNC2)cn1
Reactant: C=CS(C)(=O)=O
Solvent: CC(C)O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCN(CCS(C)(=O)=O)C2)cn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 63.6 %

Procedure:
(R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate (Example 262, 0.150 g, 0.24 mmol) was taken up in isopropanol (2 mL) and methyl vinyl sulfone (0.026 mL, 0.29 mmol) was added. The reaction mixture was stirred at 100° C. for 18 h in a sealed vessel, then cooled to room temperature and the solvent was removed in vacuo and loaded directly onto silica. Purified by flash column chromatography on silica gel using (dichloromethane-methanol) gave (R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.110 g, 62.5%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:41])[CH2:32][CH2:31]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:9][O:8][C:6]([C:4]1[N:3]([CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([C:40](=[O:41])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:32][CH2:31]2)[CH:2]=[N:1][CH:5]=1)=[O:7]
Reactant: COC(=O)c1c[nH]cn1
Reactant: O=C(c1ccccc1)N1CCC(O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1CCN(C(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
methyl 4-imidazolecarboxylate (200 mg, 1.59 mmol) and PS-triphenylphosphine (2.15 mmol/g, 0.90 g, 1.94 mmol) are added to a solution of (4-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone (380 mg, 1.50 mmol) in THF (20 mL) at room temperature. The resulting mixture is stirred at room temperature for 5 minutes and then cooled to 0° C. DIAD (0.38 mL, 1.96 mmol) is added, and the mixture is slowly warmed up to room temperature. After 3 h, the reaction mixture is filtered to remove resin and washed with ethyl acetate. The combined ethyl acetate solution is washed with brine, and dried with anhydrous sodium sulfate. After concentration, the residue is purified by reverse phase HPLC (CH3CN:H2O=10 to 80% over 20 mins) to give the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 2.21-2.30 (m, 1 H), 2.52-2.62 (m, 1 H), 3.75-3.82 (m, 1 H), 3.89 (s, 3 H), 4.11-4.18 (m, 1 H), 6.40 (t, J=6.1 Hz, 1 H), 6.94 (d, J=7.6 Hz, 1 H), 7.01-7.09 (m, 3 H), 7.33-7.40 (m, 3 H), 7.40-7.45 (m, 1 H), 7.46-7.50 (m, 2 H), 7.85 (d, J=0.8 Hz, 1 H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:12]2[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Yield: 31.8 %

Procedure:
The title compound (43.6 mg) was prepared from 198.3 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 94.7 mg of 4-methoxyphenylboronic acid as described in Example 199. MS (ESI): exact mass calculated for C20H21N3O, 319.17; found, m/z 320.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.28-7.24 (m, 2H), 7.21-7.17 (m, 3H), 7.07 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 3.81 (s, 3H), 3.11-3.08 (m, 2H), 3.04-3.01 (m, 2H), 3.00-2.97 (m, 2H), 2.68-2.65 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:57]([N:60]([CH2:62][C@H:63]1[CH2:67][CH2:66][CH2:65][NH:64]1)[CH3:61])(=[O:59])[CH3:58].ClCl>O1CCCC1.ClCCl.C(O)C>[C:57]([N:60]([CH2:62][C@H:63]1[CH2:67][CH2:66][CH2:65][N:64]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:5])[CH3:61])(=[O:59])[CH3:58]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(=O)N(C)C[C@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N(C)C[C@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 17 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and (R)-2-[(N-acetyl-N-methylamino)methyl]pyrrolidine in tetrahydrofuran. Yield: 17%; Rf value: 0.40 (silica gel: dichloromethane/ethanol=9:1); C25H27Cl2N5O3 (516.426); mass spectrum: (M+H)+=516/518/520 (chlorine isotope).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=4)[C:7]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.B(Br)(Br)Br.COC1C=CC2NC3CC(C(OCC4C=CC=CC=4)=O)C4C(=O)NC(=O)C4C=3C=2C=1>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=4)[C:7]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1cccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)c1
Agent: BrB(Br)Br
Agent: COc1ccc2[nH]c3c(c2c1)C1C(=O)NC(=O)C1C(C(=O)OCc1ccccc1)C3
Product: O=C1NC(=O)c2c1c(-c1cccc(O)c1)cc1[nH]c3ccc(O)cc3c21
Yield: 88 %

Procedure:
9-Hydroxy-4-(3-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (prepared as decribed in example 35) was reacted with BBr3 using the procedure described in the proceedure described in example 80 of Scheme 2 to give 9-hydroxy-4-(3-hydroxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (25) (I, Ar=3-hydroxyphenyl) in a yield of 88%; mp 282–285° C. (dec). 1H NMR δ [(CD3)2SO] 11.73 (br s, 1H), 11.00 (br s, 1H), 9.48 (br s, 1H), 9.24 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.54 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.24 (dd, J=7.7, 7.7 Hz, 1H), 7.05 (dd, J=8.7, 2.4 Hz, 1H), 7.01–6.96 (m, 2H), 6.82 (dd, J=8.2, 2.1 Hz, 1H). FABMS found [M+H]+: 345.0865. C20H13N2O4 requires 345.0875.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:24]([Cl:34])[CH:23]=2)[C:8](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:36]>O1CCOCC1.O>[Cl:34][C:24]1[CH:23]=[C:22]([C@@H:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([OH:9])=[O:36])[CH:27]=[CH:26][C:25]=1[S:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=S(=O)(O)O
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](CC1CCCC1)c1ccc(SC2CCCC2)c(Cl)c1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@H](CC1CCCC1)c1ccc(SC2CCCC2)c(Cl)c1
Temperature: 105 °C

Procedure:
A solution of (R)-3-cyclopentyl-2-(3-chloro-4-cyclopentylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (1.5 mmol) in dioxane (5 mL) is treated with a 9 N aqueous sulfuric acid solution (1.5 mL). The resulting solution is then heated at 105° C. for 16 h. The reaction is then cooled and diluted with water (13 mL) and extracted with a chloroform/methanol solution (3:2, 3×20 mL) and then combined the organic extracts and dried over magnesium sulfate, filtered and concentrated. Purification on an AnaLogix Intelliflash system (silica gel column) will afford (R)-2-(3-chloro-4-cyclopentylsulfanyl-phenyl)-3-cyclopentyl-propionic acid.
Reaction SMILES: [C@@H:1]1([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([C:23](O)=[O:24])[C:18](=[O:22])[O:19]3)=[CH:14][CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]([CH2:58][CH2:59][CH3:60])[C:55]([OH:57])=[O:56].[Si](O)(O)(O)O>CN(C)C=O.O.C(N(CC)CC)C>[C:55]([CH:54]([CH2:58][CH2:59][CH3:60])[CH2:53][CH2:52][CH2:51][CH2:50][NH:49][C:23]([C:17]1[C:18](=[O:22])[O:19][C:20]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C@@H:1]1[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3])[CH:21]=2)=[O:24])([OH:57])=[O:56]
Reactant: CCCC(CCCCN)C(=O)O
Reactant: O=C(O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Agent: O[Si](O)(O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCCCNC(=O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A solution of 734 milligrams (mg) [2 millimol (mmol)] of 7-β-galactosylcoumarin-3-carboxylic acid and 210 mg (2 mmol) of N-hydroxysuccinimide in 20 ml of dimethylformamide was cooled to -10° C. while stirring under an inert atmosphere. To this was added 412 mg (2 mmol) of dicyclohexyl carbodiimide. After 15 minutes at -10° C., a clear solution was obtained. The reaction was allowed to warm to room temperature and stirred for 2 hours. It was again cooled to -10° C. and the precipitate of dicyclohexyl urea removed by filtration under vacuum. The filtrate, now containing the activated ester (3), was placed in a dropping funnel and added dropwise over a 15 minute period to a 0° C. solution consisting of 346 mg (2 mmol) of 6-amino-2-n-propylhexanoic acid (2), n=4, and 0.5 ml of triethylamine in 20 ml of water. After 1 hour at 0° C., the reaction was allowed to warm to room temperature and stirred for 2 hours. Ten grams of silicic acid was added and the solvent removed on the rotary evaporator under high vacuum. The impregnated silicic acid was placed atop a column of 120 g of silicic acid packed in 3:2 (v:v) ethyl acetate:ethanol. The column was eluted with this solvent and 15 ml fractions were collected. Fractions 28 to 40 were combined, evaporated, and the residue recrystallized from ethanol to give 365 mg (35% yield) of the labeled conjugate (4), n=4, as cream colored crystals, mp 162° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[NH2:13])=[O:5].C([O-])(=O)C.[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:13][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=1)=[O:5]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1CCCCC[C@@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
cis-2-Amino-cycloheptanecarboxylic acid methyl ester hydrochloride (0.8 g, 3.86 mmol) was suspended in methanol (20 mL). Sodium acetate (0.63 g, 7.7 mmol) was added followed by 4 Å powdered molecular sieves (0.8 g) followed by 4-fluoro-benzaldehyde (0.48 g, 3.86 mmol). Sodium cyanoborohydride (0.48 g, 7.7 mmol) was added and the mixture stirred at 25° C. for 16 h. The mixture was poured into a 1:1 mixture of saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous brine solution (50 mL), dried over magnesium sulfate and concentrated in vacuo to afford the crude product, cis-2-(4-fluoro-benzylamino)-cycloheptanecarboxylic acid methyl ester (0.56 g, 2 mmol, 52%), as a clear oil. LC-MS (ESI) calcd for C16H22FNO2 279.16, found 280.3 [M+H+].
Reaction SMILES: C1C(CC2C=CC(N=C=O)=CC=2)=CC=C(N=C=O)C=1.[CH2:20]([OH:24])[CH2:21]CC.CCCC[CH:29]([C:32]([O-:34])=O)CC.CCCC[CH:39]([C:42]([O-])=[O:43])CC.[Sn+2]>>[CH3:39][CH2:42][O:43][CH2:29][CH2:32][O:34][C:20]([CH3:21])=[O:24]
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: CCCCO
Agent: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Agent: [Sn+2]
Product: CCOCCOC(C)=O
Temperature: 70 °C

Procedure:
A mixture of 495.7 g. (3.95 equivalents) of 4,4'-methylenebis(phenyl isocyanate) and 2.81 g. (0.038 equivalents) of 1-butanol was heated at 50° C for 3 hours. A portion (131.2 g.) of the resulting mixture was then added, with vigorous agitation, to a portion (306.8 g.) of the above polyol blend to which had been added 0.09 g. of stannous octoate. The resulting mixture was poured into a tray and cured by heating at 70° C for 20 hours. The resulting elastomer, which had a hardness of 45 Shore D, was chopped into granules and heated with 657 g. of Cellosolve acetate at 155° C until a clear solution was obtained (about 1 hour heating). The resulting coating composition, containing 40% w/w of elastomer, had a viscosity of 14,900 cps. at 25° C. A film was cast from this solution and found to have a tensile strength of 2100 psi and an elongation at break of 820%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[OH-].[K+].[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.CCO>C1(C)C=CC=CC=1.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:34]3[CH:33]=[N:32][N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH:35]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cn1

Procedure:
6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (Intermediate 6) (10 g, 26.0 mmol), PEPPSI™ (1.764 g, 2.60 mmol), KOH (4.37 g, 78 mmol) and 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS No. 847818-71-7 available from Milestone PharmTech USA Inc.) (11.78 g, 46.7 mmol) were combined in a mixture of toluene (80 mL), EtOH (40 mL) and water (50 mL). The mixture was degassed and then heated at reflux under a nitrogen atmosphere for 6 h. The solution was cooled, diluted with EtOAc (200 mL) and washed with water (200 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo to give a pale yellow gum. This yellow gum was purified by silica gel column chromatography (330 g column, eluting with 0-100% EtOAC/cyclohexane followed by 10% MeOH/EtOAc). The appropriate fractions were collected and the solvent evaporated in vacuo to give the crude product which was further purified by preparative HPLC (Method HpH) and then dried overnight in a vacuum oven at 55° C. to give 6-(((2S,4R)-1-acetyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (4.62 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([Sn:35]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCOc2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(OCCCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 1-3 (6.97 g, 17.5 mmoles) in THF (150 ml) was cooled to -75° C. and treated with n-butyl lithium (n-BuLi)(17.5 mmoles) dropwise. After stirring at -70° C. for 1 hr, tributyltin chloride (5.70 g, 17.5 mmol) was added dropwise. This was stirred at -70° C. for 2 hours and then overnight as the temperature was allowed to rise to ambient temperature. The solvent was subsequently removed and the residue was taken up in ether (500 ml), washed with H2O and brine, and dried with Na2SO4. Solvent removal gave 1-4 as a viscous oil.
Reaction SMILES: [C:1]([N:6]([C:9]1[CH:10]=[N:11][O:12][C:13]=1[CH3:14])[CH2:7][CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]>CCO.[Pd]>[C:13](/[C:9](/[N:6]([CH2:7][CH3:8])[C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[CH:10]\[NH2:11])(=[O:12])[CH3:14]
Reactant: CCCC(=O)N(CC)c1cnoc1C
Agent: [Pd]
Solvent: CCO
Product: CCCC(=O)N(CC)/C(=C/N)C(C)=O

Procedure:
A solution of 4-(N-butyryl-N-ethylamino)-5-methylisoxazole (Method 10; 45 g, 230 mM) in EtOH (1.5 l) was hydrogenated over 10% Pd/C (11.25 g) at 4 bar. The catalyst was filtered off and the solution was evaporated. The residue was triturated with ether and the crystalline intermediate was filtered off (33.94 g). This was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)([C:21](OCC)=[O:22])=[O:20]>O1CCCC1>[CH:9]([N:8]1[C:19](=[O:20])[C:21](=[O:22])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]1=2)([CH3:11])[CH3:10]
Reactant: CC(C)Nc1ncccc1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1c(=O)c(=O)[nH]c2cccnc21
Reaction time: 2 h

Procedure:
To a stirred solution of 3-amino-2-isopropylamino-pyridine (2.0 g, 10.6 mmole) and triethylamine (4.8 ml, 34.6 mmole) in tetrahydrofuran (30 ml) was dropwise added ethoxalyl chloride (2.68 ml, 24 mmole). Stirring was continued for two hours after the addition. The mixture was filtered through a glass filter funnel and the filtrate was evaporated to give the title compound as white crystals. M.p. 246°-24720 C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.ClC(Cl)(Cl)C(=N)O[C:15]([CH3:18])([CH3:17])[CH3:16].[Cl-].[Na+].C(OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A boron trifluoride-diethyl ether complex (91.7 μL) was added dropwise to a suspension of 2-methylpyrazine-5-carboxylic acid (1 g) and tert-butyl 2,2,2-trichloroacetimidate (4.75 g) in tetrahydrofuran (20 mL) under ice-cooling. The reaction solution was warmed to room temperature, followed by stirring for two hours. A saturated sodium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was separated by filtration. The filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (1.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[OH:19])/[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[O:19][C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)/[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.6 %

Procedure:
To a solution of (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-hydroxyiminoacetic acid (86.3 g : 0.30 Mol.) in dimethylformamide (600 ml) are added potassium carbonate (92 g : 0.67 Mol.) and triphenylmethyl chloride (100 g : 0.36 Mol.), and the mixture is stirred at room temperature for 3 days. The reaction mixture is poured into a mixture of concentrated hydrochloric acid (111 ml) and ice water (1500 ml) and extracted with ethyl acetate. The extract is washed with water, aqueous 5% sodium hydrogen carbonate, 2% hydrochloric acid and brine, dried over sodium sulfate, and concentrated. The residue is crystalized from dichloromethane to give (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl) 2-trityloxyiminoacetic acid (144 g) as colorless crystals. Yield: 91%. mp.157 to 158° C.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCCCCCCCCC.C1([CH2:24][CH2:25][CH2:26][C:27]([O-])=[O:28])C=CC=CC=1>>[C:1]1([O:17][C:27](=[O:28])[CH2:26][CH2:25][CH3:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=C([O-])CCCc1ccccc1
Product: CCCC(=O)Oc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sixty-five gram (65 g) of white petrolatum (Riedel-de Haen), 15 g of cetyl alcohol (Riedel-de Haen), 260 g of soft paraffin (Merck), 155 g of liquid paraffin (Merck), and 5 g of 4-phenylbutyrate (Merck) were mixed in a beaker and heated at 70° C. to form a paste. The paste was stirred at 400 rpm for 1 hour, and then cooled at room temperature.