Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH:3]([N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[NH2:17])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:36](Cl)(=[O:40])/[CH:37]=[CH:38]/[CH3:39]>C(Cl)Cl>[C:36]([NH:17][C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[CH2:9][N:8]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:3](=[CH2:2])[C:4]([O:6][CH3:7])=[O:5])(=[O:40])/[CH:37]=[CH:38]/[CH3:39]
Reactant: C/C=C/C(=O)Cl
Reactant: COC(=O)C(CO)N(Cc1cc(C)ccc1N)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1cc(C)ccc1NC(=O)/C=C/C)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
As described for Reference Examples 181 and 182, a mixture of 1.41 g (3.455 mmol) of methyl 3-hydroxy-2-[-(4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate, 1.75 g (17.3 mmol) of triethylamine and 0.809 ml of trans-crotonyl chloride in 15 ml of CH2Cl2 was stirred overnight to give 1.52 g of methyl 2-{[2-(trans-crotonylamino)-5-methylbenzyl]-(4-methoxybenzenesulfonyl) amino}acrylate as a brown oil; Mass spectrum (ES) 459.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([NH:30][CH3:31])=[O:29])[N:26]=2)=[N:10]1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][C@H:33]1[C:38]([OH:40])=[O:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([NH:30][CH3:31])=[O:29])[N:26]=2)[NH:12][C:13]([CH2:20][N:32]2[CH2:37][CH2:36][O:35][CH2:34][C@H:33]2[C:38]([OH:40])=[O:39])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc(CC(=O)NC)cs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)[C@@H]1COCCN1
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nc(CC(=O)NC)cs2)=NC1c1ccc(F)cc1Br
Yield: 52.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2-(methylamino)-2-oxoethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.15 g, 2 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.39 g, 3 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.66 g, 53%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[CH:28]=[CH:27][CH:26]=[C:4]([CH2:5][N:6]2[C:10](=[O:11])[N:9]([CH2:12][CH:13]([OH:18])[C:14]([F:15])([F:17])[F:16])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:7]2)[CH:3]=1
Reactant: O=c1n(Cc2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: OB(O)c1ccccc1Cl
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: C1COCCO1
Solvent: O
Product: O=c1n(Cc2cccc(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
72 mg (0.15 mmol) of the compound from Example 101A and 59 mg (0.23 mmol) of 2-chloro-phenylboronic acid were dissolved in 2 ml of dioxane. A stream of argon was passed through this solution for 10 min, and 8.7 mg (0.008 mmol) of tetrakis(triphenylphosphine)palladium(0) were added under argon. The mixture was heated to the boil, and 0.15 ml (0.30 mmol) of a 2 N aqueous sodium carbonate solution was added under argon. The mixture was then stirred under reflux for 20 h. After cooling to RT, the mixture was diluted with 10 ml of water and extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 51 mg (61% of theory) of the target compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[N:5]=[CH:6][CH:7]=[N:8]2.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(#N)C>[N:13]1([CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[N:5]=[CH:6][CH:7]=[N:8]3)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: BrCc1cccc2nccnc12
Solvent: CC#N
Product: c1cc(Cn2ccnc2)c2nccnc2c1
Reaction time: 1.5 h
Yield: 20.5 %

Procedure:
A mixture of 15.5 parts of 5-(bromomethyl)quinoxaline, 23.5 parts of 1H-imidazole and 160 parts of acetonitrile was stirred for 1.5 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted three times with 65 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product was filtered off and dried, yielding 3 parts (20.5%) of 5-(1H-imidazol-1-yl-methyl)quinoxaline; mp. 121.2° C. (comp. 41).
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15](=[O:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].[Br-:21].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:21][CH2:16][C:15]([C:11]1[C:12]([CH3:14])=[CH:13][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[CH:9][C:10]=1[CH3:18])=[O:17]
Reactant: [Br-]
Reactant: CCc1ccc(Oc2cc(C)c(C(C)=O)c(C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CCc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.4 %

Procedure:
To a solution of 1-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)ethanone (6.00 g, 22.4 mmol) in acetonitrile (44.7 mL) was added tetrabutylammoniumtribromide (TBABr3, 10.8 g, 22.4 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)ethanone (8.2 g), which was used directly for the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH3:33])=[CH:30][C:29]([OH:34])=[CH:28][CH:27]=2>>[CH3:23][C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH3:33])=[CH:30][C:29]([O:34][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)=[CH:28][CH:27]=2
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 39.5 %

Procedure:
Using an analogous procedure to that described in Example 34, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (110 mg, 0.34 mmol), (prepared as described for the starting material in Example 10), was reacted with 2,3-dimethyl-5-hydroxyindole (66 mg, 0.41 mmol), (Arch. Pharm. 1972, 305, 159). The crude product was purified by column chromatography eluting with methanol/methylene chloride (1/9) followed by 3M ammonia in methanol/methanol/methylene chloride (5/15/80) to give 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (60 mg, 40%).
Reaction SMILES: C1(C2N=C(C(C(N[C:15]([CH:17]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[CH2:18][S:19]([CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:21])=[O:20])=[O:16])CC)=O)ON=2)CC1.FC(F)(F)C(O)=O.[NH2:42][CH:43]([CH2:55][CH3:56])[C@@H:44]([C:46]1[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[O:48][N:47]=1)[OH:45].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:23]1([CH2:22][S:19]([CH2:18][C@H:17]([NH:26][C:27]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[O:28])[C:15](=[O:16])[NH:42][C@H:43]([CH:44]([OH:45])[C:46]2[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[O:48][N:47]=2)[CH2:55][CH3:56])(=[O:20])=[O:21])[CH2:24][CH2:25]1
Reactant: CCC(N)[C@H](O)c1noc(C(F)(F)F)n1
Reactant: CCC(NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1)C(=O)c1nc(C2CC2)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](NC(=O)[C@H](CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1)C(O)c1noc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A solution of (R)-3-cyclopropylmethanesulfonyl-2-[(morpholine-4-carbonyl)-amino]-propionic acid (266 mg, 0.83 mmol, Reference Example 4) in dimethylformamide (10 mL) was treated successively with (S)-2-amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol trifluoroacetate (282 mg, 0.83 mmol, Reference Example 13), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (316 mg, 0.83 mmol) and diisopropylethylamine (0.289 mL, 1.66 mmol). Reaction stirred at room temperature overnight. Solvent evaporated under reduced pressure. Residue taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous bicarbonate solution and water, dried over Na2SO4 and solvent evaporated under reduced pressure to give morpholine-4-carboxylic acid ((R)-2-cyclopropylmethanesulfonyl-1-{(S)-1-[hydroxy-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-methyl]-propylcarbamoyl}-ethyl)-amide as a brown oil (370 mg). MS: 528 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].OS(C(F)(F)F)(=O)=O.[I:19]N1C(=O)CCC1=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([I:19])=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (5 g, 35.43 mmol) in triflic acid (15.6 ml, 177.15 mmol, 5 eq.) at 0° C. was added N-iodosuccinimide (9.57 g, 42.5 mmol, 1.2 eq.) portionwise and the mixture was stirred at RT for 1 h. The mixture was quenched by the addition of water and extracted with diethylether (3×150 ml). The combined organic layer was washed with water, aqueous sodium thiosulfate, brine and dried over sodium sulphate. The solvent was distilled off and the crude residue was purified by column chromatography (60-120 silica gel, 5% ethyl acetate in hexane) to afford the compound in 66% yield (6.2 g). 1H NMR (300 MHz, DMSO-d6): δ 8.42 (dd, 1H), 8.18-8.13 (m, 1H), 7.46-7.39 (m, 1H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH:3]1[OH:12].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C)C=O>[N:13]([CH:2]1[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH:3]1[OH:12])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)N1CCC(Br)C(O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(N=[N+]=[N-])C(O)C1
Temperature: 84 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the bromide (70 mg, 0.27 mmol, Example 307) in dimethylformamide (3 mL), sodium azide (80 mg, 1.23 mmol) was added and the mixture was stirred at 84° C. overnight. The solvent was removed and the residue was chromatographed (50% ethyl acetate/hexane) to give the desired product as a colorless oil. 51 mg, 86%. H1NMR (300 MHz, CDCl3), ppm: 1.60–1.70 (m), 1H; 2.05–2.20(m), 1H; 2.80–3.05 (m), 2H; 2.83 (s), 3H; 3.10 (br), 1H (OH); 3.40–3.51 (m), 1H; 3.51–3.62 (m), 1H. 3.65–3.80 (m), 2H.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([N:17]=[C:18]1[N:22]([CH3:23])[C@H:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[CH2:11]([O:14][C:15]([N:17]=[C:18]1[N:22]([CH3:23])[C@H:21]([CH:24]=[O:25])[CH2:20][CH2:19]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N=C1CC[C@@H](CO)N1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N=C1CC[C@@H](C=O)N1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
To a solution of oxalyl chloride (0.52 ml) in dichloromethane (15 ml) was added dropwise dimethyl sulfoxide (0.60 ml) at -78° C. After stirring at -78° C. for 10 minutes, to the mixture was added dropwise a solution of (2S)-5-allyloxycarbonylimino-2-hydroxymethyl-1-methylpyrrolidine (0.63 g) in dichloromethane (10 ml). After stirring at -78° C. for 10 minutes, to the mixture was added dropwise triethylamine (2.1 ml) and the resulting mixture was allowed to warm to 0° C. The mixture was washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of acetone and dichloromethane (1:4 V/V) to give (2S)-5-allyloxycarbonylimino-2-formyl-1-methylpyrrolidine (0.46 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH2:13][OH:14]>C(O)C>[OH:14][NH:13][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:4][CH:5]=1
Reactant: NO
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: N=C(NO)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 105.6 %

Procedure:
To a solution of 4-(trifluoromethyl)benzonitrile (10 g) in ethanol (100 ml) was added 50% hydroxylamine aqueous solution (11.6 g), and stirred at 80° C. overnight. After completion of the reaction, the solvent was evaporated, and water was added thereto. The insoluble matter was collected by filtration, and then dried to give N-hydroxy-4-(trifluoromethyl)benzamidine (12.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:21]=[O:22]>C(#N)C.O>[OH:22][C:21]1[C:3]([CH3:10])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH:2]=[O:1]
Reactant: C=O
Reactant: Cc1cc(C=O)ccc1O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)cc(C=O)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
The 4-hydroxy-3-methylbenzaldehyde (7.0 g, 51.41 mmole) and magnesium chloride (7.3 g, 77.12 mmole) were mixed in acetonitrile (100 mL) and cooled to 0° C. (ice bath). Triethylamine (19.51 g, 192.79 mmole) followed by para-formaldehyde (10.41 g, 347 mmole) were added to above mixture, which was stirred for 1 hour. The mixture was warmed to room temperature and then heated to 90° C. for 18 hours. The contents were poured into water (100 mL) and extracted with EtOAc (2 X 100 mL). The combined extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid which was subject to flash chromatography (silica gel) and eluted with 100% CH2Cl2 to give an off-white solid (2.2 g, 26%). GCMS m/z 164.0 (M+). 1H NMR (CDCl3/400 MHz) 11.82 (s, 1H), 9.96 (s, 1H), 9.89 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#N)[CH:6]=1.C(O)=[O:15]>[Al].[Ni]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[O:15])[CH:6]=1
Reactant: O=CO
Reactant: COC(=O)Cc1cccc(C#N)c1
Agent: [Ni]
Agent: [Al]
Product: COC(=O)Cc1cccc(C=O)c1
Temperature: 25 °C

Procedure:
A mixture of (3-cyano-phenyl)-acetic acid methyl ester (1.56 g, 8.91 mmol), aluminum-nickel alloy (1.63 g) and 75% formic acid (25 mL) was heated at reflux for 1.75 h. The mixture was cooled to room temperature and the solids were removed by filtration through Celite with the aid of boiling EtOH. Water was added and the aqueous solution was washed with CH2Cl2 (3×). Aqueous saturated NaHCO3 was carefully added to the organic solution until the pH was about 8-9. The organic solution was washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (5:1 hexanes:EtOAc) provided the title compound as a clear and colorless oil (870 mg). 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 7.77 (m, 2H), 7.55-7.46 (m, 2H), 3.68 (s, 5H).
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:15][C:16]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].C(Cl)Cl>COCCOC.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]>[NH2:8][C:3]1[C:2]([C:24]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:15])[CH:25]=2)=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1nccnc1Cl
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nccnc2N)cc1F
Temperature: 100 °C
Yield: 84 %

Procedure:
To 3-chloropyrazin-2-amine (27 g, 208 mmol) in DME (391 mL) and sodium carbonate (66.3 g, 625 mmol) was added methyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (64.2 g, 229 mmol) and PdCl2(dppf).CH2Cl2 adduct (8.51 g, 10.42 mmol). The reaction mixture was purged with N2 and heated in oil bath at 100° C. for 3h. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was recrystallized by EtOAc and heptane (2:3) to give methyl 4-(3-aminopyrazin-2-yl)-2-fluorobenzoate in 84% yield. LCMS (m/z): 248.1 (MH+), 0.58 min.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Cl[CH2:13][CH2:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH2:1]([NH:4][S:15]([CH:14]=[CH2:13])(=[O:17])=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNS(=O)(=O)C=C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled, 0° C., solution of allylamine (1.926 g, 33.7 mmol) and triethylamine (12.789 mL, 92.0 mmol) in anhydrous methylene chloride (50 mL) was slowly added a solution of 2-chloroethanesulfonyl chloride (5.000 g, 30.7 mmol) in methylene chloride (10 mL). The resulting mixture was allowed to warm to room temperature and stirred for 4 hrs. The mixture was successively extracted with 1 N aqueous hydrochloric acid (2×), water, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to give a yellow liquid. 1H NMR (300 MHz, CDCl3) δ 6.57-6.48 (dd, 1H, J=9.9, 16.8 Hz), 6.28-6.22 (d, 1H, J=16.8 Hz), 5.96-5.92 (d, 1H, J=9.6 Hz), 5.90-5.77 (m, 1H), 5.30-5.29 (m, 1H), 5.24-5.17 (m, 1H), 4.44 (br s, 1H), 3.69-3.64 (tt, 2H, J=1.5, 6.0 Hz).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:26]([NH2:28])[CH3:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([NH:28][CH2:26][CH3:27])=[O:24])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Reactant: CCN
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCNC(=O)C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
The compound (9 mg, 0.03 mmol) prepared in Example 42 was dissolved in N,N-dimethylformamide (1 ml). Ethylamine hydrochloride (3 mg, 0.03 mmol), EDC (8 mg, 0.04 mmol), HOBT (5 mg, 0.04 mmol) and triethylamine (8 mg, 0.08 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (4 mg, Yield 41%).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([OH:31])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]([C:26]([CH:28]2[CH2:30][CH2:29]2)=[O:27])[CH2:24][CH3:25])[CH:11]=1)C.S(C1C=CC(C)=CC=1)(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:28]1([C:26]([N:23]([CH2:22][C:13]2[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=2[C:10]2[CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:32])[CH:7]=[N:8][C:9]=2[O:31][CH2:37][C:38]([F:41])([F:40])[F:39])[CH2:24][CH3:25])=[O:27])[CH2:29][CH2:30]1
Reactant: CCOC(=O)Cc1cnc(O)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)cnc1OCC(F)(F)F)C(=O)C1CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
(5-{2-[(N-Cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-hydroxy-pyridin-3-yl)-acetic acid ethyl ester (0.175 g, 0.39 mmol), 2,2,2-trifluoroethyl tosylate (0.151 g, 0.58 mmol), and potassium carbonate (0.070 g, 0.51 mmol) were combined in DMF (1.8 mL) and stirred at 55° C. overnight. Additional 2,2,2-trifluoroethyl tosylate and potassium carbonate were added, and the reaction was stirred at 75° C. overnight. After cooling, the crude material was used directly in the hydrolysis step. The ester was hydrolyzed to the acid as described in Example 3, Step 7. The acid was purified by preparative HPLC.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][C:11]([C:25]1[CH:34]=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1)([C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH3:12])(=O)=O.C(OCC)(=O)C>CS(C)=O>[O:29]1[C:28]2[CH:33]=[CH:34][C:25]([C:11]([C:13]3[C:21]4[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)([CH3:12])[CH2:10][CH2:9][C:1]#[N:2])=[CH:26][C:27]=2[O:32][CH2:31][CH2:30]1
Reactant: CSCc1cccc2c(C(C)(CCOS(C)(=O)=O)c3ccc4c(c3)OCCO4)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSCc1cccc2c(C(C)(CCC#N)c3ccc4c(c3)OCCO4)c[nH]c12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
150 mg (2.30 mmol) of potassium cyanide were added to 530 mg (1.15 mmol) of the compound from Example 117A in 10 ml of DMSO. The mixture was stirred at 80° C. for 16 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 328 mg (73% of theory) of the target compound were obtained.