Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][I:8].[OH:9][C:10]1[C:11](=[O:21])[C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>C1C=CC=CC=1.[Ag]>[I:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:20][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:21])[C:10](=[O:9])[CH:19]=1
Reactant: ICCCCCCI
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag]
Solvent: c1ccccc1
Product: O=C1C=C(OCCCCCCI)c2ccccc2C1=O
Yield: 57 %

Procedure:
A mixture of 1,6-diiodohexane (10.14 g, 30 mmol) and the silver salt of 2-hydroxy-1,4-naphthoquinone (2.81 g, 10 mmol) in benzene (60 mL) was stirred for 12 h at room temperature. The reacton mixture was filtered through Celite, concentrated in vacuo, and purified by flash chromatography (hexane/EtOAc 4:1) to give a yellow solid (2,19 g, 57%); mp 85-87° C.; 1H NMR (CDCl3) 8.12 (dd, J=6.5, 1.0 Hz, 1H), 7.86 (dd, J=6.9, 0.9 Hz, 1H), 7.70 (dt, J=7.6, 1.5 Hz, 1H), 7.58 (dt, J=7.5, 1.3 Hz, 1H), 5.95 (s, 1H), 4.15 (t, J=6.3, 2H), 3.22 (t, J=6.9 Hz, 2H), 1.80-2.05 (m, 4H), 1.45-2.10 (m, 4H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2].[I:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:19]([OH:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([I:15])[CH:17]=2)[C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CC(=O)N1C(=O)Cc2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1C(=O)C(=C(O)c2cccc(I)c2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10.5 g 1-acetyl-6-chloro-2-indolinone (educt V.1), 13.6 g 3-iodobenzoic acid and 17.7 g TBTU are placed in 100 ml of dimethylformamide, 35 ml triethylamine are added and the mixture is stirred for 12 hours at ambient temperature. After this time the solvent is eliminated, the residue is combined with water, suction filtered and washed with a little water, methanol and ether and dried in vacuo at 100° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[NH2:39][O:40][CH2:41][CH2:42][OH:43]>C1COCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:3]2[C:2]([F:1])=[C:10]([F:11])[CH:9]=[CH:8][C:4]=2[C:5]([NH:39][O:40][CH2:41][CH2:42][OH:43])=[O:7])=[C:14]([F:21])[CH:15]=1)#[CH:20]
Reactant: NOCCO
Reactant: C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
The product of Example 1, Step C, 3,4-difluoro-2-[(4-ethynyl-2-fluorophenyl)amino]benzoic acid (349 mg, 1.20 mmol) was dissolved in dry THF (15 mL), to which was added carbonyldiimidazole (CDI) (389 mg, 2.40 mmol). Within 10 minutes, a bright yellow solution was obtained and conversion to the imidazolide was confirmed by TLC (50% EtOAc/hexanes). A solution of 2-(aminooxy)ethanol (370 mg, 4.80 mmol) in THF (5 mL) was then added and the mixture stirred for 15 hours at room temperature. The reaction solvent was removed under reduced pressure and the residue partitioned between 1 M HCl (100 mL) and EtOAc (100 mL). The EtOAc layer was then washed with water (100 mL) and saturated NaCl solution (100 mL), dried (Na2SO4), and the solvent removed under reduced pressure to afford an oil which was purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a pale yellow solid (232 mg, 55%); m.p. (EtOAc/hexanes) 158-161° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.84 (br s, 1 H), 7.43 (ddd, J=8.8, 5.9, 1.9 Hz, 1 H), 7.34 (dd, J=12.2, 1.9 Hz, 1 H), 7.25 (ddd, J=9.9, 9.0, 7.3 Hz, 1 H), 7.16 (ddd, J=8.3, 1.9, 0.9 Hz, 1 H), 6.79 (ddd, J=9.1, 8.3, 4.9 Hz, 1 H), 4.71 (br s, 1 H), 4.10 (s, 1 H), 3.84 (t, J=5.0 Hz, 2 H), 3.56 (t, J=5.0 Hz, 2 H). Anal. Calcd for C17H13F3N2O3: C, 58.5; H, 4.1; N, 8.0. Found: C, 58.3; H, 3.7; N, 8.0.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)[OH:4].[NH2:14][C:15]1[C:23]2[C:18](=[N:19][C:20]([N:27]3[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]3)=[CH:21][C:22]=2[CH2:24][CH2:25][CH3:26])[S:17][C:16]=1[C:34]([NH2:36])=[O:35].[BH4-].C(O)(=O)C>C1COCC1.CO>[NH2:14][C:15]1[C:23]2[C:18](=[N:19][C:20]([N:27]3[CH2:28][CH2:29][CH:30]([NH:1][CH2:2][CH:3]([C:5]4[S:9][C:8]5[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=5[CH:6]=4)[OH:4])[CH2:31][CH2:32]3)=[CH:21][C:22]=2[CH2:24][CH2:25][CH3:26])[S:17][C:16]=1[C:34]([NH2:36])=[O:35]
Reactant: CCCc1cc(N2CCC(=O)CC2)nc2sc(C(N)=O)c(N)c12
Reactant: NCC(O)c1cc2ccccc2s1
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCc1cc(N2CCC(NCC(O)c3cc4ccccc4s3)CC2)nc2sc(C(N)=O)c(N)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
The above 2-amino-1-benzo[b]thiophen-2-yl-ethanol (57.9 mg, 0.300 mmol), 3-amino-6-(4-oxo-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (50.0 mg, 0.15 mmol), MP-borohydride (100 mg) and acetic acid (0.075 mL, 1.31 mmol) were mixed in a 2-dram vial in THF (4 mL) and shaken at room temperature for 21 h overnight. The reaction was filtered, and the borohydride resin was rinsed with MeOH, and then filtered again. The combined filtrates were concentrated in on a rotary evaporator to afford crude product. The residue was dissolved into a minimal amount of MeOH, applied to a 1 mm prep plate (Merck) and eluted with 5% MeOH/CH2Cl2, 1% NH3 to give 21.3 mg, 27.9% of the title compound. ES+ 510.1 m/z (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH:24]3[CH2:26][CH2:25]3)=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[C:27]([N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35])(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])[C:31]1=[O:35])(=[O:29])[CH3:28]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2Br)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Yield: 58.1 %

Procedure:
Using (2-bromo-4-chlorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (870 mg) described in Preparation Example 235 and 1-acetylimidazolidin-2-one (384 mg) and by the reaction and treatment in the same manner as in Preparation Example 234, the title compound (560 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:30][CH:29]=4)[CH3:21])[C:14]=3[Cl:44])[C:5]2=[N:4][C:3]=1[CH3:45].[CH2:46](O)[CH3:47].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:41])[CH2:36][CH2:37][C:38]([O:40][CH2:46][CH3:47])=[O:39])=[CH:32][CH:33]=4)[CH3:21])[C:14]=3[Cl:44])[C:5]2=[N:4][C:3]=1[CH3:45]
Reactant: CCO
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)CCC(=O)O)cc4)c3Cl)cccn2c1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(=O)Nc1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccn4c(Br)c(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-[N-[4-(3-carboxypropionamido)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (60 mg), ethanol (12 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg), 1-hydroxybenzotriazole (17 mg) and N,N-dimethylformamide (0.6 ml) was stirred for 3 hours at ambient temperature. Ethyl acetate was added thereto, and the mixture was washed with water four times, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=10:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-[4-(3-ethoxycarbonylpropionamido)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (7 mg) as an amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](O)([CH3:13])[CH2:9][CH:10]1[CH2:12][CH2:11]1.S(=O)(=O)(O)O.[H][H]>CO.[Pd]>[CH:10]1([CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])[CH3:13])[CH2:12][CH2:11]1
Reactant: CC(O)(CC1CC1)c1ccccc1N
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(CC1CC1)c1ccccc1N

Procedure:
To a solution of 2.96 g (15.5 mmol) of 2-(2-aminophenyl)-1-cyclopropyl-propan-2-ol in 70 ml methanol is added 4.43 g (43.4 mmol) conc. sulfuric acid (96%). The resulting mixture is hydrogenated over 600 mg Pd/C(10%) for 20 hours at 30–35° C. After that time no more hydrogen uptake is detected. The catalyst is filtered off and the solvent removed in a water-jet vacuum. The residue is taken up in ethylacetate/water and the water phase is neutralised by the addition of sodium carbonate. The water phase is extracted twice with ethylacetate, then the combined organic phase is dried over sodium sulfate. After removal of the solvent in a water-jet vacuum, the crude amine is obtained. The obtained raw material is purified by column chromagraphy over silica gel (eluant: hexane/ether=5:1). Yield: 2.1 g 2-(2-cyclopropyl-1-methyl-ethyl)phenylamine in the form of a brown oil (1H-NMR).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][CH:6]=1.[H-].[Na+].[CH3:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:15][O:16][CH2:17][N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[C:4]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCCl
Reactant: Cc1c[nH]c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1cc(C)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.8 %

Procedure:
To a solution of 1.0 g (6.32 mmol) of 4-methyl-2-phenylimidazole in 25 mL of DMF at 0° C. was added 278 mg (6.95 mmol, 60% in oil) of NaH. After stirring for 5 min, 0.528 mL (6.95 mmol) of chloromethyl methyl ether was added, and the reaction was warmed to 25° C. and stirred 4 h. The reaction was poured into H2O, and the product was extracted with hexanes/EtOAc (1:1). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel flash column chromatography using hexanes/EtOAc (5:95) as eluent provided 816 mg (64%) of title compound: low resolution MS (ES) m/e 225 (MNa+), 203 (MH+).
Reaction SMILES: [CH2:1]([C@:8]1([NH:19]C(=O)OC(C)(C)C)[C:15](=[O:16])[N:14]2[C@@H:10]([S:11][CH2:12][C@H:13]2[C:17]#[N:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(SC)C=CC=CC=1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:19][C@@:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:15](=[O:16])[N:14]2[C@@H:10]([S:11][CH2:12][C@H:13]2[C:17]#[N:18])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@]1(Cc2ccccc2)C[C@@H]2SC[C@@H](C#N)N2C1=O
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@@H]1CS[C@H]2C[C@](N)(Cc3ccccc3)C(=O)N12
Reaction time: 0.25 h

Procedure:
A mixture consisting of 50 mg of tert-butyl (3R,6R,7aS)-(6-benzyl-3-cyano-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl)-carbamate, 0.1 ml of thioanisole and 1 ml of trifluoroacetic acid is stirred in an ice bath for 15 minutes. After room temperature was reached, the mixture was concentrated in vacuo at 40° C., and the residue was stirred with diisopropyl ether and the solid product was filtered off with suction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][C@H:10]2[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.C1(C)C(C)=CC=CC=1.[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[SH:34]>CO>[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][C@@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C@@H:10]([OH:14])[C:11]([NH2:13])=[O:12]
Reactant: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Reactant: CN(C)CCNc1ccccc1S
Solvent: CO
Solvent: Cc1ccccc1C
Product: COc1ccc([C@H](Sc2ccccc2NCCN(C)C)[C@@H](O)C(N)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide and xylene is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-(2-dimethylaminoethylamino)thiophenol and ferrous sulfate heptahydrate in methanol is added immediately into the reaction mixture, and the mixture is reacted at the same temperature, and cooled to room temperature. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved with heating in ethanol and water. The mixture is allowed to cool to 0° C., and the precipitated crystals are collected by filtration, washed with chilled 50% ethanol, and dried to give (2S,3S)-3-[2-(2-dimethylaminoethylamino)phenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionamide.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:7][N:6]1[C:2]([C:17]2[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=2)=[CH:3][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5]1
Reactant: COC(=O)c1cc(Br)n(C)c1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)n(C)c1
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A solution of methyl 5-bromo-1-methyl-1H-pyrrole-3-carboxylate (950 mg, 4.36 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1088 mg, 5.23 mmol)[prepared according to Preparation 3], potassium carbonate (3011 mg, 21.78 mmol) and bis(tri-t-butylphosphine)palladium(0) (111 mg, 0.218 mmol) in 1,4-Dioxane (18.200 ml) and Water (3.64 ml) was stirred at 80° C. in a sealed tube for 1 h. Additional 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1088 mg, 5.23 mmol) and bis(tri-t-butylphosphine)palladium(0) (111 mg, 0.218 mmol) were added and the solution stirred for 1 h. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 4-25% EtOAc in hexanes) yielding methyl 1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxylate (300 mg, 1.341 mmol, 30.8% yield) as a clear oil: LCMS m/e ES 220 (M+H)+.
Reaction SMILES: C([Li])(CC)C.[C:6]([OH:16])(=[O:15])[C:7]1[CH:12]=CC(OC)=C[CH:8]=1.CN(CCN(C)C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31]CC)=O.[CH2:37]1[CH2:41][O:40][CH2:39][CH2:38]1>>[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([C:8]1[CH:38]=[CH:37][C:41]([O:40][CH3:39])=[CH:12][C:7]=1[C:6]([OH:16])=[O:15])=[O:31]
Reactant: CCOC(=O)c1cccc(F)c1
Reactant: C1CCOC1
Reactant: COc1ccc(C(=O)O)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Product: COc1ccc(C(=O)c2cccc(F)c2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
s-Butyllithium (52 mL, 1.4 M in pentane, 72 mmol) was added at −78 C over 90 min. to a solution of p-Anisic acid (5 g, 33 mmol) and TMEDA (11 ml, 72 mmol) in THF (80 mL). After stirring for 15 min. ethyl 3-fluorobenzoate (5 mL, 40 mmol) was added in one portion. The reaction mixture was stirred for 15 min. then it was quenched with water (20 mL). The reaction mixture was then warmed to room temperature poured into water (1.5 L) 1N NaOH (30 ml) was added and the reaction mixture was then extracted with EtOAc. The extracts were discarded. The aqueous phase was then acidified with conc. HCl to pH 1 and extracted with EtOAc. Drying (Na2SO4) and concentration gave a residue which was recrystallized from hexanes/EtOAc to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[C:26]([O:27][CH3:28])=[CH:25][C:23]([NH2:24])=[C:22]([CH3:29])[CH:21]=1>>[ClH:1].[CH3:18][O:19][C:20]1[C:26]([O:27][CH3:28])=[CH:25][C:23]([NH:24][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:3]=2)=[C:22]([CH3:29])[CH:21]=1
Reactant: COc1cc(C)c(N)cc1OC
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: COc1cc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)cc1OC
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4,5-dimethoxy-2-methylaniline (48 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (64 mg, 79%). 1H NMR (CDCl3): 8.82–8.80 (m, 1H), 8.55 (d, J=7.8 Hz, 1H), 7.88–7.82 (m, 1H), 7.51 (s, 1H), 7.43–7.38 (m, 1H), 6.80 (s, 1H), 6.76 (s, 1H), 6.50 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1.C(N(C(C)C)CC)(C)C.[C:32]1([C:38]#[CH:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.CCOC(C)=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.[Cu](I)I>[F:1][C:2]1[C:3]([C:39]#[C:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(C#Cc2ccccc2)cc1=O)S(C)(=O)=O
Yield: 82.8 %

Procedure:
A solution of ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (500 mg, 1.12 mmol) and diisopropylethylamine (6.0 mL, 30 mmol) in tetrahydrofuran (15 mL) was degassed with nitrogen. Pd(PPh3)4 (65.4 mg, 0.056) and copper iodide (21.8 mg, 0.112 mmol) were added to the solution, followed by phenylacetylene (150 uL, 1.4 mmol). The reaction was allowed to stir until complete via TLC. The reaction was diluted with EtOAc (100 mL) and washed with saturated aq NH4Cl (100 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated. The crude residue was purified via flash chromatography using a Varian SF15-24 g column and an eluent of EtOAc in hexanes (30-80%) to afford the title compound as a yellow solid (389 mg, 82.6%). MS (LCMS) m/z 420.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, 3H) 1.75 (s, 3H) 2.42-2.61 (m, 2H) 3.11 (s, 3H) 3.91-4.00 (m, 1H) 4.19-4.27 (m, 1H) 4.30 (q, J=7.02 Hz, 2H) 6.72 (d, J=6.63 Hz, 1H) 7.27 (t, J=2.34 Hz, 2H) 7.35-7.44 (m, 2H) 7.55-7.60 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(Cl)Cl.O=S(Cl)Cl.C(N(C(C)C)CC)(C)C.[F:30][C:31]([F:40])([F:39])[CH2:32][NH:33][CH2:34][C:35]([F:38])([F:37])[F:36]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:33]([CH2:32][C:31]([F:30])([F:39])[F:40])[CH2:34][C:35]([F:38])([F:37])[F:36])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: FC(F)(F)CNCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Fluoro-3-nitrobenzoic acid (2.50 g, 13.5 mmol) was refluxed in a 2:1 mixture of CH2Cl2/SOCl2 (150 mL) for 5 h. The solvent was concentrated and the residue was dissolved in CH2Cl2 (50 mL). Another CH2Cl2 solution (50 mL) of diisopropylethylamine (DIPEA) (3.50 mL, 20.3 mmol) and bis(2,2,2-trifluoroethyl)amine (4.90 g, 27.0 mmoL) was then added dropwise to the cold stirring solution (0° C.) of the acid chloride. The solution was stirred at RT overnight. The solution was then washed with 5% KHSO4 solution, saturated NaHCO3 solution, and brine and dried over anhydrous MgSO4. The product was purified by flash chromatography on silica gel using 3:1/HEX:EtOAc. Yield: 3.08 g (66%); 1H NMR (CDCl3) 4.17 (brs, 4H), 7.40 (t, J=8.59 Hz, 1H), 7.66 (m, 2H), 8.10 (d, J=6.84 Hz, 1H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].[CH2:15](S)C.[OH-].[K+]>>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:11])([CH3:10])[CH3:12])=[N:5][N:4]=[C:3]1[S:13][CH2:14][CH3:15]
Reactant: CSc1nnc(C(C)(C)C)c(=O)n1N
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Product: CCSc1nnc(C(C)(C)C)c(=O)n1N
Temperature: 10 °C

Procedure:
A mixture of 230 g (1 mole of 93% active ingredient) of 4-amino-6-t-butyl-3-methylthio-1,2,4-triazin-5-one and 310 g (5 moles) of ethyl mercaptan and 0.5 g of crushed solid KOH was stirred and refluxed onto a 10° C. condenser. The vapors which pass through the condenser (methyl and ethyl mercaptans) were collected in a dry ice or caustic trap. The reaction was continued until thin layer chromotography indicated that the starting material was gone (usually 2-8 hours). The unreacted ethyl mercaptan was then distilled off while ~600 ml of warm (40° C.) water was added at such a rate that the water addition was complete when ~1/3 of the mercaptan had distilled. Distillation was continued until ~100 ml of water distilled at 100° C. The solution was then allowed to cool with rapid stirring. The product crystallized at 60°-70° C. and at 20° C. was filtered and washed with water, then dried. The final product, 4-amino-6-t-butyl-3-ethylthio-1,2,4-triazin-5-one, was obtained in nearly quantitative yield and contained less than 1% of the starting 3-methylthio compound.
Reaction SMILES: [Mg].[Si:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1.C(OC)(C)(C)C>[O:9]([C:10]1[CH:15]=[CH:14][C:13]([B:17]([OH:20])[OH:18])=[CH:12][CH:11]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
Magnesium turnings (0.53 g, 22 mmol) and 20 mL of THF were placed into a two-necked flask. Next, tert-butyldimethylsilyloxyphenyl bromide (5.64 g, 19.6 mmol) was added and the mixture was heated under reflux for 2 h before it was cooled to room temperature. The brown mixture was added to a solution of trimethyl borate (2.43 g, 24 mmol) in 5 mL of THF through a dropping funnel at −78° C. and allowed to warm to room temperature overnight. After hydrolysis with 90 mL of ca. 0.1 M hydrochloric acid followed by standard work-up with methyl tert-butyl ether, the brown residue was washed with 20 mL of cold hexane, and the resulting white product (3.86 g, 78%) was dried in vacuo. Mp: 175° C. (1H NMR (300 MHZ, CDCl3): δ0.25 (s, 6H); 1.01 (s, 9H); 6.95 (d, J=8.5 Hz, 2H); 8.11 (d, J 8.5 Hz, 2H). 13C NMR (75 MHZ, CDCl3): δ−4.3; 18.1; 25.7; 119.8; 137.5; 159.8. Reference: Bolm, C.; Derrien, N.; Seger, A. Synlett 1996, 387.