Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]2[S:25][CH:26]([CH2:29][C:30]([OH:32])=O)[CH2:27][N:28]=2)=[CH:14]3)=[CH:6][CH:5]=1.Cl.C(N=C=N[CH2:39][CH2:40][CH2:41][N:42](C)C)C.ON1C2C=CC=CC=2N=N1.C1(N)CC1>O.CN(C)C=O>[CH:41]1([NH:42][C:30](=[O:32])[CH2:29][CH:26]2[S:25][C:24]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[CH:12][C:11]([O:10][C:7]3[CH:8]=[N:9][C:4]([CH2:3][O:2][CH3:1])=[CH:5][CH:6]=3)=[CH:19][C:18]=4[O:20][CH:21]([CH3:23])[CH3:22])=[N:28][CH2:27]2)[CH2:39][CH2:40]1
Reactant: CCN=C=NCCCN(C)C
Reactant: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C4=NCC(CC(=O)NC5CC5)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
A mixture of {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), cyclopropylamine (75 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (170 mg, 52%) as pale yellow prisms. MS 495 (MH+). mp 100-101° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22].N1C=CC=CC=1>ClCCl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23][CH3:24])=[O:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1ccc(S(=O)(=O)Nc2ccsc2C(=O)OC)cc1

Procedure:
Synthesized as described for 52 using commercially available 4-n-butylbenzenesulfonyl chloride (0.47 g; 2 mmol), methyl 3-aminothiophene-2-carboxylate (314 mg; 2 mmol), pyridine (0.2 mL; 2.4 mmol), and anhydrous dichloromethane (10 mL). This afforded the title compound as a clear oil which later solidified (0.6 g).
Reaction SMILES: Br[N:2]1[CH2:5][C:4]([CH2:8][Br:9])([CH2:6][Br:7])[C:3]1=[O:10].C1(C)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:7][CH2:6][C:4]1([CH2:8][Br:9])[CH2:5][NH:2][C:3]1=[O:10]
Reactant: O=C1N(Br)CC1(CBr)CBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1NCC1(CBr)CBr

Procedure:
A 22.4 g (0.067 mole) sample of the 1-bromo-3,3-bis(bromomethyl)-2-azetidinone was dissolved in 450 ml carbon tetrachloride. The insoluble residue (2.0 g) was discarded. A 7 ml (6.07 g, 0.067 mole) portion of toluene was added to the stirred solution. The reaction mixture was irradiated by a 275 watt General Electric Sunlamp and allowed to reflux for one hour. The reaction mixture was decanted hot from a small amount of residue on the stirrer and flask wall and then cooled in ice. White crystals were collected on a filter and dried in vacuo to yield 12.1 g of product. Mother liquor with a few seed crystals was kept cold overnight to yield a second crop of 1.0 g. Total yield of 13.1 g of 76.6% of 3,3-bis(bromomethyl)-2-azetidinone was recovered.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.Br[C:40]1[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=1.CCCCCCC>C1(C)C=CC=CC=1>[F:20][C:17]([F:18])([F:19])[C:15]1[CH:14]=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:40]3[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=3)[N:7]=[CH:8]2)[CH:16]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: NS(=O)(=O)c1cncc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.503 g, 0.7 mmol), commercially available 5-bromo-pyridine-3-sulfonic acid amide (0.183 g, 0.77 mmol), tetrakis(triphenyl-phosphine)palladium (0.040 g, 0.030 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (258 mg, 72%). MS (ISP) 514.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:10]([CH3:11])[N:9]=[N:8][N:7]=1)[C:2]([CH3:4])=[O:3].F[C:13](F)(F)S(OC)(=O)=O.C(Cl)[Cl:22]>CO>[Cl-:22].[CH2:1]([S:5][C:6]1[N:10]([CH3:11])[N:9]=[N:8][N+:7]=1[CH3:13])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)CSc1nnnn1C
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: ClCCl
Solvent: CO
Product: CC(=O)CSc1n(C)nn[n+]1C
Product: [Cl-]
Reaction time: 8 h

Procedure:
The 5-acetonylthio-1-methyltetrazole, prepared as above described, was dissolved in 20 ml of methylene chloride and to the resulting solution was added 0.617 gram (0.0055 mol) of methyl trifluoromethanesulfonate and the mixture allowed to stand overnight at room temperature. Thereafter, the solvent was vaporized off and an oily residue obtained. The latter was dissolved in aqueous methanol and the methanol solution passed over a Dowex-1 (Cl-) ion exchange column. The eluate from the column was evaporated to obtain a waxy material which was triturated with hexane to obtain a waxy solid which after drying in high vacuum amounted to 0.80 gram of 5-acetonylthio-1,4-dimethyltetrazolium chloride, m.p. 102°-104° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([OH:24])([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=O.Cl.[NH2:28][OH:29].N1C=CC=CC=1>C(O)C.C(OC)(C)(C)C>[F:1][C:2]([F:26])([F:25])[C:3]([OH:24])([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[N:28][OH:29]
Reactant: Cc1ccc(C(=O)CC(O)(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: Cc1ccc(C(CC(O)(c2cccc(C(F)(F)F)c2)C(F)(F)F)=NO)cc1
Yield: 96.2 %

Procedure:
A solution of 4,4,4-trifluoro-3-hydroxy-1-(4-methylphenyl)-3-[3-(trifluoromethyl)phenyl]butan-1-one (1.0 g), hydroxylamine hydrochloride (0.28 g) and pyridine (0.42 g) in ethanol (10 mL) was heated to reflux for 5 hours. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield 4,4,4-trifluoro-3-hydroxy-1-(4-methylphenyl)-3-[3-(trifluoromethyl)phenyl]butan-1-one oxime (1.0 g).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1([CH3:39])[C:37](O)=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:32]1([CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(O)c1ccc(C(=O)[O-])cc1
Reactant: Cc1ccccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
To the solution of 4-(1-hydroxyethyl)benzoate (300 mg. 1.67 mmol) in tetrahydrofuran (50 mL) was added triphenylphosphine (570 mg, 2.2 mmol) and o-cresol (180 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, then diisopropylazodicarboxylate (568.3 mg, 2.2 mmol) was added dropwise to the solution at 0° C., the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl 4-(1-(o-tolyloxy)ethyl)benzoate (151 mg, 33%) as oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:21][C:22]1[N:26]([CH:27]2[CH2:29][CH2:28]2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[Cl:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([C:23]1[CH:24]=[N:25][N:26]([CH:27]2[CH2:29][CH2:28]2)[C:22]=1[OH:21])=[O:5]
Reactant: Oc1ccnn1C1CC1
Reactant: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C4CC4)c3O)c2Cl)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
At 0–5° C., a solution of 1.0 g (3 mmol) of 2-chloro-3-(3-methyl-4,5-dihydroisoxazol-5-yl)-4-methylsulfonylbenzoyl chloride in 50 ml of dimethoxyethane was added dropwise to a solution of 0.47 g (3 mmol) of 5-hydroxy-1-cyclopropylpyrazole and 0.5 g (3.6 mmol) of potassium carbonate in 36 ml of anhydrous dimethoxyethane. After 12 hours of stirring at room temperature, a further 1.0 g (7.2 mmol) of potassium carbonate were added and the batch was refluxed for 6 hours. After cooling, the reaction mixture was stirred into 600 ml of water and extracted with methylene chloride. The aqueous phase was then adjusted to pH 4 using 10% strength hydrochloric acid and extracted with methylene chloride. Drying of the organic phase and removal of the solvent gave 0.8 g (1.8 mmol, 63%) of the desired compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[C:30]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([N:39]3[CH2:40][CH2:41][N:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:37][CH2:38]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(N3CCN(c4ccccc4)CC3)n2)cc1
Yield: 73 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 μL of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (40 mg, 73% yield.) MS/ES+: m/z=476.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][C@H:39]1[O:44][C@@H:43]([CH3:45])[CH2:42][NH:41][CH2:40]1>>[CH3:45][C@H:43]1[O:44][C@@H:39]([CH3:38])[CH2:40][N:41]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: C[C@@H]1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)C[C@H](C)O1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and (2R,6S)-2,6-dimethylmorpholine according to conditions described in general procedure C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](O)(=[O:38])[CH2:36][CH3:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]1)=[O:27]
Reactant: CCC(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 99.2 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by propionic acid (22 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-(cis-4-propionylamino-cyclohexyl)-nicotinamide (104 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.F[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([C:32]2[CH:41]=[C:40]([CH3:42])[C:35]3[NH:36][C:37](=[O:39])[O:38][C:34]=3[CH:33]=2)=[O:31])[CH:29]=1)[C:25]#[N:26]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([C:32]5[CH:41]=[C:40]([CH3:42])[C:35]6[NH:36][C:37](=[O:39])[O:38][C:34]=6[CH:33]=5)=[O:31])[CH:29]=4)[C:25]#[N:26])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(C(=O)c2cc(F)cc(C#N)c2)cc2oc(=O)[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C#N)cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c3)CC1)C(=O)N2

Procedure:
0.22 g (0.80 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 0.12 g (0.40 mmol) 3-fluoro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-benzonitrile were heated to 300° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCCCCc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCCCCCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 9.1 g of 6-(4-nitrophenyl)hexanoic acid in 200 ml of dried tetrahydrofuran was added, dropwise, a solution of borane-dimethyl sulfide complex (0.042 mole) in 40 ml of dried tetrahydrofuran. The resulting mixture was stirred at room temperature for 16 hours and then heated at reflux for 1 hour before it was cooled again to room temperature. Water (10 ml) was added, the mixture was stirred for 15 minutes, most of the solvent was removed, and water was added to the residue. The resultant aqueous mixture was extracted with diethyl ether and the extract was washed with aqueous saturated sodium bicarbonate solution, water, and aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was then evaporated to leave 6-(4-nitrophenyl)hexanol as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][OH:31])[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][O:31][S:42]([CH3:41])(=[O:44])=[O:43])[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(CO)c3)n2)cc1F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(COS(C)(=O)=O)c3)n2)cc1F
Temperature: 25 °C
Yield: 97 %

Procedure:
At 0° C., into a solution of methyl 2-fluoro-4-{5-[2-(hydroxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoate, prepared as in example 58, step 1, (500 mg; 1.19 mmol) in DCM (15 mL) was added DIEA (610 μL; 3.58 mmol) and methanesulfonyl chloride (139 μL; 1.79 mmol). The reaction was allowed to warm to RT for 2 h30. Water (5 mL) was added and the DCM extract was rapidly washed twice more with water. The organic layer was then dried over magnesium sulfate, filtered and concentrated to afford the title compound as a yellow foam (573 mg; 97%). 1H NMR (DMSO-d6, 300 MHz) δ 8.47 (d, J=1.8 Hz, 1H), 8.30 (dd, J=8.0, 1.8 Hz, 1H), 8.18-8.13 (m, 1H), 8.09 (dd, J=8.1, 1.5 Hz, 1H), 8.02 (dd, J=11.2, 1.4 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.40-7.29 (m, 3H), 7.19 (d, J=7.0 Hz, 1H), 5.11 (d, J=11.4 Hz, 1H), 5.05 (d, J=11.4 Hz, 1H), 3.92 (s, 3H), 3.04 (s, 3H), 2.05 (s, 3H). LC/MS (Method B): 497.3 (M+H)+. HPLC (Method A) Rt 5.52 min (Purity: 96.7%).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl.[CH3:23][NH:24][O:25][CH3:26].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([N:24]([O:25][CH3:26])[CH3:23])=[O:14])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.2 %

Procedure:
To a solution of Boc-Glu(OtBu)-OH (15 g) in dichloromethane (150 ml) was added N,O-dimethyl-hydroxylamine hydrochloride (5.3 g) and [2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate] (15.87 g) and the pH was adjusted to pH 8-8.5 by adding triethylamine. The reaction mixture was stirred for 16 h at room temperature. The mixture was washed successively with cold 0.3M hydrochloric acid solution, water, 5% aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (eluent: dichloromethane/methanol=98/2 v/v %) to yield Boc-Glu(OtBu)-NMeOMe (17.5 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.C(N(CC)CC)C.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].O>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc(Br)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(C#C[Si](C)(C)C)cs1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A flask was charged with 4-bromo-2-methylthiazole (400 mg, 2.247 mmol) and triethylamine (8 mL) and sparged with nitrogen for 15 min. To this was added ethynyltrimethylsilane (0.381 mL, 2.70 mmol) and purged 15 min longer. To this was added copper(I) iodide (21.39 mg, 0.112 mmol), and Pd(PPh3)2Cl2 (79 mg, 0.112 mmol). The reaction stirred at room temperature for 72 h. The reaction was diluted with ethyl acetate (16 mL) and poured into water. The black heterogeneous emulsion was filtered through a plug of celite and the layers separated. The organics were washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (5%-->6% EtOAc/Hex) gave 307 mg (70%) as a light amber oil. 1H-NMR (CDCl3, 500 MHz) δ 7.34 (s, 1H), 2.72 (s, 3H), 0.27 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 165.6, 137.0, 123.0, 98.4, 94.6, 19.3, −0.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:17]2)=[O:14])=[CH:4][CH:3]=1
Reactant: c1cncc(C2CCNC2)c1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3cccnc3)C2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (15 mg, 0.068 mmol) in dichloromethane (1 mL) was added 3-pyrrolidin-3-ylpyridine (11 mg, 0.074 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H19N3O2: 333.1477, found 333.1471.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10](=S)[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[O:8])=[CH:5][CH:4]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[N:30]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:28][C:29]1[N:30]=[C:31]([NH:35]/[C:10](/[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:9]\[C:7](=[O:8])[C:6]2[CH:24]=[CH:25][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(NC(=S)NCc1ccccc1C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(N)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cccc(N/C(=N\C(=O)c2ccc(C(F)(F)F)cc2)NCc2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A solution of 4-(trifluoromethyl)-N-((2-(trifluoromethyl)benzyl)carbamothioyl) benzamide (2.0 g, 4.92 mmol), 2,6-diaminopyridine (591 mg, 5.41 mmol), and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC hydrochloride) (1.13 g, 5.91 mmol) in DMF (49 mL) was heated to 65° C. for 30 minutes, then allowed to cool to room temperature. The mixture was then diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution, washed with brine, dried over sodium sulfate, and concentrated to provide the crude product. The crude product was purified by chromatography (gradient: 9:1 hexanes:EtOAc to 6:4 hexanes:EtOAc) to provide (Z)—N-(((6-aminopyridin-2-yl)amino)((2-(trifluoromethyl) benzyl)amino)methylene)-4-(trifluoromethyl)benzamide as a yellow solid (1.31 g, 55% yield).