Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[O:11][CH:10]=[CH:9][C:8]2=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=1)([CH3:3])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl>[Br:25][C:10]1[O:11][C:7]2[C:8](=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)[CH:9]=1
Reactant: COC(=O)c1cc(OC(C)C)cc2occc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OC(C)C)cc2oc(Br)cc12
Temperature: 60 °C
Reaction time: 1.2 h
Yield: 87 %

Procedure:
A mixture of methyl 6-isopropoxybenzofuran-4-carboxylate (344a) (2.17 g, 9.25 mmol) and NBS (4.12 g, 23.1 mmol) in 50 mL of CHCl3 was heated at 60° C. for 5 hrs, followed by addition of another batch of NBS (2.50 g, 14.0 mmol). After stirring for an additional 1.2 h, the reaction was concentrated, and the residue was purified with Biotage column chromatography eluting with CHCl3 to give a yellow oil (2.52 g, 87% yield). 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=2.27 Hz, 1 H) 7.22 (s, 1 H) 7.18 (d, J=2.01 Hz, 1 H) 4.56-4.64 (m, 1 H), 3.97 (s, 3H), 1.37 (d, J=6.04 Hz, 6 H); LCMS for C13H13BrO4m/z 312.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@H:35]([CH2:38][CH3:39])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@@H:35]([CH2:36][OH:37])[CH2:38][CH3:39])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CC[C@@H](N)CO
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: CC[C@H](CO)NCCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3c(OC)ccc(F)c3F)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (R)-2-amino-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H35N6O5SF2 [(M+H)+] 557.2352, observed 557.2360.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[N:8]([CH:18]2[CH2:20][CH2:19]2)[C:7]1=[O:21])C.[OH-].[K+].Cl>CO>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:8]([CH:18]3[CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH2:5][C:4]([OH:22])=[O:3])[CH:10]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cn1cc(-c2ccc(Br)cc2)n(C2CC2)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1cc(-c2ccc(Br)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
502 mg (1.28 mmol) of ethyl[4-(4-bromophenyl)-3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-acetate from Example 124A are placed in 0.94 ml methanol, treated with 0.34 ml 20% aqueous potassium hydroxide and stirred overnight at room temperature. It is adjusted to pH 3 with 1 N hydrochloric acid, the resulting precipitate recovered by filtration, and the product washed with water and dried in vacuo. 369 mg (80% of theory) of the target compound, which is reacted without further purification, are thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH3:48])[C:11]([CH2:13][O:14][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:21]4=[O:45])=[CH:17][CH:16]=3)=[N:12][C:7]2=[CH:6][CH:5]=1)[CH3:2].C(O)(=O)C>O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH3:48])[C:11]([CH2:13][O:14][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:45])=[CH:17][CH:16]=3)=[N:12][C:7]2=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2n1
Yield: 90.6 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 2.75 g of 5-{4-(5-ethoxy-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 99) were treated with 24 ml of a 3:1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 1.57 g of the title compound, melting at 245°-246° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>CS(C)=O.C(Cl)Cl>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Fc1ccc(Cn2cccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a stirred solution of pyrazole (300 mg, 4.4 mmol) in DMSO (2 ml) at RT was added NaH (176 mg, 4.4 mmol, 60% in mineral oil) portionwise. The mixture was stirred at RT for 1 h and 4-fluorobenzylbromide (1.0 g, 5.3 mmol) added dropwise. The mixture was stirred at 50° C. for 0.5 h, cooled to RT and diluted with DCM (20 ml). The resulting mixture was filtered and the filtrate washed with brine (10 ml). The organic layer was then dried (NaSO), filtered and concentrated at reduced pressure. Purification by silica flash column chromatography (eluting with DCM/MeOH 95:5) provided the title compound as colourless oil (650 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:57]([CH:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:58]>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:66][CH:59]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH2:57][CH3:58])=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18]
Reactant: Cc1c(C)n(Cc2ccc(F)cc2F)c2ccc(C(=O)O)cc12
Reactant: CCC(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(F)cc1F)c1ccccc1
Reaction time: 0.08 h

Procedure:
To a mixture of 1-(2,4-difluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid in DMF was added DIPEA (1.3 equiv) and HATU (1.2 equiv). The mixture was stirred for 5 min, and then α-ethylbenzylamine (1.1 equiv) was added. The reaction mixture was stirred at rt for 1 h. After the reaction was completed, the solvent was removed in vacuo to obtain the crude which was purified by flash chromatography to obtain the title compound. LC-MS 433 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C@@H:8]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:5])[CH3:2].[ClH:20]>O1CCOCC1>[ClH:20].[NH:10]1[CH2:11][CH2:12][C@@H:8]([O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:9]1
Reactant: CCOC(=O)CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CO[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (3R)-3-(ethoxycarbonylmethoxy)pyrrolidine-1-carboxylate (4.0 g, 15.42 mmol) was dissolved in 4N HCl in 1,4-dioxane (50 mL), stirred at ambient temperature for 3 hrs, evaporated, co-evaporated with 1,4-dioxane (3×50 mL) and dried under high vacuum to give (R)-ethyl 2-(pyrrolidin-3-yloxy)acetate hydrochloride as an orange oil that solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([CH3:17])([CH3:16])[C:8]3[CH:18]=[C:19]([O:22]C)[CH:20]=[CH:21][C:7]=3[C:6](=[O:24])[C:5]2=1.[Cl-].[NH+]1C=CC=CC=1.C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([CH3:17])([CH3:16])[C:8]3[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:7]=3[C:6](=[O:24])[C:5]2=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)c(Cl)cc3c1C2=O
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 160 °C
Reaction time: 7 h

Procedure:
Mixture of 2,3-dichloro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound Y3, 16.5 mg, 0.0457 mmol) and pyridinium chloride (0.2 g) was stirred at ambient temperature of 160° C. for 7 hr. The reaction mixture was cooled to room temperature and added with ethyl acetate and water. The mixture was extracted three times with ethyl acetate. The organic layer was washed twice with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was used for the next step without further purification (brown solid, 14.8 mg, 94%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH:9]([CH:27]([CH3:29])[CH3:28])[C:10]([NH:12][C@@H:13]([CH3:26])[C:14]([NH:16][C@@H:17]([CH3:25])[C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH:9]([CH:27]([CH3:29])[CH3:28])[C:10]([NH:12][C@@H:13]([CH3:26])[C:14]([NH:16][C@@H:17]([CH3:25])[C:18]([OH:20])=[O:19])=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)O
Yield: 145.2 %

Procedure:
Following the procedure as described in Example 11, except using material from Example 26 (213 mg, 0.499 mmol), CH2Cl2 (75 mL) and TFA (25 mL, 324 mmol), 268.4 mg (quantitative yield) of the title compound is obtained as a white solid as a mono TFA salt. LC/MS (Condition A): ret. T=2.15 min, (M+H)+ 371.14.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[N:3]=1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[C:28]([F:29])=[CH:27][C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][C:24]=2[F:34])=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[F:34][C:24]1[CH:25]=[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])[CH:27]=[C:28]([F:29])[C:23]=1[C:17]1[S:16][C:15]([NH:14][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[N:3]=2)=[C:19]([C:20]([NH2:22])=[O:21])[CH:18]=1
Reactant: Cn1cc(-c2cccc(Br)n2)nn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cn1cc(-c2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)nn1

Procedure:
The title compound was synthesized from 2-bromo-6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine (96 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the general procedure in Example 1.
Reaction SMILES: C1([C:7]2[C:8]3[C:16](CO)=[CH:15][CH:14]=[C:13]([NH:19][C:20](=[O:29])[C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:28])[C:9]=3[O:10][C:11]=2[CH3:12])CCCCC1.C([SiH]([CH2:35][CH3:36])CC)C>FC(F)(F)C(O)=O>[CH:35]1([CH2:36][C:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:19][C:20](=[O:29])[C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:28])[C:9]=3[O:10][C:11]=2[CH3:12])[CH2:9][CH2:8][CH2:7][CH2:11][CH2:12]1
Reactant: CC[SiH](CC)CC
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)ccc(CO)c2c1C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.2 %

Procedure:
A mixture of 3-(1-cyclohexyl)hydroxymethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (65 mg) and triethylsilane (87 mg) in trifluoroacetic acid (3 ml) was stirred at ambient temperature for overnight. The reaction mixture was concentrated in vacuo. To the residue was added aqueous saturated sodium bicarbonate and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from hexane to give 3-cyclohexylmethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (42 mg).
Reaction SMILES: [NH:1]1[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>[OH-].[Na+]>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:1]2[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])=[O:19])=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1ccc(Cl)cc1
Temperature: -1 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
9.4 g (71.685 mmol) of L-hydroxyproline are dissolved in 71.68 ml of NaOH solution (c=1 mol/l) at from −2 to 0° C., a solution of 11.008 g (71.685 mmol) of 4-chlorophenyl isocyanate in 70 ml of IBMK is subsequently added, and the mixture is stirred at −1° C. for 1 hour. Conventional work-up gives 18.52 g of (2S,4R)-1-(4-chlorophenyl-carbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid;
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([N:15]1[CH2:19][CH2:18][C@@H:17]([NH2:20])[CH2:16]1)[CH3:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][C@@H:17]2[CH2:18][CH2:19][N:15]([CH2:13][CH3:14])[CH2:16]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: CCN1CC[C@@H](N)C1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CC[C@@H](NC(=O)c2ccc(N)c(OC)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (Aldrich; 424 mg, 2.54 mmol) and (3R)-1-ethylpyrrolidin-3-amine (Intermediate 246; 312 mg, 2.73 mmol) in DMF (10 mL) was added DIPEA (1.4 ml, 8.04 mmol). The resultant solution was treated with HATU (1.21 g, 3.18 mmol) and stirred, under nitrogen, at ambient temperature overnight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([CH2:28]O)[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.COCCN(S(F)(F)[F:43])CCOC.[Cl-].[NH4+].C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([CH2:28][F:43])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CO)cc(OC)c1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CF)cc(OC)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 100 mg of {2-(3-hydroxymethyl-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 1.5 ml of dichloromethane there was added 0.057 ml of [bis(2-methoxyethyl)amino]sulfur trifluoride at −78° C. After stirring at −78° C. for 5 minutes, the mixture was stirred at room temperature for 1 hour and 25 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried through PRESEP™. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (59 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH3:10])[CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>O>[CH2:17]([O:16][C:14]([NH:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH:3]([C:2]([F:11])([F:12])[F:1])[CH3:10])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C[C@H](N)C(=O)O)C(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a stirred solution of the 5,5,5-trifluoro-L-leucine (12 g) in H2O (150 mL) at 0° C. was added benzyl chloroformate (4.8 mL, 34 mol), followed by dropwise addition of 1 M aqueous NaOH (120 mL, 120 mmol). More benzyl chloroformate (4.8 mL, 34 mmol) was added. The mixture was further stirred at 0° C. and the pH of the mixture became ˜7. The mixture was washed with Et2O (2×) and acidified with aqeous HCl. The aqueous layer was extracted with EtOAc (3×), dried (Na2SO4) and concentrated in vacuo to provide N-[(benzyloxy)carbonyl]-5,5,5-trifluoro-L-leucine. The crude acid was dissolved in Et2O and treated with a solution of diazomethane in Et2O. Chromatography over silica gel and elution with hexanes:Et2O (7:3) gave methyl (4S)-N-[(benzyloxy)carbonyl]-5,5,5-trifluoro-L-leucinate as the less polar fraction.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:13]([NH:15][CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38]>O>[CH:18]1([CH2:17][CH2:16][NH:15][C:13](=[O:14])[C:12]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:10]([C:9]([NH:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][C:35](=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:3][CH:4]=3)=[O:27])[CH:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)Nc1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)Nc1ccc(NC(=O)CC(C)C)nc1
Temperature: 0 °C

Procedure:
To a 25 mL round-bottomed flask was added N3-(6-aminopyridin-3-yl)-N1-(2-cyclopentylethyl)-4-methylisophthalamide (0.19 g, 0.52 mmol) and Triethylamine (0.18 ml, 1.3 mmol) to stir at 0° C. Isovaleryl chloride (0.14 ml, 1.0 mmol) was added to the solution dropwise. The reaction was allowed to stir for one hour. At which time was shown to be at completion by LC/MS. DI water was added to the reaction. The reaction was transferred to a separatory funnel, where the aqueous layer was extracted 3 times with DCM. The combined organic layers were washed with brine, saturated NaHCO3, dried with MgSO4, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (25M), eluting with a gradient of 1% to 10% MeOH in CH2Cl2, to provide N1-(2-cyclopentylethyl)-4-methyl-N3-(6-(3-methylbutanamido)pyridin-3-yl)isophthalamide as a white solid. MS (ESI, pos. ion) m/z: 451.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.CC[O:14]C(C)=O>>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2ncccc2c1
Reactant: CCOC(C)=O
Product: O=Cc1ccc2ncccc2c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
A mixture of SeO2 (10.89 g, 99 mmol) and 6-methylquinoline (12.87 g, 90 mmol) was heated to 150° C. and stirred for 16 h. Then it was cooled to room temperature and EtOAc (400 ml) was added. After filtration, the filtrate was concentrated to obtain the crude compound, which was purified by chromatography (silica gel, petroleum ether/EtOAc 5:1 to 2:1) to afford the title compound (2.87 g, yield 20%). LC-MS (ESI) m/z: 158 (M+1)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=1.Cl[CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]=1[CH3:29].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:13][O:14][C:15]1[CH2:20][CH2:19][CH:18]([CH2:23][C:24]2[N:25]=[CH:26][N:27]([C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:28]=2[CH3:29])[C:17](=[O:21])[CH:16]=1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC1=CC(=O)CCC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC1=CC(=O)C(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CC1
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
n-Butyllithium (1.58 M in hexane; 21 ml) was added at -78° under nitrogen to a stirred solution of diisopropylamine (4.6 ml) in dry THF (75 ml) and the solution was stirred at 0° for 30 min. The solution was cooled to -78° and added to a solution of 3-methoxy-2-cyclohexen-1 one (3.4 g) in dry THF (25 ml) at -78° under nitrogen with stirring. After stirring for 1 h at -78° and for 30 min. at 0° the solution was cooled to -78° and a solution of 4-(chloromethyl)-5-methyl-1 -(triphenylmethyl)-1H-imidazole (10 g) in dry THF (100 ml) was added dropwise with stirring under nitrogen. The solution was stirred at -78° for 3 h and at 0° for 30 min., treated with 8% aqueous sodium bicarbonate (400 ml) and extracted with ethyl acetate (2×300 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 13 g) which was purified by SPCC eluting with System A (967:30:3) to give the title compound (3.28 g), m.p. 145°-148°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:52]=[CH:51][C:8]([CH2:9][N:10]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([C:18]3[CH:19]=[C:20]([CH2:33][N:34]([CH2:39][CH2:40][OH:41])[C:35](=[O:38])[CH2:36]Cl)[CH:21]=[N:22][C:23]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=2)=[CH:7][CH:6]=1.O>C1COCC1>[CH3:3][O:4][C:5]1[CH:52]=[CH:51][C:8]([CH2:9][N:10]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([C:18]3[CH:19]=[C:20]([CH2:33][N:34]4[CH2:39][CH2:40][O:41][CH2:36][C:35]4=[O:38])[CH:21]=[N:22][C:23]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN(CCO)C(=O)CCl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOCC4=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Sodium hydride (60% in mineral oil) (0.014 g, 0.346 mmol) was added to a mixture of N-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinyl)methyl)-2-chloro-N-(2-hydroxyethyl)acetamide (0.110 g, 0.157 mmol) in 3 mL of THF at 0° C. The reaction mixture was allowed to warm up to ambient temperature. After 1 h, water was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinyl)methyl)-3-morpholinone (0.101 g, 0.152 mmol, 97% yield) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 11.66 (s, 1H); 8.71 (d, J=2.54 Hz, 1H); 8.23-8.27 (m, 1H); 8.20 (d, J=2.54 Hz, 1H); 7.89 (dd, J=8.80, 2.74 Hz, 1H); 7.15-7.24 (m, 4H); 6.80-6.90 (m, 4H); 6.70 (d, J=8.80 Hz, 1H); 4.86 (s, 2H); 4.81 (s, 2H); 4.55 (s, 2H); 4.10 (s, 2H); 3.92 (s, 3H); 3.81 (s, 3H); 3.78 (s, 3H); 3.74-3.77 (m, 2H); 3.23-3.28 (m, 2H); 2.57 (s, 3H). m/z (ESI, +ve ion) 663.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 96.4 %

Procedure:
A mixture of 3-(trifluoromethyl) benzaldehyde (25 g, 144 mmol), malonic acid (28.8 g, 277 mmol), anhydrous pyridine (100 ml) and piperidine (2 ml) was heated under reflux for 4 hours. The mixture was poured onto fresh ice (300 g) and concentrated hydrochloric acid (78 ml). The solid product was collected, dried and recrystallised (1:1 IMS/water) to give 30 g (96% of theory) of 3-(trifluoromethyl) cinnamic acid as off-white needles.