Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([CH3:25])[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:26][CH2:27][CH2:28][S:29][CH3:30])(=[O:5])[CH2:2][CH2:3][CH3:4].C([O-])(O)=[O:32].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([CH3:24])[CH3:25])=[CH:13][CH:12]=[CH:11][C:10]=2[O:26][CH2:27][CH2:28][S:29]([CH3:30])=[O:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])O
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1C(C)C
Reaction time: 1 h
Yield: 57 %

Procedure:
3-Butyryl-4-(2-isopropylphenylamino)-8-(2-methylthioethoxy)quinoline (0.22 g, 0.52 mmol) was dissolved in methylene chloride (15 ml) and added to a mixture of 0.093g NaHCO3 in 15 ml H2O. A solution of 71% m-CPBA (0.12 g, 0.50 mmol) in 7 ml methylene chloride was added dropwise at 4° C. The solution was stirred for one hour at this temperature. The reaction mixture was washed with a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. Chromatography with methylene chloride:methanol 10:1 as eluent gave 0.130 g (57%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][C:10](Cl)=[O:11]>N1C=CC=CC=1.C(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccc1
Yield: 91.1 %

Procedure:
To a solution of aniline (1 mL, 11 mmol) and CH2Cl2 (150 mL), pyridine (886 mL, 1 mmol) was added. Then 2-chloroacetyl chloride (872 mL, 11 mmol) was added dropwise over 10 min. After the addition was complete, the mixture was reacted at room temperature for 2 hours. The reaction was then quenched with water (100 mL), the layers were separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layer was washed water, brine, and dried over Na2SO4. The solvent was evaporated to give a colorless solid (1.7 g, 91% yield). The crude product was directly used for next step. 1H NMR (CDCl3, 400 MHz) δ 8.25 (br s., 1H), 7.57 (d, J=7.6 Hz, 2H), 7.39 (t, J=7.6 Hz, 2H), 7.20 (t, J=7.4 Hz, 1H), 4.22 (s, 2H).
Reaction SMILES: [Br:1][CH:2]=[CH:3][C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].P(Br)(Br)Br.FC(F)(C(F)(F)F)CCO>>[Br:1][CH2:2][CH2:3][C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C(F)(F)C=CBr
Agent: BrP(Br)Br
Agent: OCCC(F)(F)C(F)(F)F
Product: FC(F)(F)C(F)(F)CCBr

Procedure:
1-Bromo-3,3,4,4,4-pentafluoro-1-butene may be prepared by a three-step sequence beginning with reaction of phosphorous tribromide with 3,3,4,4,4-pentafluoro-1-butanol to give 4-bromo-1,1,1,2,2-pentafluorobutane. Thermal bromination of 4-bromo-1,1,1,2,2-pentafluorobutane at 350-400° C. gives 4,4-dibromo-1,1,1,2,2-pentafluorobutane, which may in turn be heated with powdered potassium hydroxide to give the desired bromobutene.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6]([CH2:9][CH:10]1[CH2:13][N:12]([C:14](OC(C)(C)C)=O)[CH2:11]1)(=[O:8])=[O:7].C(O)(C(F)(F)F)=O.[BH3-]C#N.[Na+].[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34](C=O)=[N:33]1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6]([CH2:9][CH:10]1[CH2:11][N:12]([CH2:14][C:34]2[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[S:32][N:33]=2)[CH2:13]1)(=[O:7])=[O:8]
Reactant: O=Cc1nsc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC(CS(=O)(=O)c2nccs2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(CC1CN(Cc2nsc3ccccc23)C1)c1nccs1
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
tert-Butyl 3-[(1,3-thiazol-2-ylsulfonyl)methyl]azetidine-1-carboxylate (51 mg, 0.16 mmol) was dissolved in DCM (0.5 mL) and TFA (0.5 mL) was added. The resulting mixture was stirred for 30 min. then concentrated in vacuo. The residual oil was taken up in MeOH (2 mL), then NaCNBH3 (16.2 mg, 0.26 mmol) and 1,2-benzisothiazole-3-carbaldehyde (28.6 mg, 0.18 mmol) [prepared by the method of T. Hasegawa, Y. Akiyama, T. Imai, E. Sato, Y. Yamamoto, J. Tanaka, H. Nagaso, K. Fuji, K. Murase, M. Shiiyama, WO 98/08816] were added. The mixture was stirred overnight then partitioned between 0.5 N NaOH (20 mL) and EtOAc (20 mL). The aqueous phase was washed with EtOAc (20 mL) and the organic layers were combined, washed with saturated brine (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified using column chromatography, on silica gel, eluting with 50–60% EtOAc in DCM to give the title compound as a colourless oil (19 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 2.96–3.06 (1H, m), 3.12 (2H, m), 3.57 (2H, t, J=7.6 Hz), 3.72 (2H, d, J=7.3 Hz), 4.04 (2H, s), 7.41–7.45 (1H, m), 7.50–7.54 (1H, m), 7.74 (1H, d, J=3.1 Hz), 7.91 (1H, d, J=8.2 Hz), 8.05 (1H, d, J=3.0 Hz), 8.10 (1H, d, J=8.1 Hz). m/z (ES+) 366 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([OH:25])[CH2:22][C@H:21]1[C:26](=[O:30])[NH:27][CH2:28][CH3:29])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:22][C@H:21]1[C:26](=[O:30])[NH:27][CH2:28][CH3:29])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCNC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
13.81 ml of triethylamine and subsequently 7.65 ml of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 23.20 g of (2S, 4S)-1-t-butoxycarbonyl-2-ethylcarbamoyl-4-hydroxypyrrolidine dissolved in 250 ml of dry tetrahydrofuran, and then the mixture was stirred at 0° to 5° C. for 30 minutes. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 26.54 g of the title compound as colorless crystals, melting at 138°-140° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:16][C:1]1([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(C2CCCCC2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C2(Br)CCCCC2)cc1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 58.9 %

Procedure:
4-Cyclohexylnitrobenzene (22.6 g, 0.11 mol) and N-bromosuccinimide (21.6 g, 0.12 mol) were suspended in tetrachloromethane (200 mL) and a catalytic amount of dibenzoylperoxide was added. The reaction mixture was stirred at 80° C. for 4.5 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (400 mL) and washed with water (100 mL). The aqueous phase was extracted with ethyl acetate (200 mL) and the combined organic phases were washed with water (3×150 mL), dried over MgSO4 and concentrated in vacuo. The residue was crystallised from ethyl acetate and heptane to give 18.4 g of 1-(bromocyclohexyl)-4-nitrobenzene.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:16])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[CH3:15])=O)(=[O:3])[CH3:2].CC([O-])=O.[K+].Cl.[O:23]([NH2:25])[CH3:24]>CCO.O>[C:1]([O:4][CH:5]([CH3:16])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[CH3:15])=[N:25][O:23][CH3:24])(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OC(C)C(=O)c1ccc(Br)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CON=C(c1ccc(Br)cc1C)C(C)OC(C)=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a mixture of 2-(4-bromo-2-methylphenyl)-1-methyl-2-oxoethyl acetate (5.0 g, 17.5 mmol) and KOAc (2.75 g, 28.0 mmol) in EtOH (90 mL) was added methoxylamine hydrochloride (2.34 g, 28.0 mmol) and the resulting milky suspension was stirred at 70° C. for 4 h. An additional 0.5 equivalents of KOAc and methoxylamine hydrochloride were added and the reaction mixture was stirred at 70° C. for 8 h. The reaction mixture was diluted with water, and the EtOH was removed under reduced pressure. The aqueous residue was extracted with diethyl ether (2×75 mL), and the ether extracts were combined, washed with aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give 2-(4-bromo-2-methylphenyl)-2-(methoxyimino)-1-methylethyl acetate (5.0 g, 91%) as a racemic mixture of the E- and Z-methoxime isomers as a gold oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][NH:23][CH:24]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[F:25][CH2:26][CH:27]1[CH2:29][O:28]1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][N:23]([CH2:29][CH:27]([OH:28])[CH2:26][F:25])[CH:24]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: O=C(NCC1(O)CCCCCC1)c1cc(-c2c[nH]cn2)ccc1Cl
Reactant: FCC1CO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCC1(O)CCCCCC1)c1cc(-c2cn(CC(O)CF)cn2)ccc1Cl
Yield: 87.6 %

Procedure:
A solution of 2-chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(1H-imidazol-4-yl)-benzamide (5 mg, 0.014 mmol) and 2-fluoromethyl-oxirane (0.06 mL, 0.086 mmol) in N,N-dimethylformamide (0.2 mL) was heated at 65° C. in a sealed tube for 20 h. The mixture was diluted with ethyl acetate and washed with water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (5.2 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>C(OCC)(=O)C.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>[CH3:27][Si:28]([C:31]#[C:32][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:30])[CH3:29]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCOCCc1cccc(C#C[Si](C)(C)C)c1
Temperature: 100 °C

Procedure:
tert-Butyl 3-(3-bromophenethoxy)propanoate (1.5 g), triethylamine (6 mL), trimethylsilylacetylene (1.92 mL), Pd(Ph3P)4 (0.26 g) and copper (I) iodide (0.04 g) was sealed into a microwave tube. The reaction was heated to 100° C. over a period of 5 min in the microwave reactor. The reaction mixture was diluted with ethyl acetate and filtered through a pad of Celite and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-10% ethyl acetate in isohexane to afford tert-butyl 3-(3-((trimethylsilyl)ethynyl)phenethoxy)propanoate as a yellow liquid (1.56 g). 1H NMR (300 MHz, CDCl3) δ 7.41-7.12 (m, 4H), 3.67 (t, J=6.3 Hz, 2H), 3.63 (t, J=7.1 Hz, 2H), 2.83 (t, J=7.1 Hz, 2H), 2.47 (t, J=6.5 Hz, 2H), 1.44 (s, 9H), 0.24 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[CH3:28][O:29][CH2:30][C:31]([CH3:35])([OH:34])[C:32]#[CH:33].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[C:3]([F:27])[C:2]([C:33]#[C:32][C:31]([OH:34])([CH3:35])[CH2:30][O:29][CH3:28])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: C#CC(C)(O)COC
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1cc(F)c(Br)cc1-2
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COCC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1-c1nc(C2CC2)n[nH]1
Yield: 26.3 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-10-(3-hydroxy-4-methoxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 1-methoxy-2-methyl-but-3-yn-2-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 17 mg of the titled compound (26.3% yield). M+1=467.2. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J=8.3 Hz, 1H), 8.38 (br s, 1H), 7.79 (br s, 1H), 7.05 (d, J=10.4 Hz, 1H), 5.66 (s, 1H), 5.00-4.81 (m, 2H), 4.65-4.52 (m, 2H), 3.47-3.34 (m, 2H), 3.37 (s, 3H), 2.13-2.04 (m, 1H), 1.45 (s, 3H), 1.03-0.95 (m, 2H), 0.93-0.87 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: ClCc1cccnc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(ccn2Cc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
5-Nitroindole (0.49, 3 mmol) was treated with sodium hydride (0.198 g, 6.6 mmol) in dry dimethylformamide (20 ml). After 15 min at room temperature, 3-picolyl chloride hydrochloride (0.49 g, 3 mmol) was added and the mixture was stirred at room temperature for 24 h, then poured into water. The precipitate was filtered off, washed with water and dried to give the title compound (0.67 g, 88%), m.p. 131-4° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[F:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[F:16]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(F)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(F)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.5 %

Procedure:
To a solution of 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (53 mg, 0.203 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (78 mg, 0.203 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.18 ml, 1.02 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (95 mg, 0.203 mmol) in one portion. The solution stirred at 25° C. over 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 40% EtOAc in hexanes) yielding 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (106 mg, 0.129 mmol, 63.5% yield) as a clear oil; LCMS (ES) m/e 591, 593 (M, M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: Cc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1Cc1ccccc1

Procedure:
To a flask were added 2.5 g 2-methylbenzimidazole, 3.9 g potassium carbonate, 60 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 3.6 g Benzyl chloride were added and the mixture was heated to 60 C for 16 hours. The reaction was quenched with 80 ml water and cooled to 22 C. The product was extracted twice with 50 ml ethyl acetate and washed with water. Following removal of solvent, the product was dissolved in 100 ml hexane and washed with two portions of water. After drying the hexane layer over sodium sulfate, the mixture was filtered and stripped down to an orange oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:23][NH:24][C:25]([C:26]1[N:27]=[CH:28][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)=[CH:30][CH:31]=1)=[O:41]
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Product: CNC(=O)c1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)C)CC4)nc3c2)cn1
Yield: 5.8 %

Procedure:
Following the General Procedure-1, the titled compound (20 mg) was prepared from Intermediate 13 (300 mg, 0.82 mmol) and N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (256 mg, 0.98 mmol) as a brown solid. M.P.: 158-161° C. MS (m/z): 423.5 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7].[OH-].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>CS(C)=O.O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][O:9][CH2:17][CH:19]1[O:21][CH2:20]1)=[NH:7]
Reactant: ClCC1CO1
Reactant: NC(=NO)c1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N=C(NOCC1CO1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
50 g (0.245 mol) of m-trifluoromethyl-benzamidoxime and 33.7 g (0.6 mol) of potassium hydroxide was dissolved in a mixture of dimethyl sulphoxide and 170 ml of water, and the mixture was cooled to 0° C. 48 ml (0.6 mol) of epichlorohydrine was added, and the reaction mixture was stirred at 0° C. for 5 hours, then kept in a refrigerator overnight. Next day 250 ml of water was added, and the mixture was extracted with ethyl acetate (4×250 ml). The combined organic phases were washed with water, dried, treated with charcoal and evaporated to dryness, to yield m-trifluoromethyl-N-(2,3-epoxypropoxy)-benzamidine, as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]([CH3:10])[CH2:5][NH:6][CH2:7][CH:8]=[CH2:9].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:11])[CH:4]([CH3:10])[CH2:5][N:6]([CH2:7][CH:8]=[CH2:9])[C:17]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=[C:13]([Cl:12])[N:18]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: C=CCNCC(C)C(=O)OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCN(CC(C)C(=O)OC)c1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 81 %

Procedure:
To a mixture of 1.71 g (0.010 mole) of (rac)-2-methyl-3-(2-propenylamino)-propanoic acid methyl ester, 1.94 g (0.010 mole) of 2,4-dichloro-5-nitro-pyrimidine, 50 mL of ethyl acetate and 25 mL of water was added 3.0 g (0.030 mole) of potassium bicarbonate. The mixture was stirred for 3 hours, and then diluted with 50 mL of ethyl acetate and 50 mL of water. The aqueous layer was extracted with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (100:0-97.5:2.5) to give 2.55 g of (rac)-3-[allyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-2-methyl-propanoic acid methyl ester (IV-65) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=2)=[C:6]([C:16](=[O:18])[CH3:17])[CH:5]=[C:4]([Cl:19])[CH:3]=1.[CH2:20]([O:22][CH:23]([N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1)[CH3:24])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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:19][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[N:26][N:25]([CH:23]([O:22][CH2:20][CH3:21])[CH3:24])[CH:29]=2)[C:7]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=2)=[C:6]([C:16](=[O:18])[CH3:17])[CH:5]=1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)c1cc(Cl)cc(Br)c1-c1cc(F)cc(F)c1
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
Product: CCOC(C)n1cc(-c2cc(Cl)cc(C(C)=O)c2-c2cc(F)cc(F)c2)cn1
Temperature: 80 °C
Yield: 53.9 %

Procedure:
A solution of 1-(6-bromo-4-chloro-3′,5′-difluorobiphenyl-2-yl)ethanone (300 mg, 0.87 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (250 mg, 0.96 mmol), and sodium carbonate (280 mg, 2.6 mmol) in 1,4-dioxane (3.0 mL, 38 mmol) was degassed with nitrogen 5 minutes, treated with tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol) degassed with additional nitrogen for 5 mins, and heated at 80° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (190 mg, 54%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[Cl:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35](O)=[O:36].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:35]([C:30]2[C:31]3[C:26](=[C:25]([Cl:24])[CH:34]=[CH:33][CH:32]=3)[CH:27]=[CH:28][CH:29]=2)=[O:36])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)Oc1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)(C)Oc1ccc(CC(NC(=O)c2cccc3c(Cl)cccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol (300 mg, 0.90 mmol) in acetonitrile (20 ml) were added 5-chloronaphthalenecarboxylic acid (186 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (258 mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (136 mg, 29%).