Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:36].[CH3:37][O:38][C:39](=[O:43])[C@@H:40]([CH3:42])O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:36][C@H:40]([CH3:42])[C:39]([O:38][CH3:37])=[O:43]
Reactant: Cc1c(N(Cc2ccc(Oc3ccc(Cl)c(O)c3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: COC(=O)[C@@H](C)O
Product: COC(=O)[C@@H](C)Oc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl

Procedure:
The product from Example 91F and methyl-(R)-lactate was processed as described in Example 62A to provide the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20](/[CH:22]=[CH:23]/[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH2:33][CH2:34][CH3:35])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH2:33][CH2:34][CH3:35])=[O:25])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: CCCOc1ccccc1C(=O)/C=C/c1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1
Agent: [Pd]
Solvent: CO
Product: CCCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(O)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.82 g quantity of (E)-3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)-2-propen-1-one obtained in Example 193 was dissolved in 50 ml of methanol. A 200 mg quantity of 5% palladium-carbon powder was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was then removed by filtration. The filtrate was diluted with 100 ml of methanol, and 500 mg of 10% palladium-carbon powder was added thereto. The mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The catalyst was removed by filtration, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the residue for crystallization to give 0.78 g of colorless powdery 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-propoxyphenyl)propan-1-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:16][CH2:17][CH3:18])[C:13]=1[O:14][CH3:15])[C:7]([O:9]C)=[O:8])[CH3:2].O.[OH-].[Na+].Cl>C(O)C>[CH2:17]([O:16][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]=1[O:14][CH3:15])[C:7]([OH:9])=[O:8])[CH3:18]
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C(=O)O)cc(OCC)c1OC
Temperature: 70 °C

Procedure:
63 g of methyl 3,5-diethoxy-4-methoxybenzoate prepared in Referential Example 2 was dissovled in 200 ml of ethanol and 80 ml of water and 44 g of caustic soda was added thereto. The mixture was heated at 70° C. for 2 hr while stirring, cooled, weakly acidified with dilute hydrochloric acid and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous magnesium sulfate, and the solvent was then distilled off to prepare 48 g of the crude product (white solid).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[CH2:23][CH2:24][CH3:25].[H-].[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[C:17]([CH2:23][CH2:24][CH3:25])[CH:18]=1)[CH3:34]
Reactant: CCCc1cc(O)ccc1OCCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(OCC(=O)OCC)ccc1OCCc1nc(-c2ccccc2)oc1C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A solution of 4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-3-propylphenol (0.37 g, 1.10 mmol) in dry DMF (4 mL) was cooled in an ice bath and treated with NaH (0.13 g, 3.3 mmol, 60% oil dispersion). After 10 min, ethyl bromoacetate (0.37 mL, 3.3 mmol) was added. The ice bath was removed, and the mixture was placed in an oil bath (T=85° C.). After 18 h, the reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between EtOAc (70 mL) and water (40 mL). The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by radial chromatography using 5% ethyl acetate in dichloromethane to give a white solid (0.34 g, 73%). 1H NMR (400 MHz, CDCl3), δ 7.97 (dd, J=7.8, 2.4 Hz, 2H), 7.41-7.39 (m, 3H), 6.77-6.73 (m, 2H), 6.61-6.63 (m, 1H, 4.54 (s, 1H), 4.28-4.24 (m, 2H), 2.96 (t, J=6.4 Hz, 2H), 2.50 (t, J=7.1 Hz, 2H), 2.37 (s, 3H), 1.51 (q, J=7.6 Hz, 2H), 1.31-1.29 (m, 5H), 0.84 (t, J=7.0 Hz, 3H); MS (FIA) m/e 424 (M+1).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[N:32][CH:31]=[C:30]([NH2:34])[N:29]=2)[CH2:24][CH2:23]1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:34][C:30]4[N:29]=[C:28]([N:25]5[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]5)[CH:33]=[N:32][CH:31]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CN1CCN(c2cncc(N)n2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Product: CN1CCN(c2cncc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)n2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (133 mg, 0.434 mmol) and 4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-ylamine (92.159 mg, 0.47689 mmol) in a manner analogous to Example 2d. Product isolated as an off-white foam (28.64 mg, 14.2%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.07 (s, 1H), 8.91 (d, J=6.6 Hz, 1H), 8.59 (s, 1H), 8.41 (d, J=8.5 Hz, 2H), 8.08 (d, J=8.3 Hz, 2H), 8.00 (d, J=7.6 Hz, 1H), 7.83 (s, 1H), 7.23 (t, J=14.5, 7.4 Hz, 1H), 3.32 (s, 3H), 3.56 (s, 4H), 2.40 (s, 4H), 2.23 (s, 3H). MS=465 (MH)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:13][C:12](=[O:14])[O:11][CH2:10][C:9]=2[CH:15]=1)(=[O:3])[CH3:2].S(Cl)([Cl:19])(=O)=O.CCOCC>C(O)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([Cl:19])[C:8]2[NH:13][C:12](=[O:14])[O:11][CH2:10][C:9]=2[CH:15]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)Oc1ccc2c(c1)COC(=O)N2
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)Oc1cc(Cl)c2c(c1)COC(=O)N2
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A quantity of 14.5 gm (0.07 mol) of 6-acetoxy-4H-3,1-benzoxazin-2-one (prepared from 6-hydroxy-4H-3,1-benzoxazin-2-one and acetic anhydride; m.p. 173°-175° C.) is dissolved in 150 ml of glacial acetic acid, mixed with 10.8 gm (6.5 ml=0.08 mol) of sulfuryl chloride, and stirred for 36 hours at ambient temperature. After addition of 30 ml of ether, the mixture is cooled to 0° C., and the precipitate is subjected to suction filtration, washed with ether, and dried.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]=2[NH:7][CH:6]=1)C.COS(OC)(=O)=O.C[O-].[Na+]>[N+](C(C)C)([O-])=O.CO>[N+:14]([C:13]([CH3:8])([CH3:12])[CH2:4][C:5]1[C:9]2[C:8](=[C:13]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:11][CH:10]=2)[NH:7][CH:6]=1)([O-:16])=[O:15]
Reactant: CN(C)Cc1c[nH]c2c([N+](=O)[O-])cccc12
Agent: C[O-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CO
Solvent: CC(C)[N+](=O)[O-]
Product: CC(C)(Cc1c[nH]c2c([N+](=O)[O-])cccc12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 131 %

Procedure:
The 7-nitrogramine salt (2.0 g, 5.8 mmol) is suspended in a mixture of 2-nitropropane (9.5 mL) and methanol (9.5 mL). Dimethylsulfate (1.09 mL, 11.5 mmol) is added dropwise via syringe, and the resulting yellow solution is stirred at room temperature for 5 minutes. Sodium methoxide (0.62 g, 11.5 mmol) is then added in one portion, and the mixture is stirred overnight at room temperature. The reaction is quenched by addition of saturated NH4Cl solution and ethyl acetate. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed with brine, and dried over Na2SO4 to give 1.0 g of 3-(2-nitro-2-methylpropyl)-7-nitroindole (69%).
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#N.[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:26]([NH2:28])[CH3:27])[CH:15]=[CH:16][C:17]=1[C:18]1[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=1.[F:29][C:30]([F:43])([F:42])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39].C(N(C(C)C)CC)(C)C>CO.ClCCl.CCCCCCC.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C@H:26]([NH:28][S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][C:30]([F:29])([F:42])[F:43])(=[O:40])=[O:39])[CH3:27])[CH:15]=[CH:16][C:17]=1[C:18]1[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: COc1cc(C(C)N)ccc1-c1cccnc1OC
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [NH4+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc([C@@H](C)NS(=O)(=O)c2ccccc2OC(F)(F)F)ccc1-c1cccnc1OC

Procedure:
A mixture of acetovanillone (0.332 g, 2.0 mmol), N-phenyl-bis(trifluoromethane-sulfonimide) (710 mg, 2.0 mmol), potassium carbonate (830 mg, 6.0 mmol) and tetrahydrofuran (3.0 ml) was heated to 120° C. for 6 min in a microwave oven. 2-Methoxypyridine-3-boronic acid (611 mg, 4 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 100 μmol), N-methylpyrrolidinone (1 ml) were then added and the mixture heated in the microwave at 120° C. for 10 min. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvent evaporated to give 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethanone in quantitative yield. Reductive amination with ammonium acetate (20 equivalents) in methanol (50 ml) containing sodium cyanoborohydride (1 equivalent) followed by aqueous work-up with saturated aqueous sodium bicarbonate and extraction into ethyl actetate gave, after solvent was evaporated 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethylamine. To 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethylamine was added 2-trifluoromethoxy-benzenesulfonyl chloride (1 equivalent) in dichloromethane, diisopropylethylamine (4 equivalents) and the mixture overnight. The racemic product was isolated by normal phase HPLC on silica gel eluting with heptane/ethyl acetate and the solvent evaporated to give a clear oily solid (72 mg). 1H NMR (400 MHz, CDCl3): δ 8.15 (d, 1H), 7.9 (d, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3-7.2 (m, 2H), 7.05 (d, 1H), 6.9 (m, 1H), 6.75-6.65 (m, 2H), 5.0 (d, 1H), 4.55 (m, 1H), 3.91 (s, 3H), 3.67 (s, 3H), 1.51 (d, 3H) ppm; MS (ESI) m/z: 483.3 [M+1]+. The racemate was resolved by chiral HPLC (CHIRALPAK-AS, eluting with 9:1 isohexane/ethanol) to give the title compound (11 mg) and its enantiomer (11) mg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[S:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1>[N+](C1C=CC=CC=1)([O-])=O>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][C:4]=2[N:10]=[C:14]2[CH2:15][CH2:16][S:11][CH2:12][C:13]=12
Reactant: O=C1CCSCC1
Reactant: Cc1ccc(C#N)c(N)c1
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc2c(N)c3c(nc2c1)CCSC3
Temperature: 50 °C
Yield: 61.2 %

Procedure:
A mixture of 4-methylanthranilonitrile (4.46 g) and freshly fused zinc chloride (6.8 g) in 20 ml of nitrobenzene was heated at 50° C. for 1 hour. To this was added tetrahydrothiopyran-4-one (5.1 g) and the mixture was heated to 130° C. for 1.5 hours. After cooling, the zinc complex was filtered, rinsed with ethyl ether and partitioned between 2-butanone (MEK) and NH4OH. The aqueous phase was extracted with MEK and the organics were washed with water and dried (saturated NaCl, MgSO4). This was concentrated to give 4.76 g of an off-white powder, m.p. 239°-245° C. d., which was recrystallized from ethyl acetate to give 2.95 g of an off-white powder, m.p. 243°-246° C. d.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:28][C:4]1[C:3]([NH:2][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][N:6]2[C:5]=1[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=1)=[C:9]([C:25]#[N:26])[CH:8]=[N:7]2
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: Cc1c(Nc2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (10.3 mg, 0.026 mmol), benzeneboronic acid (4.7 mg, 0.039 mmol), Cu(OAc)2 (0.039 mmol, 7 mg) and TEA (0.13 mmol, 13 mg) in dichloromethane (1 ml) were stirred at RT for 16 hrs. The reaction mixture was purified by silica gel flash chromatography to isolate 370 as a yellow film (1.4 mg, 15%). [M+H]+=432.1.
Reaction SMILES: N1CCCCC1.[N:7]([CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)=[N+:8]=[N-:9].[CH2:21]([C:24]#[N:25])[C:22]#[N:23]>C(O)C>[N:7]([CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:21]([C:24]#[N:25])[C:22]#[N:23])=[CH:15][CH:14]=1)=[N+:8]=[N-:9]
Reactant: [N-]=[N+]=NCCOc1ccc(C=O)cc1
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1ccc(OCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
47 μl (0.47 mmol) of piperidine are added dropwise to a solution of 3.02 g (15.79 mmol) of the compound from Example 36A and 1.09 g (16.42 mmol) of malonodinitrile in 100 ml of ethanol, and the reaction mixture is stirred at +78° C. for 3.5 h. During this time, the colour of the solution changes to orange-red. After cooling to RT, the solution is allowed to stand without stirring for 20 h. A colourless precipitate is formed. Using a rotary evaporator, the crude suspension is concentrated to half of its original volume, and the crystallization is completed with cooling in an ice bath. The resulting precipitate is filtered off with suction and washed twice with in each case 20 ml of ethanol and twice with in each case 20 ml of methyl tert-butyl ether.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:39])(=[O:38])[NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[CH:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:39])(=[O:38])[N:26]([C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1)[CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[CH:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)c(Cl)c1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(C(F)(F)F)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and ethyl 3-chloro-4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 8).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH2:23])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1.[CH3:28][C:29]1[O:33][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][C:30]=1[C:40](O)=[O:41]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH:23][C:40]([C:30]4[N:31]=[C:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[O:33][C:29]=4[CH3:28])=[O:41])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1
Reactant: COCCN1CCN(Cc2cnc3sc(-c4ccccc4N)nc3c2)CC1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)O
Product: COCCN1CCN(Cc2cnc3sc(-c4ccccc4NC(=O)c4nc(-c5ccccc5)oc4C)nc3c2)CC1

Procedure:
The title compound was prepared according to amide synthesis general method B, utilizing 2-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 5-methyl-2-phenyloxazole-4-carboxylic acid (1.5 eq). The product precipitated from the reaction mixture, and was filtered and chased with methanol. The product was purified by prep HPLC. MS Calcd for C31H32N6O3S: 568.23. Found (M+H)+ m/z=569.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])[C:12](O)=[O:13].[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21])[CH2:12][OH:13]
Reactant: COc1cc(C(=O)O)ccc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Lithium aluminum hydride (4.53 g) was added by small portions to an ice-cooled solution of 3-methoxy-4-(trifluoromethyl)benzoic acid (23.3 g) in tetrahydrofuran (400 ml) under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. After being cooled with ice, 2N sodium hydroxide (2 ml) was added to the mixture under nitrogen atmosphere. The resulting precipitates were filtered off and washed with tetrahydrofuran, and the filtrate and washings were combined and evaporated under reduced pressure to give a crude oil. The oil was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (40:1) to give 3-methoxy-4-(trifluoromethyl)benzyl alcohol (20 g) as a colorless oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[O:4][CH2:5][Cl:6]
Reactant: COCCOCCOCCOCCOCCOCCO
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOCCOCCOCCOCCOCCOC(=O)OCCl

Procedure:
In a manner similar to the method described in Example 3, chloromethyl chloroformate (Aldrich) was reacted with 2,5,8,11,14,17-hexaoxanonadecan-19-ol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give chloromethyl 2,5,8,11,14,17-hexaoxanonadecan-19-yl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), chiral-3-oxo-2,4,7,10,13-pentaoxatetradecyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C46H58Cl2F2N3O13: [(M+H)+]: 968, found: 968.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17](=O)[CH3:18]>CC(C)=O.ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:16]=[C:17]([CH3:18])[C:4]=2[CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Clc1ccccc1
Product: Cc1csc2ccc(Br)cc12
Yield: 52 %

Procedure:
A mixture of 4-bromothiophenol (3.9 g, 20 mmol), K2CO3 (5.5 g, 40 mmol) and chloroacetone (6.6 mL, 82 mmol) in acetone (50 mL) was heated at reflux over night. The reaction mixture was filtered and the solvent was evaporated giving 5.0 g crude product. The intermediate thioether was dissolved in chlorobenzene (50 mL) and polyphosphoric acid (PPA, 2.5 g) was added (Plé et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). After reflux for 24 h, the solvent was decanted and the PPA residue was treated with CH2Cl2. The combined organic extracts were washed with water and dried. Evaporation of the solvents afforded the crude product which was purified on silica (heptane as eluent) to give the title compound (2.36 g, 50% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 2.41 (d, J=1.20 Hz, 3 H) 7.11 (qd, J=1.20, 0.54 Hz, 1 H) 7.44 (ddd, J=8.53, 1.90, 0.54 Hz, 1 H) 7.70 (dd, J=8.53, 0.54 Hz, 1 H) 7.85 (dd, J=1.90, 0.54 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15]C)=[O:14].[OH-].[Na+:18]>>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O-:15])=[O:14].[Na+:18]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(-c2ccccc2)sc1C(=O)[O-]

Procedure:
A mixture of methyl 3-amino-5-phenylthiophene-2-carboxylate (9.6 g) and 0.9M aqueous sodium hydroxide solution (50 ml) was stirred and boiled under reflux for 4 hours to give a solution of sodium 3-amino-5-phenylthiophene-2-carboxylate.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1)=[O:7])C>O.O1CCOCC1.[OH-].[Na+]>[F:19][C:17]([F:18])([F:20])[C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][C:11]=2[CH:13]=1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2o1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (78 mg, 3.7 mmol) in water (6 ml) was added to a solution of 5-(trifluoromethyl)benzofuran-2-carboxylic acid ethyl ester (705 mg, 2.73 mmol) in 1,4-dioxane (6 ml). 1,4-Dioxane was added until a clear solution was obtained. The reaction mixture was stirred for 16 h at room temperature. It was diluted with an 1 N aqueous solution of sodium hydroxide and washed with tert-butyl methyl ether (2×30 ml). The aqueous solution was acidified with a 10% aqueous solution of sodium hydrogen sulphate until pH 3 was obtained. It was extracted with ethyl acetate (3×40 ml). The combined ethyl acetate layers were dried over magnesium sulphate. The solvent was removed in vacuo to give crude 5-(trifluoromethyl)benzofuran-2-carboxylic acid which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[S:5][CH:6]=1.[C:24]([NH:28][S:29]([C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:36]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[S:33][C:34]([C:2]2[N:3]=[C:4]([C:7]3[CH:12]=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[CH:10]=[C:9]([CH3:23])[N:8]=3)[S:5][CH:6]=2)=[CH:35][CH:36]=1)(=[O:30])=[O:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(Br)cs2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)cs2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-thiazol-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.80) (0.150 g, 0.375 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.143 g, 0.413 mmol) according to the general procedure VI. Obtained as a white solid (0.130 g, 64%). MS (ISP) 538.3 [(M+H)+]; mp 171° C.