Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([OH:25])([CH3:24])[CH3:23])[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Br:36]N1C(=O)CCC1=O>CC#N.CCOC(C)=O>[Br:36][C:21]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)=[CH:12][CH:13]=2)[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])=[N:19][C:20]=1[C:22]([OH:25])([CH3:24])[CH3:23]
Reactant: CC(C)(O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(O)c1nc(-c2ccccc2C(F)(F)F)n(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c1Br
Reaction time: 2 h
Yield: 86291.9 %

Procedure:
To a solution of 2-[1-(3′-methanesulfonyl-biphenyl-4-yl)-2-(2-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-propan-2-ol (100 mg, 0.20 mmol) in MeCN (2 mL, anhyd) was added N-bromosuccinimide (45 mg, 0.25 mmol). After 2 h, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, water (3×10 mL) and brine, then dried (Na2SO4) and concentrated. The residue was purified by chromatography (silica), eluting with EtOAc/hexanes (65:40 to 95:5) to yield the title compound (100 g, 86%) as a white solid. 1H-NMR (CD2Cl2): δ 8.10 (1H, m), 7.92 (1H, m), 7.86 (1H, m), 7.60-7.74 (4H, m), 7.47 (2H, m), 7.25-7.31 (3H, m), 3.56 (1H, s), 3.06 (3H, s), 1.66 (6H, s); MS (ES): 579, 581 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13](=O)[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH2:17]([NH2:19])[CH3:18].C([BH3-])#N.[Na+].Cl>CO>[CH2:17]([NH:19][CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: CCN
Reactant: CC(=O)CCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNC(C)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.9 %

Procedure:
A 300 ml round bottom flask fitted with a calcium sulfate drying tube was charged with 6.681 g (0.0322 mol) of 5-(4-nitrophenyl)-2-pentanone in 100 ml of methanol. This mixture was charged with 13.2 g (0.161 mol) of ethylamine hydrochloride and 2.03 g (0.0322 mol) of sodium cyanoborohydride. The resulting suspension was stirred at room temperature over the weekend (about 72 hours) and acidified with concentrated hydrochloric acid. The volatiles were evaporated under reduced pressure and 300 ml of water was added to the residue. The mixture was extracted twice with diethyl ether and the organic phase was washed with water and a saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. This material was discarded. The aqueous phase was basified with 5N sodium hydroxide and extracted three times with diethyl ether. The organic extracts were combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 6.838 g of N-ethyl-α-methyl-4-nitrobenzenebutanamine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH3:38])[C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=1.C[Si](Cl)(C)C>C(O)CCC>[C:11]([C:10]1[C:5]2[C:4]([NH:23][CH:24]3[CH2:25][CH2:26]3)=[N:3][C:2]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([N:34]([CH3:38])[C:35](=[O:37])[CH3:36])=[CH:32][CH:33]=3)=[N:7][C:6]=2[NH:8][CH:9]=1)#[N:12]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NC3CC3)c3c(C#N)c[nH]c3n2)cc1
Temperature: 135 °C
Reaction time: 20 h
Yield: 32.6 %

Procedure:
A mixture of 2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (165 mg, 0.425 mmol), N-(4-aminophenyl)-N-methylacetamide (107 mg, 0.652 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (50 mg). MS 362.3 (M+H); UV 202.8, 254.0, 280.4 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:26])[CH:3]=1.Cl.[NH2:28][OH:29].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:28][OH:29])=[C:4]([CH3:26])[CH:3]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(O)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(C[C@@H](c2ccc(O)cc2)c2ccc(Cl)cc2C)=NO)ccn1

Procedure:
In analogy to example 132, step 6, from (S)-3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow foam, MS (ESI+): m/z=381.2 ([M+H]+).
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[O:17]=[C:11]([CH2:9][C:8](=[O:10])[C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccncc1
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)c1ccncc1

Procedure:
The title compound was prepared in the same manner as intermediate 29 using sodium metal (0.466 g, 20.26 mmol), 1-(4-pyridinyl)ethanone (1 g, 6.66 mmol), and diethyl ethanedioate (2.388 mL, 17.62 mmol). The crude product was purified using column chromatography (0 to 100% EtOAc/hexanes) to give 0.95 g of product (24%). LCMS E-S (M+H)=222.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37-1.55 (m, 3 H), 4.43 (q, J=7.07 Hz, 2 H), 7.06-7.16 (m, 1 H), 7.72-7.92 (m, 2 H), 8.82-8.94 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:27]=O)=[CH:24][C:25]=1[CH3:26])=[O:20])[CH3:13]>>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:27]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[CH:24][C:25]=1[CH3:26])=[O:20])[CH3:30]
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)cc1C
Yield: 15 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (106 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 35 mg (15%) of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13].O>C(O)CCC>[I:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[C:4]([NH2:5])=[N:12][NH:13]2
Reactant: N#Cc1c(F)cccc1I
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2cccc(I)c12
Temperature: 107.5 °C

Procedure:
A mixture of 2-fluoro-6-iodobenzonitrile (2 g, 8.1 mmol) and hydrazine hydrate (4 mL) in n-butanol (40 mL) was heated to 105-110° C. for 5 hours, cooled to room temperature, poured into water, and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide 1.88 g of the desired product. Rf=0.25 (5% methanol/dichloromethane).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2].Cl[C:23]([O:25][CH3:26])=[O:24].C(OC(=O)C)(=O)C.C(NC1C=C2C(=CC=1C1C=NN(C3CC3)C=1)N(C(OC(C)C)=O)C[C@H](C)N2C(=O)C)(=O)C>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:23]([O:25][CH3:26])=[O:24])[CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(N)ccc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: COC(=O)Cl
Agent: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Nc1ccc2c(c1)N(C(C)=O)[C@@H](C)CN2C(=O)OC(C)C

Procedure:
Isopropyl (S)-4-acetyl-6-((methoxycarbonyl)amino)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate and methyl chloroformate (instead of acetic anhydride) according to the procedure described above for isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 235). MS (ESI, pos. ion) m/z 372 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]([OH:23])[CH3:22])=[N:6][CH:7]=1.[C:24]([C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)([O:26][CH3:27])=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]([O:23][C:31]2[CH:32]=[CH:33][C:28]([C:24]([O:26][CH3:27])=[O:25])=[CH:29][CH:30]=2)[CH3:22])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(O)c1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Product: COC(=O)c1ccc(OC(C)c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1

Procedure:
Prepared from 1-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}ethanol (INTERMEDIATE B6.1) and 4-carbomethoxyphenol using a similar procedure as described in the preparation of example B2.1. MS: M+H=485.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][C:10]=1[CH2:16][C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CS(O)(=O)=O>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[CH:11][C:10]=1[CH2:16][C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1ccccc1
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: NC(=O)Cc1cnc(Nc2ccccc2)cc1NCc1ccccc1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To 25 mg of 4-(benzylamino)-6-chloropyridine-3-carboxyamide suspended in 0.2 mL of diphenylether, 18 mg of aniline and 9 mg of methanesulfonic acid were added and stirred at 180° C. for 30 minutes. After cooling, the reaction mixture was dissolved in chloroform, washed with saturated aqueous sodium bicarbonate, and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (chloroform:methanol=40:1-10:1) to obtain 30 mg (99%) of the title compound as a slight yellow crystalline powder.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.[O:8]([CH2:15][C:16]1[O:17][C:18]2[CH2:19][NH:20][CH2:21][CH2:22][C:23]=2[N:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1.CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:1]1([CH2:4][C:5]([N:20]2[CH2:21][CH2:22][C:23]3[N:24]=[C:16]([CH2:15][O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[O:17][C:18]=3[CH2:19]2)=[O:7])[CH2:2][CH2:3]1
Reactant: c1ccc(OCc2nc3c(o2)CNCC3)cc1
Reactant: O=C(O)CC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CC1CC1)N1CCc2nc(COc3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.6 %

Procedure:
Cyclopropylacetic acid (0.019 mL, 0.25 mmol) was added portionwise to a stirred solution of 4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (0.047 g, 0.21 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.078 g, 0.21 mmol), and triethylamine (0.043 mL, 0.31 mmol) in a mixture of THF (0.5 mL) and DMF (0.5 mL). The reaction mixture was stirred at room temperature for 15 hours and diluted with a saturated solution of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-(cyclopropylacetyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (0.043 g, 67% yield) as an oil. C18H20N2O3. (mixture of rotamers 70:30) 1H NMR (400 MHz, CDCl3) δ ppm 0.10-0.27 (m, 2 H), 0.50-0.66 (m, 2 H), 0.98-1.16 (m, 1 H), 2.33 (d, J=6.7 Hz, 0.6 H), 2.38 (d, J=6.7 Hz, 1.4 H), 2.59-2.82 (m, 2 H), 3.72 (t, J=5.7 Hz, 1.4 H), 3.92 (t, J=5.7 Hz, 0.6 H), 4.52 (br. s, 0.6 H), 4.71 (br. s, 1.4 H), 5.11 (s, 1.4 H), 5.12 (s, 0.6 H), 6.81-7.01 (m, 1 H), 7.02 (d, J=7.9 Hz, 2 H), 7.27-7.46 (m, 2 H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][Mg]Br>C1COCC1>[C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:26])[F:27])([OH:8])[CH3:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (Example 1, 0.260 g, 0.688 mmol) was taken into THF (5 mL) and cooled to 0° C. Next, methylmagnesium bromide (0.45 mL of 3.0 M solution in Ether, 1.35 mmol) was added and the reaction was allowed to stir overnight allowing to warm to room temperature. TLC indicated the starting material was still present, therefore additional methylmagnesium bromide was added and the reaction was heated at 50° C. overnight. The reaction was allowed to cool and was quenched with saturated NH4Cl and extracted with CH2Cl2 dried over sodium sulfate and concentrated. The product was purified via column chromatography using 10% ethyl acetate in hexane as the eluent to afford 0.176 g (64.8%) of desired product. MS (ESI) m/z 394 ([M+H]+); Anal. Calcd. for C24H18F3NO 0.5H2O: C, 71.63; H, 4.76; N, 3.48. Found: C, 71.45; H, 4.66; N, 3.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([CH2:18][N:19]2C(=O)C4C(=CC=CC=4)C2=O)[N:12]=[C:11]3[N:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH3:31])=[CH:4][CH:3]=1.BrC1C=C2C(=CC=1)N=C(CN1C(=O)C3C(=CC=CC=3)C1=O)N=C2N(C1C=CC(OC)=CC=1)C>>[NH2:19][CH2:18][C:13]1[N:12]=[C:11]([N:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH3:31])[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)[N:14]=1
Reactant: COc1ccc(N(C)c2nc(CN3C(=O)c4ccccc4C3=O)nc3ccc(-c4ccc(Cl)cc4)cc23)cc1
Agent: COc1ccc(N(C)c2nc(CN3C(=O)c4ccccc4C3=O)nc3ccc(Br)cc23)cc1
Product: COc1ccc(N(C)c2nc(CN)nc3ccc(-c4ccc(Cl)cc4)cc23)cc1

Procedure:
2-{6-(4-chloro-phenyl)-4-[(4-methoxy-phenyl)-methyl-amino]-quinazoline-2-yl-methyl}-isoindole-1,3-dione: The title compound was prepared from 2-{6-bromo-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione similar to Example 243. LC-MS (ESI+; 501 ([M+H]+)).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:34]1[C:43]2[C:38](=[C:39]([O:44][CH3:45])[CH:40]=[CH:41][CH:42]=2)[N:37]=[CH:36][CH:35]=1>C(O)(C)C>[CH3:45][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:38]=1[N:37]=[CH:36][CH:35]=[C:34]2[N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:2][CH2:3]1
Reactant: COc1cccc2c(Cl)ccnc12
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCN1CCN(c2ccnc3c(OC)cccc23)CC1)C1CCc2ccc(O)cc2C1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a mixture of 9a (0.6 g, 1.89 mmol) and diisopropylethylamine (0.4 mL, 2.08 mmol, 1.1 equiv) in 15 mL isopropanol was added 4-chloro-8-methoxyquinoline (17) (0.366 g, 1.89 mmol, 1 equiv). The mixture was refluxed with stirring for overnight. It was then evaporated and concentrate was dissolved in CH2Cl2 (50 mL) and the solution obtained was washed with 5% NaHCO3 (3×50 mL), brine (2×50 mL), and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was purified through column chromatography using 20% methanol in ethyl acetate to give 18a as white wax (0.66 g, 73% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.93-0.95 (t, 3H, 4 Hz), 1.75 (m, 3H), 2.11-2.21 (m, 2H), 2.69-3.07 (m, 13H), 3.23 (s, 4H), 3.47 (s, 1H), 4.02 (s, 3H), 6.60 (s, 1H), 6.66-6.68 (d, 1H, J=8 Hz), 6.82-6.84 (t, 2H, J=4 Hz), 6.98-7.00 (d, 1H, J=8 Hz), 7.36-7.42 (t, 1H, J=12 Hz), 7.50-7.52 (d, 1H, J=8 Hz), 8.67-8.68 (d, 1H, J=4 Hz).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:11]([N:14]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]2)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=O)C>Cl>[NH2:4][C:5]1[S:6][C:7]([S:11]([N:14]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]2)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)N2CCC(O)C2)s1
Agent: Cl
Product: Cc1nc(N)sc1S(=O)(=O)N1CCC(O)C1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
A stirred suspension of (RS)-1-(2-acetamido-4-methyl-thiazole-5-sulfonyl)-pyrrolidin-3-ol (0.82 g, 2.68 mmol) in 6N hydrochloric acid (13 ml) was heated for 2 h at 80° C. evaporated, and saturated NaHCO3 solution (20 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml), the combined organic layers washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by crystallization (dichloromethane/MeOH/hexane) to yield the title compound (0.62 g, 88%) as a white solid. MS (ISP) 263.8 [(M+H)+]; mp 165° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([F:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[F:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:3]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C#CC(O)(CCC)CCC
Reactant: CC(C)(C)OC(=O)NCCC(F)c1cccc(Br)c1
Product: CCCC(O)(C#Cc1cccc(C(F)CCNC(=O)OC(C)(C)C)c1)CCC

Procedure:
Sonogashira coupling of tert-butyl 3-(3-bromophenyl)-3-fluoropropylcarbamate and 4-ethynylheptan-4-ol following the method described in Example 12 gives tert-butyl 3-fluoro-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propylcarbamate.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)C=O.[H-].[Na+]>C(O)(=O)C>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 25 °C

Procedure:
A mixture of 30.0 g (0.157 mole) of 5-bromofuroic acid, 43.7 g (0.157 mole) of oleylalcohol and 500 ml of dried dimethylformamide is flushed with nitrogen and stirred at room temperature after which 7.55 g (0.314 mole) of sodium hydride is added. The mixture is stirred at room temperature for an hour then heated to reflux. The mixture is refluxed for 92 hours after which the mixture is poured into an ice-water mixture, acidified with acetic acid and extracted with ether. The ether layer is washed with water and salt water, dried over sodium sulfate, filtered and evaporated replacing the ether with hexane. Upon cooling a solid is formed which is recrystallized from methanol to give 5-(cis-9-octadecenyloxy)-2-furoic acid, M.P. 93°-96° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:12][C:13]([CH3:15])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:13]([CH3:15])[CH3:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ethylpiperidine-4-carboxylate (1 eq) in methanol was added acetone (1 eq) and acetic acid (5%) and the resulting mixture was stirred for 2 h at ambient temperature. To it was then added sodium cyanoborohydride (1 eq) and continued stirring for 16 h. The mixture was then concentrated and to it was added sodium bicarbonate and was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate and concentrated to yield ethyl-1-(methylethyl)piperidine 4-carboxylate. To this was then added concentrated hydrochloric acid and water (2:1) and the mixture was refluxed for 5 h. The resulting 1-(methylethyl)piperidine-4-carboxylic acid was then azeotroped with toluene. MS: MH+=172.
Reaction SMILES: [OH:1][CH:2]([C:17]1([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH2:20][CH2:19][CH2:18]1)[C:3]1[C:8]([NH:9]C(=O)OC(C)(C)C)=[CH:7][CH:6]=[CH:5][N:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:9][C:8]1[C:3]([CH:2]([C:17]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[CH2:20][CH2:19][CH2:18]2)[OH:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C(O)C1(c2cccc(C(F)(F)F)c2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccnc1C(O)C1(c2cccc(C(F)(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 120D (96 mg, 0.229 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperature for about 2 hours, and concentrated in vacuum. The residue was treated with saturated NaHCO3 and extracted with ethyl acetate three times. Combined organic phases were washed with water and brine sequentially, dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC (Column: BOSTON-C18 20×250 mm 10 μm, eluent: water (0.05% NH4HCO3): acetonitrile, 1:1 to 5:95) (60 mg, 30%) to provide the title compound. LC-LC-MS: m/z (M+H) 323. 1H NMR (400 MHz, CDCl3): δ 7.78-7.80 (m, 1H), 7.35-6.99 (m, 4H), 6.82-6.86 (m, 1H), 6.58-6.61 (m, 1H), 4.77 (s, 1H), 3.00 (b, 3H), 2.69-2.82 (m, 2H), 2.14-2.27 (m, 2H), 1.65-1.95 (m, 2H).