Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][SH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCCc1ccccc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(SCCCc2ccccc2)cc1

Procedure:
A mixture of 174.6 grams (1.15 mole) of 3-phenylpropyl thiol, 158.8 grams (1.15 mole) of p-fluoroacetophenone and 158.8 grams (1.15 mole) of potassium carbonate in 500 ml. of dry dimethylformamide is stirred at its reflux temperature for approximately 24 hours. The reaction mixture is cooled, water added and extracted with methylene chloride. The extract is washed with water, a solution of 2 N sodium hydroxide, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is recrystallized from isopropyl alcohol to yield the desired p-(3-phenylpropylthio)acetophenone having a m.p. of 76°-8° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12.[Na].[CH2:24]([OH:26])[CH3:25]>>[CH2:24]([O:26][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12)[CH3:25]
Reactant: CCO
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Agent: [Na]
Product: CCOc1c2c(nc3c1cnn3CC)C(=O)c1ccccc1CC2

Procedure:
6.2 g. of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]-cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.02 mol.) are added to a solution of 0.5 g. of sodium (0.022 mol.) in 150 ml. of absolute ethanol. The mixture is heated at 120° (bath temperature) in an autoclave for four hours. After cooling, the crystallized 4-ethoxy-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]-pyridin-11(1H)-one is filtered off and washed with water; yield: 3.5 g. An additional crop of 2.1 g. is obtained by work up of the mother liquor, total yield: 5.6 g. (87.5%). m.p. 150°-152° (recrystallized from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[OH:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Cl)cc2)cc1C(O)C1CCCCC1
Yield: 83 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-(4-chlorophenyl)-2-methyl-3-furaldehyde (1.7 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (15 mL) to give the title compound (2.0 g, 83%) as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:6]([CH2:8][C:9]#[N:10])=O.O.[NH2:17][NH2:18]>C(O)C>[NH2:10][C:9]1[CH:8]=[C:6]([C:5]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:18][N:17]=1
Reactant: NN
Reactant: COc1ccc(C(=O)CC#N)cc1OC
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(N)n[nH]2)cc1OC

Procedure:
3,4-Dimethoxybenzoylacetonitrile (3.6 g) was dissolved in ethanol (20 ml), to which was subsequently added hydrazine monohydrate (0.87 ml) under cooling with ice. The mixture was heated under ref lux for 7 hours, allowed to cool and then the solvent was distilled away under a reduced pressure. The resulting residue was recrystallized from ethyl acetate to obtain the title compound (2.92 g) as colorless crystals (melting point: 124-125° C.).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[S:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:16])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[Cl:16][C:4]1[N:3]=[C:2]2[S:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=S)Nc1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nc2ccc(Cl)nc2s1
Temperature: 50 °C

Procedure:
A mixture of ethyl 2-(2,6-dichloropyridin-3-ylamino)-2-thioxoacetate (49.11 g, 175.9 mmol) and cesium carbonate (57.32 g, 175.9 mmol) in THF (350 mL) was heated at 50° C. for 6 h. The reaction suspension was then diluted with water (700 mL) and THF was removed in vacuo at 23° C. The resulting suspension was cooled to 0° C., and the precipitated solid was collected via vacuum filtration, washed with water, and dried in vacuo to provide ethyl 5-chlorothiazolo[5,4-b]pyridine-2-carboxylate as a yellow-orange solid. MS (ESI) m/z: Calculated: 242.0; Observed: 243.0 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([O-:7])=[O:6].[K+].[CH2:11](I)[CH3:12]>CN(C=O)C>[CH2:11]([O:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[CH2:3][CH2:2][OH:1])[CH3:12]
Reactant: CCI
Reactant: CC(C)(CCO)C(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCO
Reaction time: 2 h
Yield: 169 %

Procedure:
To a solution of potassium 4-hydroxy-2,2-dimethylbutyrate (1.92 mmol; 327 mg) in DMF (6 mL) is added ethyl iodide (2.30 mmol; 359 mg). The reaction mixture is stirred for 2 hours, and quenched with saturated ammonium chloride solution. The product is extracted three times with EtOAc. The combined organic layer is washed with aqueous 0.1 M HCl then brine, dried over Na2SO4, filtered, concentrated under reduced pressure to give 4-Hydroxy-2,2-dimethylbutyric acid ethyl ester (520 mg) contaminated with DMF.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[O:9][N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[S:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40].C(N(CC)C(C)C)(C)C>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([S:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:38]=2)=[O:21])[O:9][N:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)no4)c3)c2cc1OC
Temperature: 50 °C
Yield: 55 %

Procedure:
Using the procedure described in Example 159B, a mixture of phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate described in Example 159A (0.158 g, 0.5 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) were heated at 50° C. for 5 hours, to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]urea as solid (0.114 g, 55%). 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.10 (s, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.56 (d, 1H), 7.46 (t, 1H), 7.34 (m, 3H), 6.22 (s, 1H), 4.70 (m, 2H), 4.55 (m, 2H), 3.99 (s, 6H), 1.28 (s, 3H); LC-MS (ESI) m/z 516 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c[nH]c2ccccc12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc([N+](=O)[O-])c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a solution of 3-nitro-1H-indole (1 g, 6.17 mmol) in dry DMF (10 ml), under nitrogen, sodium hydride (60% w/w dispersion in mineral oil, 0.259 g, 6.48 mmol) was added. The mixture was stirred at room temperature for 15 minutes, and then ethyl 2-bromoacetate (0.723 ml, 6.17 mmol) was added. After stirring at the same temperature for 45 minutes, the mixture was partitioned between aqueous sat. NaHCO3 and Et2O; the aqueous layer was extracted with Et2O and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed and the resulting crude solid was purified by flash chromatography on silica gel (petroleum ether:Et2O from 6:4 to 1:1) to give ethyl 2-(3-nitro-1H-indol-1-yl)acetate (983 mg, 3.96 mmol, 64% yield). MS/ESI+ 249.1 [MH]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:6]1.C(N(CC)CC)C.[CH2:27]([O:29][C:30](=[O:41])[C:31]1[CH:36]=[C:35]([CH2:37]Br)[CH:34]=[CH:33][C:32]=1[O:39][CH3:40])[CH3:28]>ClCCl>[CH2:27]([O:29][C:30](=[O:41])[C:31]1[CH:36]=[C:35]([CH2:37][N:17]2[CH2:18][CH2:19][CH:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:6]=3)[CH2:15][CH2:16]2)[CH:34]=[CH:33][C:32]=1[O:39][CH3:40])[CH3:28]
Reactant: COCCn1cc(C2CCNCC2)c2ccccc21
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(CN2CCC(c3cn(CCOC)c4ccccc34)CC2)ccc1OC
Yield: 87.9 %

Procedure:
Over a solution of 6.5 g (0.025 mol) of 1-(2-methoxyethyl)-3-piperidin-4-yl-1H-indole in 90 ml of dichloromethane and 3.9 ml (0.026 mol) of triethylamine, a solution of 7.2 g (0.026 mol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester in 15 ml of dichloromethane was added. The crude mixture was stirred at room temperature for 24 hours. After standard work-up and purification by chromatography over silica gel, 9.9 g (70% of yield) of 2-methoxy-5-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]piperidin-1-ylmethy}-benzoic acid ethyl ester were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5](=[C:12]1[CH:17]2[CH2:18][CH:14]3[CH:15]([CH2:16]2)[CH:13]13)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C1C=CC=CC=1>[CH2:19]([N:21]([CH2:22][CH3:23])[CH2:2][CH2:3][O:4][C:5](=[C:12]1[CH:17]2[CH2:18][CH:14]3[CH:15]([CH2:16]2)[CH:13]13)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:20]
Reactant: ClCCOC(=C1C2CC3C(C2)C13)c1ccccc1
Reactant: CCNCC
Solvent: c1ccccc1
Product: CCN(CC)CCOC(=C1C2CC3C(C2)C13)c1ccccc1

Procedure:
A solution of 14 g. (53.6 mMol) of β-chloroethyl-{α-[tricyclo-(2.2.1.02.6)hept-3-ylidene]-benzyl}-ether and 20 g. (0.273 mol) of diethyl amine in 130 ml. of benzene was heated for 5 hours to 140° C. in a 0.5 liter autoclave. After cooling, the diethyl amine hydrochloride was filtered off under suction, benzene and diethyl amine distilled off in vacuo and the residue left subjected to acid-alkaline working up. The basic fraction was fractionated in vacuo.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C(OC([N:36]1[C:40]([C:41]#[N:42])=[CH:39][CH:38]=[C:37]1B(O)O)=O)(C)(C)C>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:37]3[NH:36][C:40]([C:41]#[N:42])=[CH:39][CH:38]=3)[C:3]([N:22]3[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1B(O)O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2C[C@H](O)[C@@H](O)C2)[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 29 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamide (Stage 46.1) and (1-(tert-butoxycarbonyl)-5-cyano-1H-pyrrol-2-yl)boronic acid (Stage 29.1) to afford a rose solid. UPLC-MS (Condition 3) tR=0.97 min, m/z=490.0 [M+H]+, m/z=487.9 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.02 (d, J=11.86 Hz, 2H) 3.46 (dd, J=11.86, 3.55 Hz, 2H) 3.90 (br. s, 2H) 5.09 (d, J=2.93 Hz, 2H) 6.29 (dd, J=3.67, 2.45 Hz, 1H) 7.03 (dd, J=3.67, 2.32 Hz, 1H) 7.34 (d, J=9.17 Hz, 2H) 7.83-7.90 (m, 2H) 8.07 (d, J=2.32 Hz, 1H) 8.76 (d, J=2.32 Hz, 1H) 10.18 (s, 1H) 12.63-12.68 (m, 1H).
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[I:29]N1C(=O)CCC1=O.C(Cl)Cl>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[I:29][C:13]1[C:12]([O:11][C@H:8]2[CH2:7][CH2:6][C@@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]2)=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([C@:22]1([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]1)=[CH:18]2
Reactant: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reactant: O=C1CCC(=O)N1I
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2I)CC1
Yield: 85.6 %

Procedure:
A mixture of (R)-4-(6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 5, 113.2 mg, 0.0002967 mol), N-iodosuccinimide (74.8 mg, 0.000332 mol) and zirconium tetrachloride (10 mg, 0.000044 mol) in methylene chloride (2.43 mL, 0.0380 mol) was heated to reflux under argon in a vial overnight. The precipitate was filtered off and the residue was purified with Isco column eluted with EtOAc in hexane from 0 to 40% to give the product as a solid (128.9 mg, 86% yield). NMR showed identity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].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>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55]([F:57])([F:56])[F:58])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3ccc(F)cc3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A mixture of [2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C3) (114 mg, 1.1 equiv), ethyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}propanoate (Int. B3) (139 mg, 1 equiv), DMF (1.2 ml) and DIPEA (0.16 ml, 3 equiv) was shaken at room temperature, then HATU (176 mg, 1.5 equiv) was added with vigorous agitation and shaking continued for 30 min. A further portion of Intermediate D5 (21 mg, 0.2 equiv) was added, followed 1 h later by further HATU (23 mg, 0.2 equiv), then shaking was continued for 18 h. Reverse phase HPLC (Preparative Method B) gave ethyl 2-{4-[{[2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}-2-methylpropanoate as a white solid (149 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[O:7][C:6]1=[O:25].[CH:35]([C@H:37]1[CH2:42][CH2:41][C@H:40]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:39][CH2:38]1)=O.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:24][C:21]([F:22])([F:23])[C:13]1[CH:12]=[C:11]([C@H:8]2[O:7][C:6](=[O:25])[N:5]([CH2:4][C:3]3[CH:26]=[C:27]([O:30][C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][C:2]=3[NH:1][CH2:35][C@H:37]3[CH2:38][CH2:39][C@H:40]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:41][CH2:42]3)[C@H:9]2[CH3:10])[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Reactant: CCOC(=O)C[C@H]1CC[C@H](C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H]1CC[C@H](CNc2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred solution of (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Intermediate 16; 820 mg; 1.63 mmol) and ethyl (trans-4-formylcyclohexyl)acetate (Intermediate 14; 270 mg; 1.36 mmol) in toluene (8 mL) was heated at reflux for 3 h. The reaction was concentrated in vacuo and redissolved in EtOH (8 mL). Sodium borohydride (103 mg; 2.72 mmol) was added and the reaction stirred at room temperature for 14 h. The reaction was quenched with sat. NH4Cl and partitioned between EtOAc (25 mL) and H2O (25 mL). The aqueous layer was re-extracted with EtOAc (3×25 mL) and the combined organic layers were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford ethyl [trans-4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]amino}methyl)cyclohexyl]acetate as a yellow gum. LCMS=685.1 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.89 (s, 1 H), 7.73 (s, 2 H), 7.13 (d, J=8.7 Hz, 1 H), 6.92 (d, J=2.3 Hz, 1 H), 6.72 (d, J=9.0 Hz, 1 H), 5.66 (d, J=8.2 Hz, 1 H), 4.74 (d, J=15.6 Hz, 1 H), 4.14-4.02 (m, 4 H), 3.05-2.97 (m, 2 H), 2.19 (d, J=6.9 Hz, 2 H), 1.96-1.90 (m, 2 H), 1.85-1.78 (m, 2 H), 1.71-1.62 (m, 1 H), 1.51-1.39 (m, 2 H), 1.25 (t, J=7.1 Hz, 3 H), 1.12-1.03 (m, 3 H), 0.80 (d, J=6.4 Hz, 3 H).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:18])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:3]\[CH2:4][C:5]([OH:7])=[O:6].[CH3:19][O:20][C:21](=[O:30])[C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O.CO.C1CCC(N=C=NC2CCCCC2)CC1>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[CH3:19][O:20][C:21]([C@@H:22]([O:6][C:5](=[O:7])[CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:18])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC(=O)O
Reactant: COC(=O)[C@@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: CO
Product: COC(=O)[C@@H](OC(=O)C/C=C(\C)CC/C=C(\C)CCC=C(C)C)c1ccccc1
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a solution of 12.5 g (50 mmol) (E,E)4,8,12-trimethyl-trideca-3,7,11-trienoic acid (isomeric purity of 95%) [K. Ishihara et al., J. Am. Chem. Soc. 2002, 124, 3647-3655] in 100 ml MTBE were added at r.t. 8.4 g (50 mmol) (S)-(+)-mandelic acid methyl ester [α]D=+144.9 (c=1.04, MeOH) and 1.5 g DMAP. After stirring for 15 min, 10.5 g (51 mmol) DCC is added, during which the temperature raised to 35° C. The reaction mixture was stirred for 4 h at 35° C., cooled to room temperature and filtered. The resulting solution was concentrated in vacuo to a volume of ca. 50 ml and filtered over 100 g of silicagel. The product was eluted with ca. 600 ml hexane/MTBE 1:1. Concentration of the combined fractions in vacuo and drying of the product in high vacuo (50° C./0.08 Torr) afforded 19.8 g (98%) of (E,E)-4,8,12-Trimethyl-trideca-3,7,11-trienoic acid (S)-methoxycarbonyl-phenyl-methyl ester (2) in form of a colorless oil.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[NH:44][C:43](=[O:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[CH:40][C:41]=3[O:46][CH3:47])[N:36]=2)=[CH:31][C:30]=1[CH3:50]>CN(C=O)C>[Br:5][CH2:2][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[NH:44][C:43](=[O:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[CH:40][C:41]=3[O:46][CH3:47])[N:36]=2)=[CH:31][C:30]=1[CH3:50]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)c(C)c3)nc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCBr)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tetrabromomethane (3.26 g, 9.82 mmol) was added to a solution of triphenylphosphine (2.58 g, 9.82 mmol) in anhydrous DMF (20 mL) at 0° C. A solution of 2-[4-(2-hydroxy-ethoxy)-3-methyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (1.75 g, 4.91 mmol) in DMF (7 mL) was then added dropwise and stirred the reaction mixture at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with dichloromethane (4×25 mL). The combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed and the solid was triturated with ether. The resulting slurry was filtered and washed with ether several times (to remove the triphenylphosphine oxide) and finally with a solution of dichloromethane-ether (1:1) to obtain 2-[4-(2-bromo-ethoxy)-3-methyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as an off-white solid. Yield: 0.70 g (34%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([O:22][C:23](=[O:25])[CH3:24])=[C:17]([CH3:26])[CH:16]=4)[C:4]=2[C:3]=1[CH3:27])[CH:12]=[CH:11][CH:10]=[CH:9]3.[Br:28]Br>C(Cl)Cl>[Br:28][C:7]1[C:5]2[S:6][C:2]([CH3:1])=[C:3]([CH3:27])[C:4]=2[C:14]([C:15]2[CH:16]=[C:17]([CH3:26])[C:18]([O:22][C:23](=[O:25])[CH3:24])=[C:19]([CH3:21])[CH:20]=2)=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[CH:12]2
Reactant: BrBr
Reactant: CC(=O)Oc1c(C)cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C
Yield: 55.3 %

Procedure:
A solution of acetic acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenyl ester (10.0 g, 26.7 mmol) and ferric chloride (0.23 g, 1.4 mmol) in anhydrous methylene chloride (231 mL) was placed at −78 C. under nitrogen. The reaction mixture was protected from light and a solution of bromine (1.5 mL, 29.4 mmol) in anhydrous methylene chloride (38 mL) was added dropwise over a period of 50 min. After 30 min the reaction was quenched with dilute sodium bisulfite, diluted with water, and the resulting mixture was extracted with diethyl ether. The diethyl ether layer was washed twice with water, brine, and then dried (MgSO4). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (97:3, then 95:5) gave the title compound as a white solid (6.7 g, 55%): NMR (DMSO-d6): δ8.27 (d, 1H), 7.60 (d, 1H), 7.56-7.52 (ddd, 1H), 7.38-7.34 (ddd, 1H), 7.06 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.22 (s, 6H), 1.64 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 452/454; Anal. Calc. for C24H21BrO2S: C, 63.58; H, 4.67; N, 0.00. Found: C, 63.41; H, 4.45; N, 0.08.