Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][O:32][C@@H:33]1[C@@H:39]([CH2:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=2[Cl:50])[O:38][C@H:35]([O:36][CH3:37])[C@@H:34]1[OH:51]>C(Cl)Cl.CCOCC.C([O-])(O)=O.[Na+]>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][O:32][C@@H:33]1[C@@H:39]([CH2:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=2[Cl:50])[O:38][C@H:35]([O:36][CH3:37])[C:34]1=[O:51]
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To an ice-cold suspension of Dess-Martin periodinane (50.0 g, 118 mmol) in anhydrous CH2Cl2 (350 mL) under argon (Ar) was added a solution of the compound from Step A (36.2 g, 75 mmol) in anhydrous CH2Cl2 (200 mL) dropwise over 0.5 h. The reaction mixture was stirred at 0° C. for 0.5 h and then at room temperature for 3 days. The mixture was diluted with anhydrous Et2O (600 mL) and poured into an ice-cold mixture of Na2S2O3.5H2O (180 g) in saturated aqueous NaHCO3 (1400 mL). The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 (600 mL), water (800 mL) and brine (600 mL), dried (MgSO4), filtered and evaporated to give the title compound (34.2 g) as a colorless oil, which was used without further purification in Step C below.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.C(N(CC)CC)C.[NH2:29][C:30]1[C:38]([CH3:39])=[CH:37][C:36]([I:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>C(#N)C.O>[Br:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:32](=[O:33])[C:31]3[CH:35]=[C:36]([I:40])[CH:37]=[C:38]([CH3:39])[C:30]=3[N:29]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: Cc1cc(I)cc(C(=O)O)c1N
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(I)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methanesulfonyl chloride (0.54 ml, 6.94 mmol) in acetonitrile (15 mL) was added dropwise a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Step D) (2.0 g, 6.6 mmol) and triethylamine (0.92 ml, 6.6 mmol) in acetonitrile (5 mL) at 0° C. The reaction mixture was then stirred for 15 minutes at 0° C. Then, 2-amino-3-methyl-5-iodobenzoic acid (i.e. the product from Example 1, Step A) (1.8 g, 6.6 mmol) was added, and stirring was continued for an additional 5 minutes. A solution of triethylamine (1.85 mL, 13.2 mmol) in acetonitrile (5 mL) was then added dropwise while keeping the temperature below 5° C. The reaction mixture was stirred 40 minutes at 0° C., and then methanesulfonyl chloride (0.54 ml, 6.94 mmol) was added. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were washed successively with 10% aqueous sodium bicarbonate (1×20 mL) and brine (1×20 mL), dried (MgSO4) and concentrated to afford 2.24 g of the title product as a crude yellow solid.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:18]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:18]3[CH:19]=[CH:20][C:21]([CH:23]=[O:24])=[CH:22][C:17]=3[F:16])=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Reactant: O=Cc1ccc(B(O)O)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc(C=O)cc3F)n2n1
Temperature: 80 °C
Yield: 64 %

Procedure:
A mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (810 mg, 3.0 mmol), 2-fluoro-4-formylphenylboronic acid (1.2 g, 7.5 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (200 mg, 0.30 mmol), potassium phosphate (1.9 g, 9.0 mmol), DME (9 mL) and H2O (3 mL) was maintained in a sealed vessel at 80° C. for 12 h. The organic layer was separated and concentrated under reduced pressure to afford a yellow solid that was purified by reverse phase HPLC to afford 4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-3-fluoro-benzaldehyde (600 mg, 64%) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 10.02 (d, J=1.8 Hz, 1H), 8.84-8.93 (m, 1H), 8.12 (d, J=4.3 Hz, 1H), 7.79 (dd, J=8.1, 1.5 Hz, 1H), 7.68-7.76 (m, 2H), 6.55 (d, J=9.6 Hz, 1H), 3.43 (td, J=7.1, 5.6 Hz, 2H), 1.67-1.78 (m, 2H), 1.49 (dq, J=15.0, 7.4 Hz, 2H), 1.01 (t, J=7.3 Hz, 3H); LCMS (ESI) m/e 313.1 [(M+H)+, calcd for C17H18FN4O 313.1].
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Product: CCCCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.097 g, 0,349 mmol) was reacted with N-(2-azidoethyl)-4-hexylbenzamide (0.096 g, 0.349 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-hexylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J=8.1 Hz, 2H), δ 7.55 (t, J=6.7 Hz, 1H), δ 7.26 (s, 1H), δ 7.09 (d, J=7.8 Hz, 2H), δ 6.39 (s, 1H), δ 6.04 (s, 2H), δ 4.48 (t, J=4.8 Hz, 2H), δ 3.83 (q, J=5.6, 4.8 Hz, 2H), δ 2.56 (q, J=7.5, 8.1 Hz, 4H), δ 2.24 (t, J=6.9 Hz, 2H), δ 1.50 (m, 13H), δ 1.21 (m, 1H), δ 0.77 (t, J=5.7 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.3, 148.3, 147.3, 138.7, 131.4, 128.7, 127.4, 122.2, 106.4, 84.9, 73.9, 49.5, 40.2, 36.0, 31.8, 31.3, 29.9, 29.3, 29.1, 28.9, 28.2, 28.1, 28.0, 25.6, 22.8, 14.3 ppm; HRMS (ESI) calcd for C30H45N7O3 (M+) 551.3584. found 551.3581, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-hexylbenzamide hydrochloride (0.164 g, 96% yield). 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), δ 7.67 (d, J=7.6 Hz, 2H), δ 7.21 (d, J=7.6 Hz, 2H), δ 6.43 (s, 1H), δ 4.72 (s, 2H), δ 3.87 (s, 2H), δ 2.74 (s, 2H), δ 2.58 (t, J=7.6 Hz, 2H), δ 2.31 (t, J=6.8 Hz, 2H), δ 1.66 (s, 2H), δ 1.55 (s, 4H), δ 1.35 (s, 2H), δ 1.25 (s, 6H), δ 0.66 (t, J=8.8 Hz, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 169.2, 159.5, 147.4, 147.3, 131.2, 108.4, 51.2, 48.5, 48.3, 48.1, 47.9, 47.7, 47.5, 47.3, 39.5, 36.5, 35.6, 31.6, 31.7, 31.2, 28.8, 28.2, 27.9, 27.7, 24.1, 23.9, 22.6, 13.3, 9.9 ppm; HRMS (ESI) calcd for C25H37N7O (M+) 451.3059. found 451.3058.
Reaction SMILES: [C:1]1([P:7]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:8]2[CH:42]=[CH:41][CH:40]=[CH:39][C:9]=2[CH:10]=[N:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[N:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:33]1([P:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][NH:18][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[NH:11][CH2:10][C:9]2[CH:39]=[CH:40][CH:41]=[CH:42][C:8]=2[P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C(=NC1CCCCC1N=Cc1ccccc1P(c1ccccc1)c1ccccc1)c1ccccc1P(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(P(c2ccccc2)c2ccccc2CNC2CCCCC2NCc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of N1,N2-bis(2-(diphenylphosphino)benzylidene)cyclohexane-1,2-diamine (2.18 g, 2.83 mmol) (prepared according to the literature procedure: Laue, S.; Greiner, L.; Woltinger, J.; Liese, A. Adv. Synth. Catal. 2001, 343, 711) and sodium borohydride (NaBH4) (0.64 g, 17 mmol) in ethanol (30 ml) was refluxed with stirring for 6 hours. The resulting solution was cooled to room temperature and water (15 ml) was added to destroy excess NaBH4. The mixture was extracted with dichloromethane and the combined extracts were washed with saturated aqueous ammonium chloride solution [NH4Cl] and then water. The organic layer was dried over magnesium sulfate and then filtered through silica gel. The filtrate was then evaporated to dryness to obtain a yellow solid. Yield: 2.0 g (91%). 1H NMR (400 MHz, CD2Cl2): δ 7.58-6.80 (m, 20H, Ph-H), 3.86 (d, 4H, NCH2), 3.65 (br, 2H, NH), 2.21 (s, 24H, CH3), 1.80 (m, 8H, cyclohexane-H). 31P{1H} NMR (162 MHz, CD2Cl2): δ−13.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Br:11]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CBr)nc1
Yield: 52 %

Procedure:
1st step: To a stirred suspension of 6-methylnicotinic acid (commercially available) (500 mg, 3.64 mmol) in THF (14 mL) at RT, was added 1,3-dibromo-5,5-dimethylhydantoin (DDH) (1.06 g, 3.71 mmol). Stirring was continued over night and concentrated under vacuo. Column chromatography (SiO2, CH2Cl2/MeOH: 8/2) yielded 410 mg (52%) of 6-bromomethyl-nicotinic acid as a light orange solid. ES-MS m/e: 214.2-216.3 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[N:15]=2)=[CH:10][C:9]=1[OH:20].[CH2:21]([O:23][C:24]([C:26]1[C:27]2[S:35][CH:34]=[C:33]([CH2:36]Br)[C:28]=2[C:29]([Cl:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]>O1CCCC1.CN(C)C=O>[CH2:21]([O:23][C:24]([C:26]1[C:27]2[S:35][CH:34]=[C:33]([CH2:36][O:20][C:9]3[CH:10]=[C:11]([C:14]4[O:18][N:17]=[C:16]([CH3:19])[N:15]=4)[CH:12]=[CH:13][C:8]=3[CH3:7])[C:28]=2[C:29]([Cl:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]
Reactant: Cc1noc(-c2ccc(C)c(O)c2)n1
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nc(C)no4)ccc3C)csc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of cesium carbonate (1.02 g, 3.13 mmol), 2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenol (0.42 g, 2.20 mmol) (from Example 52 supra) in tetrahydrofuran/N,N-dimethylformamide (5:2, 21 mL) was heated at 70° C. for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.68 g, 2.04 mmol) (from Example 1 supra) was added. Heating was continued for 1 hour. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (2×). The combined organic phase washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 5-10% ethyl acetate in dichloromethane to give 4-chloro-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.51 g, 57%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].B(Cl)([C@@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1>C1COCC1>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C@H:2]([OH:3])[CH3:1])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: COc1cc(C(C)=O)ccc1F
Agent: C[C@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: C1CCOC1
Product: COc1cc([C@@H](C)O)ccc1F
Temperature: -20 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
A solution of 4-fluoro-3-methoxyacetophenone (1 g) in THF (10 mL) was added dropwise to a solution of (+)-DIPCl™ (2.29 g) in THF (30 mL) in a nitrogen atmosphere at −20° C., and the reaction solution was stirred at −20° C. for 5 hours. The reaction solution was heated to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with an ether, diethanolamine (1.25 mL) was added to the diluent, and the reaction solution was stirred at room temperature overnight. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 918 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37]([OH:39])=O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[NH2:40][C@H:41]([CH2:64][C:65]1[CH:74]=[CH:73][C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH:66]=1)[C:42]([N:44]([CH3:63])[C@@H:45]([C:57]1[O:61][N:60]=[C:59]([CH3:62])[N:58]=1)[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1)=[O:43].FC(F)(F)C(O)=O.C(N(CC)CC)C>CN(C)C=O>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][CH:34]([C:37](=[O:39])[NH:40][C@@H:41]([C:42](=[O:43])[N:44]([CH3:63])[C@@H:45]([C:57]2[O:61][N:60]=[C:59]([CH3:62])[N:58]=2)[CH2:46][C:47]2[CH:56]=[CH:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH:48]=2)[CH2:64][C:65]2[CH:74]=[CH:73][C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH:66]=2)[CH2:35][CH2:36]1)=[O:30])([CH3:25])([CH3:26])[CH3:27]
Reactant: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.42 g, 2.2 mmol) and 1-hydroxybenzotriazole monohydrate (0.34 g, 2.2 mmol) were added to a solution of N-tert-butoxycarbonyl-4-piperidine carboxylic acid (0.50 g, 2.2 mmol) in N,N-dimethylformamide (5 ml). After 30 min at 20° C. a mixture of (2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid (0.9 g, 1.54 mmol) and triethylamine (0.16 g, 1.54 mmol) in N,N-dimethylformamide (10 ml) were added. After 18 h at 20° C. the reaction mixture was poured on water (85 ml) and extracted several times with ethyl acetate (total 90 ml). The organic phases were collected and washed with aqueous citric acid (10%, 15 ml), a saturated solution of sodium hydrogencarbonate (15 ml) and water (3×15 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and the residue was chromatographed on silica (110 g) using ethyl acetate and heptane (1:1) as eluent to give 0.50 g of 4-((1R)-1-{N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)carbamoylpiperidine-1-carboxylic acid tert-butylester.
Reaction SMILES: BrC(Br)C.[CH:5]1[C:10]([CH2:11]Br)=[CH:9][CH:8]=[C:7]([C:13]#[N:14])[CH:6]=1.I[C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1>C1COCC1.[Zn]>[C:21]([N:19]1[CH:20]=[C:16]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:13]#[N:14])=[CH:6][CH:5]=2)[N:17]=[CH:18]1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(Br)Br
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
To a suspension of activated zinc dust (3.57 g, 54.98 mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred under argon for 45 minutes, at 20° C. The suspension was cooled to 0° C. and a-bromo-p-tolunitrile (9.33 g, 47.6 mmol) in THF (100 mL) was added dropwise over a period of 10 minutes. The reaction was then allowed to stir at 20° C. for 6 hours and bis(triphenylphosphine)Nickel II chloride (2.40 g, 3.64 mmol) and 4-iodo-1-tritylimidazole (15.95 g, 36.6 mmol, S. V. Ley, et al., J. Org. Chem. 56, 5739 (1991)) were added in one portion. The resulting mixture was stirred 16 hours at 20° C. and then quenched by addition of saturated NH4Cl solution (100 mL) and the mixture stirred for 2 hours. Saturated aq. NaHCO3 solution was added to give a pH of 8 and the solution was extracted with EtOAc (2×250 mL), dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-20% EtOAc in CH2Cl2) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[NH:7][C:8](=O)[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1)[CH3:2].P(Cl)(Cl)([Cl:25])=O.CN(C)C1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[N:7]=[C:8]([Cl:25])[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nc2scc(-c3ccccc3)c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)Cc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reaction time: 18 h

Procedure:
A stirred solution of (4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)acetic acid ethyl ester (1.0 g, 3.185 mmol), phosphoryl chloride (15 ml) and N,N-dimethylaniline (4.8 ml) was heated under reflux for 6 hours and then left to stand at ambient temperature for 18 hours. The excess phosphoryl chloride was removed in vacuo to give a dark residue, which was dissolved in dichloromethane (100 ml) and then washed with water (2×50 ml) followed by saturated sodium hydrogen carbonate solution (50 ml). The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane and 40°-60° petroleum ether (3:1) gave (4-chloro-5-phenylthieno[2,3-d]pyrimidin-2-yl)acetic acid ethyl ester as a pale-yellow solid (0.86 g).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=O)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]1[C@@H:35]([OH:36])[CH2:34][NH:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH2:25][N:33]3[CH2:32][CH2:31][C@@H:35]([OH:36])[CH2:34]3)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:29])([F:30])[F:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O[C@@H]1CCNC1
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O[C@@H]1CCN(Cc2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 20 mg, 0.049 mmol), 3R-Pyrrolidinol (21.23 mg, 0.244 mmol), sodium triacetoxyborohydride (31.0 mg, 0.146 mmol) and dichloromethane (1 mL) was stirred at room temperature overnight. The mixture was concentrated and dissolved in methanol. HPLC purification (Column: Waters XBridge C18, 19×250 mm, 5-nm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) and concentration gave the titled compound (18.8 mg, 0.039 mmol, 80% yield) as a solid. The compound had an HPLC retention time=2.15 min. (Column: Supelco Ascentis Express C-18, 4.6×50 mm, 2.7 um; Solvent A=0.05% TFA in H2O:MeCN (95:5); Solvent B=0.05% TFA in H2O:MeCN (5:95)); LC/MS M+1=482.1; 1H NMR (400 MHz, MeOD) δ ppm 7.95 (1H, d, J=7.7 Hz), 7.73 (2H, d, J=7.3 Hz), 7.53-7.66 (3H, m), 7.36-7.43 (2H, m), 4.39-4.47 (1H, m), 3.87-4.01 (2H, m), 2.97-3.14 (6H, m), 2.83 (2H, d, J=19.6 Hz), 2.14-2.27 (1H, m), 1.81-1.93 (1H, m, J=13.6 Hz).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=[O:9])[CH:2]=[CH2:3].Cl.[CH3:23]O>>[CH3:23][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[C:8](=[O:9])[C:7]1[CH:19]=[CH:20][CH:21]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:6]=1
Reactant: CO
Reactant: C=CCOc1cccc(C(=O)c2ccccc2C(=O)O)c1
Agent: Cl
Product: C=CCOc1cccc(C(=O)c2ccccc2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 2-[3-(allyloxy)benzoyl]benzoic acid (9.00 g, 31.9 mmol) in methanol (100 mL) was saturated with hydrogen chloride gas. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and diluted with diethyl ether. The resulting solution was washed sequentially with a saturated sodium bicarbonate solution, water, and a saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting pale yellow oil solidified upon standing to provide 9.45 g (100%) of the desired title product as a white solid: mp 50-52° C.; NMR (CDCl3) 8.05 (d, J=7.8 Hz, 1H), 7.65 (t, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 1H), 7.40 (m, 2H), 7.32 (t, J=8 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 6.08 (m, 1H), 5.40 (d, J=16 Hz, 1H), 5.30 (d, J=11 Hz, 1H), 4.78 (d, J=4 Hz, 2H), 3.62 (s, 3H); MS-FD m/e 297 (p+1, 40), 296 (p, 100); IR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OCC(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(OCC(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionate (3.4 g, 8.49 mmol) in methanol (15 ml) was added 2N aqueous sodium hydroxide solution (8.5 ml, 17.0 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionic acid (2.78 g, 88%).