Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C2C=NN(C)C=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][C:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[C:21]([CH3:32])[O:20][N:19]=1>>[CH3:17][C:18]1[C:22]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])=[C:21]([CH3:32])[O:20][N:19]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2c(C)noc2C)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole. ESI-MS (m/z): 232 [M+1]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C@@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=O)=[O:8])[CH2:3][CH2:2]1.[NH2:21][C@H:22]([C:29]([NH:31][C@H:32]([C@@H:40]([OH:46])[CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:30])[CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]([O:9][C@@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([NH:21][C@H:22]([C:29]([NH:31][C@H:32]([C@@H:40]([OH:46])[CH2:41][CH2:42][CH:43]([CH3:44])[CH3:45])[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:30])[CH2:23][C:24]2[N:28]=[CH:27][NH:26][CH:25]=2)=[O:13])=[O:8])[CH2:5][CH2:6]1
Reactant: O=C(O)[C@H](Cc1ccccc1)OC(=O)N1CCOCC1
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)OC(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a mixture of 2(S)-morpholinocarbonyloxy-3-phenylpropionic acid (120 mg) and 2(S)-(L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (142 mg) in dry N,N-dimethylformamide (20 ml), which was cooled to 0° C., were added a solution of diphenyl phosphorylazide (108 mg) in dry N,N-dimethylformamide (5 ml) and triethylamine (40 mg). The mixture was stirred for 16 hours at ambient temperature. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml). The solution was washed with 1M sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel thin layer chromatography (chloroform:methanol, 6:1, V/V) to give 2(S)-[Nα -(2(S)-morpholinocarbonyloxy-3-phenylpropionyl)-L-histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (177 mg) as an amorphous powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CCN(CC)CC.COC(C)(C)C>[CH3:12][N:13](/[CH:15]=[CH:2]/[C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)=[O:3])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cnccn1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CN(C)/C=C/C(=O)c1cnccn1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of acetylpyrazine (5 g, 40.9 mmol) in N,N-dimethylformamide dimethyl acetal (10.9 mL, 81.8 mmol) and Et3N (5.7 mL) was heated at 110° C. for 16 h. The heating was stopped and a precipitate was formed while it was allowed to cool down to room temperature. The suspension was diluted with tert-butyl methyl ether; the solid was separated by filtration and washed with tert-butyl methyl ether. This material was triturated with the same solvent, filtered off and dried to afford the title compound 23a as a yellow solid (5.9 g, 33.3 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.09 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.66 (dd, J=2.4, 1.6 Hz, 1H), 7.84 (d, J=12.4 Hz, 1H), 6.30-6.20 (m, 1H), 3.19 (s, 3H), 2.93 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]2[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:8][C:12]=2[CH:13]=1
Reactant: O=[N+]([O-])c1cccc(F)c1-c1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: Fc1ccc2c(c1)[nH]c1cccc(F)c12
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 2,4′-difluoro-6-nitro-1,1′-biphenyl (1.100 g, 4.7 mmol) and triphenylphosphine (3.067 g, 11.7 mmol) in anhydrous 1,2-dichlorobenzene (2 mL) was heated to 175° C. in a microwave reactor for 4 hrs. The mixture was cooled to room temperature and concentrated in vacuo. The crude residue was then purified by silica gel chromatography (5-50% methylene chloride/hexanes) to afford the product as a white solid (0.84 g, 88%). 1H NMR (CDCl3, 300 MHz) δ 8.17 (br s, 1H), 8.12 (dd, 1H, J=8.7, 5.1 Hz), 7.33 (td, 1H, J=8.1, 5.1 Hz), 7.20 (d, 1H, J=8.1 Hz), 7.12 (dd, 1H, J=9.3, 2.4 Hz), 7.02 (td, 1H, J=9.3, 2.4 Hz), 6.93 (dd, 1H, J=9.6, 7.8 Hz).
Reaction SMILES: BrC[C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.[P:26]([O:33]CC)([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]>>[CH2:24]([O:23][C:21]([C:4]1[N:5]=[C:6]2[C:15](=[O:16])[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:12]=3)[N:7]2[C:3]=1[P:26]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:33])=[O:22])[CH3:25]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1P(=O)(OCC)OCC
Yield: 63 %

Procedure:
1-Bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 3) (840 mg, 2.0 mmol) and triethyl phosphite (12 ml) was heated at 120° C. for 16 h. The mixture was concentrated in vacuo and the residue submitted to flash chromatography on silica gel, eluting with dichloromethane/methanol (9:1). The purified product was washed with ether to give 600 mg (63%) of the title compound. M.p. 198°-199° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[N:28](COCC3C=CC=CC=3)[C:26]2=[O:27])[C@H:22]([O:43][CH2:44][CH2:45][O:46][CH3:47])[C@@H:21]1[OH:48])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:43][CH2:44][CH2:45][O:46][CH3:47])[C@@H:21]1[OH:48])([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)n(COCc2ccccc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Reaction time: 16 h

Procedure:
5′-O-t-Butyldiphenylsilyl-3-benzyloxymethyl-2′-O-(methoxyethyl)-5-methyluridine is dissolved in anhydrous MeOH and is added to a pressure bottle containing 10% Pd on carbon under an argon atmosphere. The vessel is pressurized with hydrogen gas to 30 psi and shaken for 16 hours. The mixture is filtered through a celite pad and the solvent is evaporated in vacuo. The residue is dissolved in 1M NEt3 in anhydrous MeOH and the solution is heated at reflux temperature for 2 hours. The solvent is evaporated in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C@@H:21]3[CH2:26][CH2:25][C@H:24]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:23][CH2:22]3)=[N:18][CH:19]=2)=[O:13])=[N:8][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C@@H:21]3[CH2:22][CH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]3)=[N:18][CH:19]=2)=[O:13])=[N:8][N:7]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(Cc4cccc(Cl)c4)s3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nnc(Cc2cccc(Cl)c2)s1)c1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)nc1
Yield: 90.1 %

Procedure:
0.264 g of tert-butyl cis-4-{5-[5-(3-chlorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]pyridin-2-yloxy}cyclohexanecarboxylate (0.5 mmol, 1 eq.) is placed in 5 mL of dichloromethane with stirring. 0.37 mL of trifluoroacetic acid (4.99 mmol, 10 eq.) is added slowly. After stirring for 18 hours at room temperature, the medium is concentrated, taken up and evaporated successively with ethanol and dichloromethane. The residue is triturated with diethyl ether, drained and filtered to give 0.213 g of cis-4-{5-[5-(3-chlorobenzyl)-[1.3.4]thiadiazol-2-ylcarbamoyl]pyridin-2-yloxy}cyclohexanecarboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[CH:35]=[N:36][NH:37][CH:38]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:50][CH2:51][O:52][CH3:53]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[CH:38]=[N:37][N:36]([CH2:50][CH2:51][O:52][CH3:53])[CH:35]=4)[CH:22]=3)[CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cn[nH]c2)c1
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(CCOC)c2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.1 %

Procedure:
A mixture of 4-{6-butyl-5-[4-cyclohexyloxy-3-(1H-pyrazol-4-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (0.14 mmol, 80.6 mg), potassium tert-butoxide (0.15 mmol, 17.2 mg, 98%) and THF (1 mL) was stirred at room temperature for 40 min. 1-Bromo-2-methoxy-ethane (0.17 mmol, 0.016 mL) was added and it was stirred for 2.5 h. More potassium tert-butoxide (0.30 mmol, 34.4 mg, 98%) was added and after stirring for 30 min, more 1-bromo-2-methoxy-ethane (0.34 mmol, 0.032 mL) was added. It was stirred overnight. The reaction mixture was partitioned between ethyl acetate (10 mL) and saturated aq. sodium bicarbonate solution (10 mL). The ethyl acetate layer was dried over sodium sulfate. Purification by column chromatography on silica gel using 20-100% ethyl acetate in hexanes to provide 4-(6-butyl-5-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-pyridazin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless solid (59.5 mg).
Reaction SMILES: [C:1]([N:9]([CH2:11][CH2:12][O:13][C:14]1[CH:27]=[CH:26][C:17]([CH:18]=[C:19]2[S:23][C:22](=[O:24])[NH:21][C:20]2=[O:25])=[CH:16][CH:15]=1)[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.[Pd]>[C:1]([N:9]([CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[NH:21][C:20]2=[O:25])=[CH:26][CH:27]=1)[CH3:10])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)C(=O)c1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CN(CCOc1ccc(CC2SC(=O)NC2=O)cc1)C(=O)c1ccccc1

Procedure:
5-(4-[2-(N-Benzoyl-N-methylamino)ethoxy]benzylidene)-2,4-thiazolidinedione (4.01 g) was dissolved in dioxan (400 ml) and hydrogenated at room temperature and pressure in the presence of 10% palladium-charcoal (4 g) for 3.5 hours. A further portion of catalyst (4 g) was added, and the reaction continued for a total of 52 hours. The reaction mixture was filtered through diatomaceous earth, and the solvent evaporated. The resulting gum was recrystallised from dichloromethane-diethyl ether to afford the title compound, mp 139-142° C.
Reaction SMILES: C(O[C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)C.BrN1C(=O)CCC1=O.[CH3:19][CH:20]([CH3:24])[C:21](=[NH:23])[NH2:22].C(=O)([O-])[O-].[Na+].[Na+].CC1CCCO1.[ClH:37].CC(O)C>C(#N)C.O>[ClH:37].[CH3:19][CH:20]([C:21]1[NH:23][C:4]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:5]=2[N:22]=1)[CH3:24]
Reactant: CC(C)C(=N)N
Reactant: CCOC1=CC(=O)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: CC1CCCO1
Solvent: CC#N
Solvent: CC(C)O
Product: CC(C)c1nc2c([nH]1)CCCC2=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-(ethyloxy)-2-cyclohexen-1-one (1000 g, 1.0 eq, 1.0 wt) was dissolved in acetonitrile (5 L, 5 vol) at 0° C. and N-bromosuccinimide (1295 g, 1.02 eq, 1.295 wt) was added in four equal portions over 1 hour at <5° C. The mixture was stirred for 15 minutes at 0° C., warmed to 20° C. and stirred for a further 15 minutes at this temperature and sampled for completion by HPLC. Reaction was complete. 2-methylpropanimidamide (981 g, 1.1 eq, 0.981 wt) was added and the mixture stirred for 5 minutes at 20° C. Anhydrous sodium carbonate (1134 g, 1.5 eq, 1.134 wt) was charged to the vessel and the contents warmed to 65° C., stirred for a further 2 hours and sampled for completion by HPLC. Reaction was complete. Water (7 L, 7 vol) was added at 60° C. and the contents stirred for a further 15 minutes. 2-methyltetrahydrofuran (7 L, 7 vol) was added at 50° C. The suspension was cooled to 25° C., filtered and the inorganic solids washed with 2-methyltetrahydrofuran (2 L, 2 vol). The biphase was stirred for 5 minutes, settled and separated. The aqueous phase was back-extracted with 2-methyltetrahydrofuran (5 L, 5 vol). The combined organic phases were concentrated by atmospheric distillation to 5 L/5 vol. Toluene (10 L, 10 vol) was added, the mixture was concentrated by atmospheric distillation to 5 L/5 vol and cooled to 60° C. 5-6M hydrochloric acid in propan-2-ol (2 L, 1.3 eq, 2 vol) was added over 35 minutes at 60° C. Crystallisation was observed towards the end of the addition. The slurry was aged at 60° C. for 1 hour, cooled to 0° C. over 4 hours and stirred at this temperature for 10 hours 45 minutes. Solids were collected by vacuum filtration, washed with chilled (5° C.) toluene/propan-2-ol (2×2.5 L, 2:1 v/v, 2×2.5 vol), followed by tert-butylmethylether (2×2.5 L, 2×2.5 vol) and dried in vacuo at 50° C. for 5 hours. Yield of title compound obtained was 887 g, however this contained 13.2% w/w succinic acid and 4.2% w/w inorganics. Corrected yield was therefore 736 g/48% theory yield/74% w/w yield.
Reaction SMILES: CS[C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.FC1C2SC([I:24])=NC=2C=CC=1>>[I:24][C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Fc1cccc2nc(I)sc12
Reactant: CSc1nc2cccc(C#N)c2s1
Product: N#Cc1cccc2nc(I)sc12

Procedure:
The title compound was prepared from 2-methylsulfanyl-1,3-benzothiazole-7-carbonitrile as described for 7-fluoro-2-iodo-1,3-benzothiazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([CH2:28][O:29]C)[O:10][N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C(C3N=CN(C4C=CC(C(=O)C)=CC=4)C=3)=C(COC)ON=2)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([CH2:28][OH:29])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COCc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Agent: COCc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(C)=O)cc2)cn1
Product: OCc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Yield: 100.9 %

Procedure:
As described for Example 140, 3-(4-fluoro-phenyl)-5-methoxymethyl-4-[1-(4-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-isoxazole (417 mg, 1.13 mmol), instead of 1-(4-{4-[3-(4-fluoro-phenyl)-5-methoxymethyl-isoxazol-4-yl]-imidazol-1-yl}-phenyl)-ethanone, was converted to the title compound (460 mg, 95%) which was obtained as yellow solid. MS: m/e=403.9 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33]C5CCCCO5)[CH:28]=4)=[C:25]([CH3:40])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:41]C5CCCCO5)[CH:23]=4)[O:18]3)=[CH:13][CH:12]=2)[CH2:4]1>C(O)(=O)C>[F:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=4)=[C:25]([CH3:40])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([OH:41])[CH:23]=4)[O:18]3)=[CH:13][CH:12]=2)[CH2:4]1
Reactant: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(OCCN3CC[C@@H](CF)C3)cc2)Oc2ccc(OC3CCCCO3)cc21
Solvent: CC(=O)O
Product: CC1=C(c2cccc(O)c2)[C@@H](c2ccc(OCCN3CCC(CF)C3)cc2)Oc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A mixture of (3R)-3-(fluoromethyl)-1-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)pyrrolidine (1.87 g, 2.9 mmol) in acetic acid (80% aq., 30 mL) was stirred at room temperature overnight. The acetic acid was removed and the residue was partitioned between ethyl acetate and sat'd aqueous NaHCO3. The organic layer was washed with sat'd aqueous NaHCO3, dried over sodium sulfate, filtered and the solvent removed. The residue was purified by flash chromatography on silica gel (0 to 5% methanol/dichloromethane) to afford 1.1 g of (R)-2-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol as a pinkish foam. 1H NMR (DMSO-d6): δ 9.43 (s, 1H), 8.94 (s, 1H), 7.18 (d, 2H), 7.14 (t, 1H), 6.78 (d, 2H), 6.73 (s, 1H), 6.67-6.65 (m, 2H), 6.65 (s, 1H), 6.49-6.45 (m, 2H), 5.83 (s, 1H), 4.35-4.30 (m, 1H), 4.23-4.19 (m, 1H), 3.96 (t, 2H), 2.71 (t, 2H), 2.60 (t, 1H), 2.46-2.40 (m, 3H), 2.36-2.31 (m, 1H), 2.02 (s, 3H), 1.83-1.76 (m, 1H), 1.39-1.30 (m, 1H); LCMS: 476 (M+H)+.
Reaction SMILES: COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)NN=2)C=CC=1OC.BrC([C:25]1[C:33]2[N:32]=[N:31][NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)C.[CH2:34]([N:41]1[N:50]=[C:49]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([O:59][CH3:60])[CH:52]=2)[C@H:48]2[C@H:43]([CH2:44][CH2:45][CH2:46][CH2:47]2)[C:42]1=[O:61])C1C=CC=CC=1.C([O-])C.[Na+]>>[N:30]1([CH2:34][N:41]2[N:50]=[C:49]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([O:59][CH3:60])[CH:52]=3)[C@H:48]3[C@H:43]([CH2:44][CH2:45][CH2:46][CH2:47]3)[C:42]2=[O:61])[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:33]=2[N:32]=[N:31]1
Reactant: CC(Br)c1cccc2[nH]nnc12
Reactant: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: CC[O-]
Agent: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: [Na+]
Product: COc1ccc(C2=NN(Cn3nnc4ccccc43)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 1-bromoethylbenzotriazole as described for compound 78, using sodium ethanolate instead of sodium hydride. Purified by chromatography [ethyl acetate:petroleum ether (60°-95° C.)/1:2]. Crystallized from methanol. M.p. 173°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:15]([C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([F:24])[CH:8]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:15]([C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:10]([C:11]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:12])=[C:9]([F:24])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ncccc1-c1cc(C(=O)O)c(F)cc1Oc1ccc(Cl)cc1
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
Solvent: ClCCl
Product: COc1ncccc1-c1cc(C(=O)NS(C)(=O)=O)c(F)cc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 117.9 %

Procedure:
To a mixture of 4-(4-chlorophenoxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoic acid (Preparation 30, 236 mg, 0.63 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (462 mg, 1.21 mmol), N,N-diisopropylethylamine (838 μL, 4.81 mmol) in dichloromethane (40 mL) and dimethylformamide (5.4 mL) which had been stirred at room temperature for 10 minutes was added methyl sulfonamide (151 mg, 1.59 mmol). The reaction was heated at 45° C. for 18 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo to afford a brown residue. The brown residue was partitioned between aqueous hydrochloric acid (0.5 M, 40 mL) and dichloromethane (100 mL). The organic extract was washed with aqueous hydrochloric acid (0.5 M, 2×40 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil (335 mg). The product was purified by flash column chromatography eluting with dichloromethane/methanol (100% to 97%) to afford a yellow gum (91.0 mg). A portion of this material (50 mg) was purified by A-HPLC to afford the title compound as an off-white solid (35.8 mg, 13%):
Reaction SMILES: Cl.ClC1C=C2C(=CC=1)OC1(CCNCC1)CC2.C([N:25]1[CH2:30][CH2:29][C:28]2([C:34]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=3[CH2:32][O:31]2)[CH2:27][CH2:26]1)C1C=CC=CC=1.ClC(OCCCl)=O>>[F:39][C:37]1[CH:36]=[CH:35][C:34]2[C:28]3([O:31][CH2:32][C:33]=2[CH:38]=1)[CH2:27][CH2:26][NH:25][CH2:30][CH2:29]3
Reactant: Fc1ccc2c(c1)COC21CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: Clc1ccc2c(c1)CCC1(CCNCC1)O2
Agent: O=C(Cl)OCCCl
Product: Fc1ccc2c(c1)COC21CCNCC1

Procedure:
This reaction was performed as described for (iii) above using 1′-benzyl-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidine] (145 mg, 0.487 mmol), chloroethyl chloroformate (0.07 mL) to give the titled compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20]([CH2:25][CH3:26])=[CH:19]4)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1>CS(C)=O.C(OCC)(=O)C>[CH2:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[C:17]1[O:27][CH:13]([CH2:12][N:28]3[CH2:29][CH:30]=[C:31]([C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[NH:36][CH:35]=4)[CH2:32][CH2:33]3)[CH2:14][O:15][C:16]1=[CH:24][CH:23]=2)[CH3:26]
Reactant: CCc1cc2c3c(ccc2[nH]1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1cc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3

Procedure:
A solution of 0.52 g (1.3 mmole) of [(2R)-8-ethyl-2,3-dihydro-7H-[1,4]-dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate and 0.80 g (4.1 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 20 mL of DMSO was heated at 65° C. for 3 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0-2% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with ether/hexane (1:1) to give 0.11 g of the (S)-enantiomer of the title compound as a yellow solid hydrate, m.p. 175-177° C.