Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[C:12](O)(=[O:14])[CH3:13]>[Fe]>[F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[NH:8][C:12](=[O:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CC(=O)O
Agent: [Fe]
Product: CC(=O)Nc1ccc(O)cc1F
Temperature: 25 °C
Yield: 64 %

Procedure:
373.3 mg of iron powder were added to a solution of 300 mg of 3-fluoro-4-nitrophenol [prepared as described in step (c) above] in 6 ml of glacial acetic acid. The resulting mixture was stirred under reflux for 6 hours, after which it was allowed to cool to room temperature. Ice-water was then added to the reaction mixture and the solvent was removed by evaporation under reduced pressure. Ethyl acetate was added to the residue and the resulting solution was washed with water and then dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a mixture of hexane and ethyl acetate as the eluent, initially using a 2:1 by volume mixture of the two solvents and then changing to a 1:1 by volume mixture, to give 206.8 mg (yield 64%) of the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:25]=[CH:24]3)[C@H:9]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH2:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[N:25]=[CH:24]3)[C@@H:9]([NH:10][C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH2:11][O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](COCc1ccccc1)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N[C@@H](COCc1ccccc1)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-[(phenylmethoxy)methyl]benzeneethanamine is synthesized in analogy to the sequence previously described in example 1: commercially available Boc-Ser(Bn)-OH is transformed into its Weinreb-amide. Reduction to the aldehyde with LiAl4, reaction with 3-fluorophenylgrignard, cleavage of the tert.-butyloxycarbonyl protecting group, liberation of the amine from the hydrochloride and etherification with 1-(4-fluorophenyl)-5-iodo-1H-indazole gives the desired amine. This amine (123.3 mg, 0.25 mmol) is dissolved in 10 mL of dichloromethane. Triethylamine (0.084 mL, 0.61 mmol) and 0.028 mL (0.3 mmol) 2-methoxyacetylchloride are added. The reaction mixture is stirred overnight at r.t., then diluted with dichloromethane, washed with water and brine and dried over Na2SO4. After filtration the solvent is evaporated and the residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane). 79.1 mg (55.9%) of the title compound as a mixture of stereoisomers are isolated.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([OH:38])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=3[OH:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(F)ccc1O
Product: Oc1ccc(F)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-fluoro-2-hydroxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 503; MS (ESI) m/z 501.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](/[CH:11]=[CH:12]/[C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)CS(=O)(=O)c1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 70-72% yield.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:18]=[C:17]([F:19])[C:16]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([CH3:27])[N:22]([CH3:28])[C:21]2=[O:29])=[CH:15][C:8]=1[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]>C(O)(=O)C>[Cl:6][C:7]1[CH:18]=[C:17]([F:19])[C:16]([N:20]2[C:25](=[O:26])[C:24]([Cl:4])=[C:23]([CH3:27])[N:22]([CH3:28])[C:21]2=[O:29])=[CH:15][C:8]=1[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Solvent: CC(=O)O
Product: Cc1c(Cl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.3 g of sulphuryl chloride are added dropwise with stirring to a solution of 15.0 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 100 ml of acetic acid at room temperature during 1 minute, during which the temperature rises to approx. 30° C. Then the reaction mixture is stirred for a further 15 minutes at room temperature and evaporated to dryness under reduced pressure. The residue is dissolved in ethyl acetate and the solution washed in turn with aqueous sodium bicarbonate solution and water. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is recrystallized from methylene chloride/diethyl ether. Isopropyl 2-chloro-4-fluoro-5-[5-chloro-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 150°-153° C., is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13].[NH2:18][C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=1>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=1)=[O:17])(=[O:14])=[O:13]
Reactant: COCCOc1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(Cl)nc(N)n1
Solvent: C1COCCO1
Product: COCCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(OC)n1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A mixture consisting of 5.15 g of 2-methoxyethoxy-phenylsulfonyl isocyanate, 3.2 g of 2-amino-4-chloro-6-methoxy-pyrimidine and 70 ml of absolute dioxane is stirred for 3 hours at a temperature of 60°-70° C. The reaction mixture is cooled to a temperature of 20° C., treated with activated carbon, filtrated and evaporated to 1/4 of the original volume. After addition of 50 ml ether to the residue, 5.6 g of N-(2-methoxyethoxy-phenylsulfonyl)-N'-(4-chloro-6-methoxy-pyrimidin-2-yl)urea are obtained in the form of crystals having a melting point of 166°-168° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:11].[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:8][CH2:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[O:11])[CH2:32][CH2:31]2)[CH:25]=1)=[O:22]
Reactant: Cc1ccc(C(=O)CCCl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 3-chloro-1-(4-methylphenyl)-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 393.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][OH:22])[O:12]1.C[Si](Cl)(C)C.[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.N>N1C=CC=CC=1.O>[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[C@H:11]2[C@H:15]3[C@H:14]([O:18][C:17]([CH3:19])([CH3:20])[O:16]3)[C@@H:13]([CH2:21][OH:22])[O:12]2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(NC(=O)c3ccc(Br)cc3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (0.400 g, 1.30 mmol) was dried by co-evaporation with pyridine, then suspended in dry pyridine (6.5 mL). TMSCl (0.330 mL, 2.60 mmol) was added and the mixture was stirred for 15 min. 4-Bromobenzoylchloride (0.342 g, 1.56 mmol) was added to the mixture and stirred for 2 h. The solution was cooled to 0° C. and 1 mL of H2O was added. After 5 min a 29% NH3 aq solution (0.847 mL) was added and the reaction mixture was stirred for 30 min while warming to r.t. The mixture was then concentrated and the residue was diluted with H2O (40 mL). The product was extracted with EtOAc (60 mL) and concentrated. The crude material was purified by flash chromatography (65 to 100% EtOAc/hexanes) to afford the title compound (0.305 g, 49%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1B(O)O>>[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cc5ccccc5o4)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and benzofuran-2-boronic acid were coupled in the same way as in Example 30 to give 2-{3-[3-(benzofuran-2-yl)-4-fluorophenyl]-8-fluoroimidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (6 mg, 3%): m/z (ES+) 405 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[C:5]=1[Cl:11].[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:13]#[N:14])[C:5]=1[Cl:11]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccnc(Cl)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccnc(C#N)c1Cl
Temperature: 190 °C
Yield: 43 %

Procedure:
A microwave vial was charged with 2,3-dichloro-isonicotinic acid methyl ester (7.6 g, 36.9 mmol), zinc cyanide (4.75 g, 40.6 mmol), tetrakis(triphenylphosphine)palladium (1.0 g, 0.9 mmol) and DMF (37 mL), then capped, evacuated and backfilled with nitrogen. The reaction solution was subjected to microwave irradiation, heating at 190° C. for 20 minutes, then filtered through a pad of Celite® which was washed further with ethyl acetate. The resulting mixture was washed with water, followed by a saturated solution of sodium hydrogen carbonate, then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to column chromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in cyclohexane) to give the title compound as a white solid (3.1 g, 43%). 1H NMR (CDCl3, 400 MHz) 8.70 (d, J=5.0 Hz, 1H), 7.87 (d, J=5.0 Hz, 1H), 4.01 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33]S(C5C=CC(C)=CC=5)(=O)=O)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:54].[CH2:55]([O:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1O)[CH3:56]>>[CH2:55]([O:57][C:58]1[CH:59]=[C:60]([CH:61]=[CH:62][CH:63]=1)[O:33][CH2:32][CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]2[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:45])[CH2:19][CH:18]2[O:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][CH2:8][C:7](=[O:54])[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=3[CH:12]=2)=[CH:25][CH:26]=1)[CH3:56]
Reactant: CCOc1ccccc1O
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCOS(=O)(=O)c4ccc(C)cc4)cc3)cc21
Product: CCOc1cccc(OCCOc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3OCc3ccc4c(c3)N(CCCOC)C(=O)CO4)cc2)c1

Procedure:
Analogously to Method I, 0.420 g of benzyl 3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[2-(toluene-4-sulphonyloxy)ethoxy]phenyl}piperidinecarboxylate and 0.124 g of ethoxyphenol are reacted. The title compound is obtained as a dark yellow oil. Rf=0.16 (1:1 EtOAc-heptane); Rt=5.68.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1.C[O:15][C:16](=[O:26])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[CH:11]([S:10][C:4]1[C:3]([CH2:2][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:16]([OH:26])=[O:15])=[CH:24][CH:23]=2)=[CH:8][C:7]([CH3:9])=[CH:6][N:5]=1)([CH3:13])[CH3:12]
Reactant: Cc1cnc(SC(C)C)c(CCl)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Product: Cc1cnc(SC(C)C)c(COc2ccc(CCC(=O)O)cc2)c1
Yield: 55 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-5-methyl-pyridine (0.052 g, 0.24 mmol) obtained in Step D of Preparation Example 30 and 3-(4-hydroxy-phenyl)-propionic acid methyl ester (0.043 g, 0.24 mol) obtained in Preparation Example 4 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (55%).
Reaction SMILES: [OH:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:37]=[C:36]([Br:38])[C:22]([O:23][C@H:24]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])=[C:21]([Br:39])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C=O>[CH2:40]([O:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:37]=[C:36]([Br:38])[C:22]([O:23][CH:24]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:25]([O:27][CH3:28])=[O:26])=[C:21]([Br:39])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(O)c3sc4ccccc4c23)cc1Br
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(OCc3ccccc3)c3sc4ccccc4c23)cc1Br
Reaction time: 17 h
Yield: 100.7 %

Procedure:
To a solution of (R)-2-[4-(6-hydroxy-benzo[b]naphtho[2,3-d]thiophen-11-yl]-2,6-dibromo-phenoxy]-3-phenyl-propionic acid, methyl ester (0.50 g, 0.755 mmol) in dry N,N-dimethylformamide (5 mL) was added benzyl bromide (0.27 mL, 2.27 mmol, 3 eq) dropwise at room temperature under a dry nitrogen atmosphere. After stirring about 17 hours the reaction was quenched with water (50 mL) and the organics were extracted with ether. The extracts were washed with water, and brine and combined with silica gel. The solvent was removed and the adsorbate was flash chromatographed (97/3 petroleum ether/ethyl acetate) and the solvents chased with benzene and petroleum ether to provide the title compound as a pale yellow solid (0.572 g, 84%): NMR (CDCl3); δ8.30 (ddd, J=8, 1, 1 Hz, 1 H), 7.82 (ddd, J=8,1,1 Hz, 1 H), 7.68 (ddd, J=8, 1, 1 Hz, 2 H), 7.62 (dd, J=3, 2 Hz, 2 H), 7.60-7.55 (m, 2 H), 7.51-7.26 (m, 10 H), 7.16 (ddd, J=8, 7,1 Hz, 1 H), 6.81 (ddd, J=8, 1, Hz, 1 H), 5.34 (s, 2 H), 5.25 (dd, J=6, 2 Hz, 1 H), 3.76 (s, 3 H), 3.59 (septet, J =Hz, 2 H); MS (EI): [M+], 2 bromine isotope pattern, 750 (2%), 752 (3.5%), 754 (2.5%); Anal Calc. for C39H28Br2O4S: C, 62.25, H, 3.75, N, 0.00; Found C, 61.66, H, 3.53, N, 0.25.
Reaction SMILES: [Br-:1].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30](=[O:44])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([C:38]([CH:41]([CH3:43])[CH3:42])=[N:39][N:40]=2)[N:37]=1>C1COCC1.C(Cl)Cl>[Br:1][CH:31]([C:32]1[CH:33]=[CH:34][C:35]2[N:36]([C:38]([CH:41]([CH3:42])[CH3:43])=[N:39][N:40]=2)[N:37]=1)[C:30]([C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[F:22])=[O:44]
Reactant: [Br-]
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
Pyridinium tribromide (0.567 g, 1.77 mmol) was added to a solution of 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.488 g, 1.54 mmol; Preparation #K.1) in THF (6 mL) and the resulting reaction mixture was stirred at ambient temperature for about 4 h. The crude mixture was diluted with DCM (20 mL) and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude title compound (0.61 g, 100%): LC/MS (Table 1, Method a) Rt=3.28 min; MS m/z: 396.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:23][CH2:24][CH2:25][O:26][Si](C(C)(C)C)(C)C)[CH:12]([F:13])[C:11](=[O:14])[N:10]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:12]([F:13])[C:11](=[O:14])[N:10]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)C(F)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@@](CCCO)(C(=O)OC(C)(C)C)C(F)C1=O
Temperature: 25 °C
Reaction time: 21.5 h
Yield: 92.9 %

Procedure:
(3S)-3-[3-(tert-Butyldimethylsilyloxy)-1-propyl]-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (8.15 g) was dissolved in tetrahydrofuran (25.0 mL). Acetic acid (22.0 mL) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran) (25.0 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 21.5 hours. The reaction solution was extracted with a 10% citric acid solution and ethyl acetate. Then, the organic layer was sequentially washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→8:2→1:1) to give 5.77 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.Cl.[NH2:26][C:27]1([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:34][C:32](=[O:33])[C:27]4([CH2:31][CH2:30][CH2:29][CH2:28]4)[N:26]=3)[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: NC(=O)C1(N)CCCC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: Cl
Product: Cc1c(C2=NC3(CCCC3)C(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 25 was synthesized from 4a (251 mg, 0.66 mmol) and 5j (140 mg, 0.98 mmol) as a white solid (140 mg, 45%) in a manner similar to that described in Example 53. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, 1H), 7.32˜7.26 (m, 3H), 7.12 (s, 1H), 7.02 (d, 2H), 2.49 (m, 2H), 2.36 (s, 3H), 2.17 (m, 2H), 1.86 (m, 4H); ESMS m/z: 473.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[C:19]([OH:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:43][CH2:44][O:45][C:46](/[C:48](/[NH2:51])=[N:49]/O)=[O:47]>C(Cl)Cl.CCOC(C)=O>[NH2:51][C:48](=[N:49][O:20][C:19](=[O:21])[C:18]([N:13]1[C:14]2[C:10](=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[N:12]1)([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:22][CH3:23])[C:46]([O:45][CH2:44][CH3:43])=[O:47]
Reactant: CCOC(=O)/C(N)=N/O
Reactant: CCC(C(=O)O)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)=NOC(=O)C(CC)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
To a suspension of 2-(4-((tert-butoxycarbonyl)amino)-1H-indazol-1-yl)-2-(4-chlorophenyl)butanoic acid from Step A above (0.16 g, 0.37 mmol) in DCM (1.5 mL) was added 1,1′-carbonyldiimdazole (0.13 g, 0.78 mmol) to give a clear solution. The mixture was stirred for 7.5 hours at RT followed by addition of ethyl 2-oximinooxamate (0.13 g, 0.93 mmol). After stirring at RT overnight, the resulting mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, water and brine. The organic layer was separated, and concentrated. The resulting crude product was re-dissolved in a mixture of acetonitrile and water and dried in a lyophilized to give the title compound as light yellow solid. LC/MS m/z=544.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH:18]([CH3:20])[CH3:19].[Li]CCCC.ClN1C(=O)CCC1=O>COCCOC.CO>[CH:18]([O:17][C:3]1[C:4]2[S:8][C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])=[N:6][C:5]=2[CH:15]=[CH:16][CH:2]=1)([CH3:20])[CH3:19]
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(OC(C)C)c2s1
Agent: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: COCCOC
Product: CCNC(=O)Nc1nc2cccc(OC(C)C)c2s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 25.1 %

Procedure:
A solution of 1-(6-bromo-7-isopropoxy-2-benzothiazolyl)-3-ethylurea (0.036 g, 0.10 mmol) in 0.5 mL DME was cooled down to about −78° C., and was treated with a solution of 1.6 M n-BuLi in hexanes (0.16 mL, 0.26 mmol, 2.6 eq). It was stirred at the temperature for about 20 min, then a solution of N-chlorosuccinimide (NCS) (0.015 g, 0.11 mmol, 1.1 eq) in 0.5 mL DME was added. It was warmed up to about 0° C. for about 0.5 hour. It was taken up in MeOH and purified by HPLC to give 0.007 g (25%) of the title compound. LC/MS 279.9 (M+1); LC retention time 3.10 min.
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)[CH3:3]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[C:2]([C:4]1[O:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=1)(=[O:1])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)O)on1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C(C)=O)on1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
4.06 g of ethyl 5-(1-hydroxyethyl)-isoxazole-3-carboxylate was dissolved in 100 ml of 1,4-dioxane, and 15.20 g of manganese dioxide was then added. The mixture was stirred and heated under reflux for 5 hours. The reaction mixture was cooled to room temperature and then filtered through Celite®. The filtrate was concentrated under reduced pressure to obtain 3.57 g of ethyl 5-acetylisoxazole-3-carboxylate.