Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:22][CH:19]([CH3:21])[CH3:20])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)NC1=C(c2ccccc2)S(=O)(=O)N(C(C)C)C1=O

Procedure:
The title compound was prepared from 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and isopropylamine in a similar manner as described for Example 24. 1H NMR (500 MHz CDCl3): δ 7.56-7.51 (m, 2H), 7.48-7.43 (m, 3H), 5.14 (d, 1H), 4.42 (sept, 1H), 3.40-3.30 (m, 1H), 1.60 (d, 6H), 1.00 (d, 6H); 13C NMR (125 MHz CDCl3): δ 158.9, 134.6, 131.7, 129.9, 128.9, 125.5, 106.3, 47.8, 44.9, 23.0, 20.4; Mass Spectrum: M+H+ 309.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)[CH:8]1[CH2:32][C:33]3[C:38]([CH:7]21)=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[NH:3])[NH2:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:72]([NH2:76])[CH:73]([CH3:75])[CH3:74]>CN(C=O)C>[CH2:72]([NH:76][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:15]2[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=2[CH:9]2[CH:8]3[CH2:32][C:33]4[C:38]([CH:7]3[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:3])[NH2:2])[CH:5]=3)[NH:10]2)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=1)=[O:31])[CH:73]([CH3:75])[CH3:74]
Reactant: CC(C)CN
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2)cc1O
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: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NCC(C)C)cc2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(0.1 mmol; 50.5 mg) of 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-4′-methoxy-biphenyl-4-carboxylic acid was dissolved in 4 mL of DMF followed by the addition of HATU (0.3 mmol; 114 mg), N,N-diisoproplyethylamine (0.6 mmol; 0.1 mL) and isobutylamine (0.6 mmol; 0.6 ml). The reaction was stirred at room temperature for 18 hours, filtered and purified by LC/MS prep system to give 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-4′-methoxy-biphenyl-4-carboxylic acid isobutyl-amide. Mass spectrum: 561 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9].[NH2:15][C:16]1[C:17]([C:38]#[N:39])=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][C:23]=2[F:37])=[CH:20][N:21]=1>>[NH2:15][C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:2]3[C:3]([S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:24][C:23]=2[F:37])=[N:18][C:17]=1[C:38]#[N:39]
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(NCCO)c1ccccc1Br
Product: N#Cc1nc(-c2ccc(-c3ccccc3S(=O)(=O)NCCO)cc2F)cnc1N

Procedure:
The title compound was prepared in manner similar to that described in Example 88 using 2-bromo-N-(2-hydroxyethyl)benzenesulfonamide and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C19H16FN5O3S, 413.10; m/z found, 414.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.81 (d, J=1.8, 1H), 8.17 (dd, J=8.0, 1.4, 1H), 8.02 (m, 1H), 7.64 (m, 1H), 7.56 (m, 1H), 7.40-7.31 (m, 3H), 5.38 (s, 2H), 4.35 (s, 1H), 3.64-3.58 (m, 2H), 2.95-2.87 (m, 2H), 1.64 (t, J=5.2, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:14]([C:16]2[CH:28]=[CH:27][C:19]3[N:20]=[C:21]([NH:23][CH:24]([CH3:26])[CH3:25])[S:22][C:18]=3[CH:17]=2)[OH:15])SCCCS1.C[OH:30].C(Cl)Cl>C(#N)C.O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:30])[CH:14]([OH:15])[C:16]1[CH:28]=[CH:27][C:19]2[N:20]=[C:21]([NH:23][CH:24]([CH3:26])[CH3:25])[S:22][C:18]=2[CH:17]=1
Reactant: CO
Reactant: CC(C)Nc1nc2ccc(C(O)C3(c4ccccc4F)SCCCS3)cc2s1
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)Nc1nc2ccc(C(O)C(=O)c3ccccc3F)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of (2-(2-fluorophenyl)-1,3-dithian-2-yl)(2-(isopropylamino)benzo[d]thiazol-6-yl)methanol (0.540 g, 1.24 mmol) in acetonitrile (8 mL) and water (1.3 mL) was added a solution bis(trifluoroacetoxy)idobenzene (0.800 g, 1.86 mmol) in acetonitrile (4 mL) at rt over 5 min. The mixture was stirred at rt for 1 hr before it was diluted with AcOEt (100 mL), washed successively with saturated NaHCO3 solution and brine, and dried over anhydrous MgSO4. The title compound (87.0 mg, 20% yield) was isolated as a light yellow waxy material by silica gel chromatography (3% MeOH/CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:42]([NH:49][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 636.4 %

Procedure:
Combined 6-chloronicotinic acid (20 g, 12.74 mmol) and HATU (72.6 g, 19.1 mmol) in DMF (200 mL) and added triethylamine (38.6 g, 38.2 mmol) drop wise, followed by benzylamine (16.36 g, 15.28 mmol) and stirred at room temperature overnight. Then the reaction mixture was poured into ice-water and stirred for 20 minutes to give a solid. The solid was collected by filtration, washed with water (30 mL×2), and dried under reduced pressure to give the title compound (20 g, 64%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:12][CH:11]([C:13]#[N:14])[CH2:10]2)[CH:7]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:15][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH:11]([C:13]#[N:14])[CH2:12]1
Reactant: N#CC1CC(Nc2cc(F)ccc2[N+](=O)[O-])C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#CC1CC(Nc2cc(F)ccc2N)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A mixture of 3-(5-fluoro-2-nitrophenylamino)cyclobutanecarbonitrile (0.38 g, 1.61 mmol), iron powder (0.36 g, 6.44 mmol) and ammonium chloride (0.50 g, 9.66 mmol) in methanol (10 mL) and water (4 mL) was stirred at 90° C. for 2 hours. After cooling the solid material was filtered off and the solution was concentrated in vacuo. The residue was partitioned between ethyl acetate (3×) and water, then the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound as a dark green gum (0.26 g, 79%). LCMS (Method B): RT 1.75 min [M+H]+ 206.0
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[CH3:13][N:14]([CH3:18])[CH2:15][C:16]#[CH:17].C(N(C(C)C)CC)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(#N)C>[CH3:13][N:14]([CH3:18])[CH2:15][C:16]#[C:17][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC#Cc1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A resealable tube was charged with 2-bromo-5-(trifluoromethyl)aniline (1.00 g, 4.16 mmol), 1-dimethylamino-2-propyne (0.520 g, 6.20 mmol), PdCl2(PPh3)2 (0.15 g, 0.21 mmol), copper iodide (0.80 mg, 0.42 mmol), diisopropylethylamine (1.0 mL) and acetonitrile (3.0 mL). The system was purged with argon, the tube sealed and the mixture stirred at room temperature for 20 h. The reaction mixture was filtered through celite and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0-10% methanol-dichloromethane) to afford 2-(3-dimethylamino-1-propynyl)-5-(trifluoromethyl)aniline as a brown oil. MS m/z=243 [M+H]+. Calc'd for C12H13F3N2: 242.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[S:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=2[S:6][C:7]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc2ccc(Cl)cc2c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc2ccc(Cl)cc2c1CBr

Procedure:
A mixture of ethyl 5-chloro-3-methyl-benzo[b]thiophene-2-carboxylate (9.0 g, 0.035 mol), N-bromosuccinimide (6.53 g, 0.037 mol) and benzoyl peroxide (130 mg) in carbon tetrachloride (150 ml) was refluxed and illuminated with a sunlamp for 2 hours. The resulting suspension was cooled, filtered and the filter cake was triturated with methanol to give 9.9 g (85%) of the methanol-insoluble ethyl 3-bromomethyl-5-chlorobenzo-[b]thiophene-2-carboxylate: mp 148°-150° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:41])[CH2:3][N:4]([C:22]([C:24]1[N:28]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[N:25]=1)=[O:23])[C@@H:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C@H:7]([C:18]([O:20]C)=[O:19])[CH2:6]1.[OH-].[Na+].Cl>CO>[C:14]([O:13][C:11]([N:9]1[CH2:10][C@@H:5]([N:4]([CH2:3][CH:2]([CH3:1])[CH3:41])[C:22]([C:24]2[N:28]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:27]3[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=3[N:25]=2)=[O:23])[CH2:6][C@@H:7]([C:18]([OH:20])=[O:19])[CH2:8]1)=[O:12])([CH3:15])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCc1ccccc1)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-[(2-methylpropyl){[1-(2-phenylethyl)-1H-benzimidazol-2-yl]carbonyl}amino]piperidine-1,3-dicarboxylate (1.12 g) was dissolved in methanol, 2M aqueous sodium hydroxide solution (10 ml) was added dropwise at room temperature. The reaction mixture was stirred at 50° C. for 3 hr. The reaction mixture was adjusted to pH 7 with 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (1.07 g).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:19])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].N(C[C@H]1OC(=O)N(C2C=CC(SC[CH2:39][F:40])=C(F)C=2)C1)=[N+]=[N-].ClC1C=C(C=CC=1)C(OO)=O>>[N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:19][CH2:39][F:40])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CS(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SCCF)c(F)c2)C(=O)O1
Agent: O=C(OO)c1cccc(Cl)c1
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(S(=O)CCF)c(F)c2)C(=O)O1

Procedure:
This compound was prepared analogously to the synthesis of 5-(S)-azidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one from 5-(S)-azidomethyl-3-[4′-(2″-fluoroethyl)thio-3′-fluorophenyl]oxazolidine-2-one (0.280 g, 0.891 mmol) and m-chloroperoxybenzoic acid (77%, 0.200 g, 0.891 mmol). Yield 0.280 g (95%). MS (m/z): [M+H]+=331.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[C@@:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])([CH3:11])[O:9]2)[CH:7]=1.CO.[Cl-].[NH4+].[N-:24]=[N+:25]=[N-:26].[Na+]>O>[N:24]([C@H:8]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=1)[C@@:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])([OH:9])[CH3:11])=[N+:25]=[N-:26]
Reactant: C[C@@]1(c2cc(F)ccc2F)O[C@@H]1c1cncc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@](O)(c1cc(F)ccc1F)[C@H](N=[N+]=[N-])c1cncc(Br)c1
Reaction time: 0.08 h
Yield: 80.8 %

Procedure:
Placed 3-bromo-5-((2R,3S)-3-(2,5-difluorophenyl)-3-methyloxiran-2-yl)pyridine (100 mg, 0.307 mmol), methanol (12 mL), water (1.500 mL), ammonium chloride (32.8 mg, 0.613 mmol), and sodium azide (120 mg, 1.840 mmol) in a microware tube and stirred for five minutes then sealed the tube and lowed it to a 110° C. oil bath for 18 hour. The reaction mixture was concentrate to provide a white solid to which was added 25 mL water then extracted it by ether (25 mL×3). Combined all ether layer, dried over magnesium sulfate, concentrated to afford clear wax which was purified via column chromatography (5% to 35% EtOAc/Hex) to provide (1R,2R)-1-azido-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol (96.2 mg, 0.248 mmol, 81% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J=2.1 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.06 (t, J=1.8 Hz, 1H), 7.40 (ddd, J=9.8, 6.2, 3.2 Hz, 1H), 7.33-7.15 (m, 2H), 6.14 (s, 1H), 5.13 (s, 1H), 1.33 (d, J=0.9 Hz, 3H), Mass spec.: 371.1 (MH)+.
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][CH2:8][C:9](=[O:21])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:13].[C:22]1(C)[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>O.ClCCl>[C:24]1([CH3:8])[C:25]([S:28]([OH:31])(=[O:29])=[O:30])=[CH:26][CH:27]=[CH:22][CH:23]=1.[NH2:7][CH2:8][C:9](=[O:21])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCCCCCOC(=O)CCC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
Sodium hydrogen carbonate (0.42 g; 5.0 mmol) was added to a solution of hexyl 5-amino-4-oxopentanoate hydrochloride (0.5 g; 2.0 mmol) in water (10 ml) and dichloromethane (5 ml). The mixture was shaken thoroughly and allowed to separate. The organic layer was pipetted off and added to p-toluenesulfonic acid (0.38 g; 2.0 mmol). The aqueous portion was extracted with dichloromethane (1×1 ml). The combined organic solutions were evaporated, leaving a yellow oil that solidified on overnight storage in a freezer. The residue was purified by flash chromatography on a 170×25 mm silica gel 60 column eluted with acetonitrile (150 ml), 5% methanol in acetonitrile (500 ml), and 10% methanol in acetonitrile (250 ml), collecting 15×50 ml fractions. Fractions containing the product were evaporated, leaving 0.31 g (40%) residue.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[O:13][CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: CCO[C@@H](Cc1ccc(O)cc1OC)C(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1OC)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-[2-methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester as colorless liquid.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CC(Br)c2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
To a stirring solution of 3-Bromo indan-1-one (400 mg, 1.90 mmol) in DMF (5 ml) was added sodium azide (1.98 g, 0.03 mol). The reaction was allowed to stir at room temperature for 15 mins. The product was partitioned between water (10 ml) and ether (10 ml). The ether layers were combined and the crude reaction mixture was passed through a plug of flash silica, eluting with petroleum ether:ethyl acetate (9:1). The product was isolated as an orange oil (283 mg, 86%).
Reaction SMILES: C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:35](#[N:39])[CH2:36][C:37]#[N:38]>CN(C=O)C>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([CH:36]([C:35]#[N:39])[C:37]#[N:38])=[O:32])=[CH:33][CH:34]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: N#CCC#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CC(C#N)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
Diethylcyanophosphonate (5 mmol) and triethylamine (15 mmol) are added to a solution of 4-benzyloxybenzoic acid (18, 5 mmol) and malononitrile (4.8 mmol) in DMF (10 mL) stirred at 0° C. After the addition is complete, stirring is continued as the solution is allowed to warm to ambient temperature. Progress of the reaction is followed by tic and when complete, the reaction solution is concentrated under reduced pressure. The residue is taken up in EtOAc and washed with cold 1N HCl and then with aq. NaHCO3. The alkaline bicarbonate wash is acidified with 6N HCl and the mixture is extracted with EtOAc. The combined EtOAc extract solutions are dried (Na2SO4), filtered and concentrated under reduced pressure, giving the desired 4-benzyloxybenzoylmalononitrile 19. The product is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([O:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH3:25])[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([NH:13][C:14]2[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([O:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[CH3:25])[CH:15]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COC(=O)c1sc(N)cc1O[C@H](C)c1ccccc1Cl
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(Nc2cc(F)c(Cl)cc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
To a solution of 1-bromo-4-chloro-5-fluoro-2-nitrobenzene (6.0 g, from a different batch prepared analogous to Example 67, Step A, 23.0 mmol) and methyl 5-amino-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate (Intermediate 30, 11.0 g, 35.0 mmol) in toluene (70 mL) was added tris(dibenzylideneacetone)dipalladium (0) chloroform complex (595 mg, 0.58 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xantphos (665 mg, 1.20 mmol) and Cs2CO3 (22.5 g, 69.0 mmol)) with vigorous stirring. The reaction flask was sealed and carefully evacuated and refilled with N2 three times and the reaction mixture was stirred at 60° C. for 15 h. The reaction mixture was filtered through a pad of silica gel washing with copious amounts of 20% EtOAc in hexanes. The volatiles were evaporated under reduced pressure to give methyl 5-[(4-chloro-5-fluoro-2-nitrophenyl)amino]-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate 7.24 g (64%). This intermediate was dissolved in acetic acid (25 mL) and added via an addition funnel to a solution of iron power (4.0 g, 75 mmol) and acetic acid (20 mL) at 55° C. with vigorous stirring. The reaction mixture was then cooled to rt, diluted with EtOAc and filtered through celite and the resulting filtrate was neutralized with 6N MaOH solution and saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layer was dried over Na2SO4 and the volatiles were evaporated under reduced pressure to give methyl 5-[(2-amino-4-chloro-5-fluorophenyl)amino]-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate. To this material was added trimethylorthoformate (150 mL) and formic acid (10 mL) and the resulting reaction mixture was stirred at 40° C. for 1 h. Silica gel was added and the volatiles were evaporated under reduced pressure and the residue was purified by flash chromatography (0 to 15% EtOAc:hexane) to afford 4.7 g (67%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 1H), 8.03 (d, J=6.8 Hz, 1H), 7.58-7.83 (m, 2H), 7.38-7.50 (m, 2H), 7.44 (s, 1H), 7.25-7.37 (m, 1H), 5.99 (q, J=8.2 Hz, 1H), 3.82 (s, 3H), 1.62 (d, J=6.2 Hz, 3H), MS (ESI): 467 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23].O.[CH3:26]N(C)C=O>>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:26])[C:8]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[C:7]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CN(C)C=O
Reactant: O=C(O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 5.98 g) was added in portions to a stirred, cooled (0° C.) solution of 5-chloro-2-(4-chlorophenyl)-1H-indole-3-propanoic acid (Description 11, 10 g, 30 mmol) in dimethylformamide (100 mL) and the mixture was stirred at 0° C. for 30 min. lodomethane (9 mL) was added and the mixture was stirred at room temperature for 30 min. Water (1.5 L) was added and the mixture was extracted with ether (3×400 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (240 mL) and aqueous sodium hydroxide (4M, 60 mL) was added. The mixture was heated under reflux for 1 h., cooled and the pH was adjusted to 1.0 with hydrochloric acid (2M). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried in vacuo to give the the title compound (7.5 g, 72%). 1H NMR (360 MHz, CDCl3) δ2.54-2.59 (2H, m), 2.96-3.00 (2H, m), 3.53 (3H, s), 7.18-7.30 (4H, m), 7.44-7.48 (2H, m), and 7.58 (1H, d, J 1.8 Hz).
Reaction SMILES: [H-].[K+].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10].[CH2:11](B(CC)CC)C.CI>O1CCCC1>[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]
Reactant: CCB(CC)CC
Reactant: CC1CCCCC1=O
Agent: [H-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C)CCCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of potassium hydride (5.5 mmol) and 2-methylcyclohexanone (5 mmol) in dry tetrahydrofuran (10 ml) is stirred for 30 mins at room temperature. Triethylborane (6.25 mmol) is slowly added dropwise and the mixture is stirred for 16 hours at room temperature. After addition of methyl iodide stirring is continued for another 8 hours, the reaction is then quenched with saturated aqueous ammonium chloride solution and twice extracted with diethyl ether. The combined organic phases are dried over sodium sulphate and concentrated to dryness in a vacuum and produce the title compound, which can be reacted without [without] purification (JACS 1985, 107, 19, 5391-5396).