Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O.O/[N:63]=[C:64](/[C:72](=[O:74])[CH3:73])\[C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66]>O1CCCC1>[O:74]=[C:72]([CH3:73])/[C:64](=[N:63]/[O:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[CH2:3]1)/[C:65]([O:67][C:68]([CH3:70])([CH3:69])[CH3:71])=[O:66]
Reactant: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)/C(=N/O[C@H]1C[C@@H](C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
4-Nitrobenzyl (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine-2-carboxylate (3.24 g, 7.28 mmol) and triphenylphosphine (2.29 g, 8.7 mmol) in dry tetrahydrofuran (60 ml) under argon were treated with dimethyl azodicarboxylate (1.28 g, 8.7 mmol) in dry tetrahydrofuran (5 ml). After 5 min tert-butyl (Z)-2-hydroxyimino-3-oxobutyrate (2.59 g, 8.7 mmol) in dry tetrahydrofuran (10 ml) was added and the mixture was stirred under an argon atmosphere for 18 h. The tetrahydrofuran was removed and the residue taken up in ethyl acetate (150 ml) and washed with water containing a trace of acetone (100 ml,×6). The ethyl acetate layer was dried (MgSO4) and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with ethyl acetate/hexane mixture to give the title compound (2.49 g, 55%) as a mixture of two conformers/rotamers; νmax (CH2Cl2) 1735, 1710, 1605, 1525, and 1350 cm-1 ; δH (250 MHz, CDCl3) 1.52 (9H, s), 2.31 (3H, s), 2.40-2.80 (2H, m), 3.75-4.0 (2H, m), 4.66 (1H, approx dt, J ca 9.3, 1.5 Hz), 4.94-5.05 (1H, m), 5.1-5.4 (4H, m), 7.35-7.55 (4H, m), and 8.05-8.25 (4H, m).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:33](=[O:34])C1.CCN(CC)CC>C(Cl)Cl.C1COCC1>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]2[C:33](=[O:34])[O:21][CH2:20][CH2:19][O:18]2)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1cc(CNOCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NOCCO)c1cc(CN2OCCOC2=O)c(F)c(F)c1Nc1ccc(I)cc1F
Yield: 11.9 %

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-benzamide (100 mg, 0.185 mmol) obtained in Example 6, N,N′-disuccinimidyl carbonate (59 mg, 0.231 mmol) and NEt3 (113 mg, 1.12 mmol) were stirred in a mixed solvent of CH2Cl2/THF (1 mL/1 mL) at room temperature for 10 hours. The reaction mixture was purified by silica gel column chromatography (CH2Cl2/MeOH as a developing solvent) to give the title compound (12.5 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18][O:19][C:20](=[O:23])[CH2:21]Br>CN(C=O)C>[CH3:18][O:19][C:20](=[O:23])[CH2:21][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 289.1 %

Procedure:
To a DMF suspension (1 ml) of (4-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester (100 mg, 0.437 mmol), NaH (60% mineral oil dispersion, 68 mg) was added with ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture, bromoacetic acid methyl ester (0.19 ml, 2.06 mmol) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate (20 ml×2). The organic layers were combined, and washed with saturated aqueous sodium chloride solution. After the organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10:1), to obtain [tert-butoxycarbonyl-(4-chloro-pyridin-2-yl)-amino]-acetic acid methyl ester as a colorless liquid (380 mg, 97%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:23][C:22](=[O:28])[CH2:21]2>>[Cl:27][C:25]1[CH:26]=[C:18]([CH3:17])[CH:19]=[C:20]2[C:24]=1[NH:23][C:22](=[O:28])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: Cc1cc(Cl)c2c(c1)CC(=O)N2
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3c(Cl)cc(C)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-methyl-7-chloro-2-oxindole to give 0.35 g of 7-chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-5-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH:1]1([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[C:13]([CH2:24][O:25][C:26]2[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=2)=[C:12]3[C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.[NH2:54][C:55]1[CH:56]=[C:57]([CH:62]=[CH:63][CH:64]=1)[C:58]([O:60]C)=[O:59].C1COCC1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH:1]1([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21]([NH:54][C:55]2[CH:56]=[C:57]([CH:62]=[CH:63][CH:64]=2)[C:58]([OH:60])=[O:59])=[O:22])[C:13]([CH2:24][O:25][C:26]2[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=2)=[C:12]3[C:36]([N:38]2[CH2:39][CH2:40][CH2:41][CH2:42]2)=[O:37])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)CCCn1c(COc2ccc3ccccc3c2)c(C(=O)N2CCCC2)c2cc(NC(=O)C3CCCC3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CCCn1c(COc2ccc3ccccc3c2)c(C(=O)N2CCCC2)c2cc(NC(=O)C3CCCC3)ccc21)Nc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
The compound of Example 50 (1 eq) was weighed into a flask and to this was added EDCI (3 eq), DMAP (1.2 eq), methyl 3-aminobenzoate (1.2 eq) followed by anhydrous THF (0.04M) and the reaction mixture was then stirred at 25° C. for 2 d. Worked up with ethyl acetate/water followed by washing the organic layer with 1N HCl, saturated bicarbonate and brine. Recrystallization from ethyl acetate/hexane afforded the desired product in 88% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:27])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:34][C:35]1[CH:36]=[C:37]([C:42]([O:44][CH3:45])=[O:43])[CH:38]=[N:39][C:40]=1Cl>CS(C)=O>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:40]2[C:35]([Cl:34])=[CH:36][C:37]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][N:39]=2)=[CH:22][CH:21]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cnc(Oc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (600 mg) and potassium carbonate (254 mg) in dimethylsulfoxide (6.0 ml) was added methyl 5,6-dichloro-3-pyridinecarboxylate (347 mg), and the mixture was stirred at room temperature for 12 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]-5-chloronicotinate (770 mg).
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][N:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1.C1OC2C=CC(N)=CC=2O1.C(#N)CC#N.[OH2:32].[NH2:33][NH2:34]>CC(C)=O>[NH2:14][C:13]1[C:12](=[N:11][NH:10][C:8]2[CH:7]=[CH:6][C:5]3[O:32][CH2:2][O:3][C:4]=3[CH:9]=2)[C:15]([NH2:16])=[N:34][N:33]=1
Reactant: NN
Reactant: O
Reactant: N#CC(C#N)=NNc1ccc2c(c1)OCO2
Agent: Nc1ccc2c(c1)OCO2
Solvent: CC(C)=O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc2c(c1)OCO2
Yield: 1 %

Procedure:
This compound was prepared using 107 mg (0.5 mmol) of 2-(benzo[1,3]dioxol-5-yl-hydrazono)malononitrile, which was derived from 3,4-methylenedioxyaniline (137 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 min after the addition of hydrazine hydrate. The resulting black solid was isolated by filtration, dissolved in acetone, and hexanes was added to precipitate a small amount of black solid. The solid was removed by filtration and the filtrate was concentrated to yield 1.0 mg (1% yield) of the title compound as a black solid. 1H NMR (200 MHz, d6 DMSO) δ: 6.0 (brs, 6H), 6.92 (d, 1H), 7.18 (d, 1H), 7.38 (s, 1H), 10.60 (brs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:30])[C:3]=1[OH:31].[C:32]([O:37]C)(=[O:36])[C@H:33]([CH3:35])O.BrBr>C(Cl)(Cl)Cl>[Br:30][C:4]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:31][C@H:33]([CH3:35])[C:32]([OH:37])=[O:36]
Reactant: COC(=O)[C@H](C)O
Reactant: Cc1sc2c(Sc3ccccc3)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(Sc3ccccc3)c3ccccc3c(-c3cc(Br)c(O[C@H](C)C(=O)O)c(Br)c3)c2c1C

Procedure:
Prepared from 2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 13) and and commercially available methyl (S)-(−)-lactate according to the procedure of Example 30. White solid: mp 237-239° C.; [a]25/D=−1.99° (10.051 mg 1 mL, CHCl3); NMR (DMSO-d6); δ 13.2 (broad s, 1H, COOH), 8.43 (d, J=8 Hz, 1H), 7.80 (s, 2H), 7.62-7.58 (m, 1H), 7.56-7.50 (m, 2H), 7.23-7.13 (m, 3H), 7.04-7.01 (m, 2H), 5.03 (quartet, J=7 Hz, 1H), 2.40 (s, 3H), 1.63 (s, 3H), 1.57 (d, J=8 Hz, 3H); MS (EI): [M+], 2 bromine isotope pattern, 640 (47%), 642 (100%), 644 (56%); Anal. calc. for C29H22Br2O3S2: C, 54.22, H, 3.45, N, 0.00. Found: C, 53.64, H, 3.33, N, 0.05.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.C(O)(=O)C.[CH3:33][N:34]([CH3:39])[C:35](=[O:38])[CH2:36][NH2:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:33][N:34]([CH3:39])[C:35]([CH2:36][NH:37][C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=1)=[O:13])=[O:38]
Reactant: CN(C)C(=O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CNC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 43.2 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid dimethylcarbamoylmethyl-amide (25 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (48 mg), glycine dimethylamide acetate (21 mg), HBTU (53 mg), and DIEA (31 uL). LC/MS: m/z 493.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (t, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 4.13 (d, 2H), 3.65 (bs, 3H), 3.03 (s, 3H), 2.87 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][O:16][CH:17]3[CH:22]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])=[CH:25][CH:24]=4)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]3)[CH:13]=2)[C:8]([CH3:51])([CH3:50])[CH2:7]1)=[N+]=[N-].N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O.CO>[NH2:1][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][O:16][CH:17]3[CH:22]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])=[CH:25][CH:24]=4)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]3)[CH:13]=2)[C:8]([CH3:51])([CH3:50])[CH2:7]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCN=[N+]=[N-])CC3(C)C)cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCN)CC3(C)C)cc1
Reaction time: 1 h

Procedure:
The solution of 0.347 g of tert-butyl 3-[1-(2-azidoethyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 1.5 ml of tetrahydrofuran is admixed with stirring at room temperature successively with 0.32 ml of water, 1.40 ml of methanol, 0.32 ml of conc. ammonia and 0.210 g of triphenylphosphine, and stirred over 1 hour. The reaction mixture is admixed with water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed successively with water (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.41 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=5.54.
Reaction SMILES: NC([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]2[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]2)=[CH:10][CH:9]=1)C#N.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:25].[OH-].[Na+]>C(Cl)Cl>[CH3:21][C:18]1([CH3:22])[O:17][C@H:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH:5]=[O:25])=[CH:9][CH:10]=2)[CH2:20][O:19]1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCC(N)C#N)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)OC[C@@H](COc2ccc(CCC=O)cc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (3-[4-((R)-2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-phenyl]-propan-1-ol (Intermediate B, Step 2) (1.18 g, 4.42 mmol) in DCM (150 mL) is added Dess-Martin periodinane (1.88 g, 4.42 mmol). The reaction mixture is stirred at RT for 3 h then treated with 1 N NaOH solution (50 mL) and stirred at RT for 1 h. The organic layer is separated, dried (MgSO4), filtered and concentrated in vacuo to give a clear oil. Purification by flash column chromatography (SiO2, EtOAc:iso-hexane, gradient 17-25%) affords the title compound. [M+H]+ 265.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[N:18]=[N:17][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:25]#[C:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:24]=3)=[N:15]2)=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:26]#[C:25][C:23]2[CH:24]=[C:19]([C:16]3[N:17]=[N:18][N:14]([CH2:13][C:10]4[CH:9]=[CH:8][C:7]([C:6]([OH:35])=[O:5])=[CH:12][CH:11]=4)[N:15]=3)[CH:20]=[N:21][CH:22]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2nnc(-c3cncc(C#CCc4ccc(F)cc4)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(Cn2nnc(-c3cncc(C#CCc4ccc(F)cc4)c3)n2)cc1
Yield: 78 %

Procedure:
The product of Step (c) was treated with trifluoroacetic acid in dichloromethane in a manner analogous to that described above in Step (c) of Example 43, then rotary evaporated in vacuo. Trituration of the resulting oil with diethyl ether gave the title product (84 mg, 78%). 1H NMR (DMSO-d6) δ 13.0 (s, 1H), 9.13 (s, 1H), 8.78 (s, 1H), 8.36 (s, 1H), 7.93 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H), 7.45 (m, 2H), 7.17 (m, 2H), 6.13 (s, 2H), 3.95 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].C(OC([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=O)[CH2:31][CH2:30]1)=O)(C)(C)C.[B-][N+](C)(C)C>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:2]=2[NH:1][CH2:35][CH:32]2[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: COC(=O)c1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: [B-][N+](C)(C)C
Product: COC(=O)c1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using a similar procedure to that described in Example 47-C&D, 2-amino-N-(5-chloropyridin-2-yl)-5-methoxycarbonylbenzamide (3.23 g, 10.6 mmol), 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (2.50 g, 11.7 mmol), and borane trimethylamine complex (2.31 g, 31.7 mmol) afforded, after purification by column chromatography (SiO2: 10 to 25% methanol:methylene chloride), 3.10 g (73%) of the title compound.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[CH2:11](Br)[CH3:12]>O.CO>[CH2:11]([S:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH3:12]
Reactant: Fc1ccc(S)cc1
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCSc1ccc(F)cc1
Yield: 79.1 %

Procedure:
To a stirring solution of NaOH (11.26 g, 281.6 mmol) in water (500 mL) was added dropwise a solution of 4-fluorothiophenol (25 mL, 234.6 mmol) in methanol (50 mL). After 15 minutes ethyl bromide (14.4 mL, 281.6 mmol) was added. After 6 hours more NaOH (1 g) was added and the reaction mixture was extracted with ether (3×300 mL). The combined organic extracts were treated with brine followed by MgSO4 then concentrated down to give 1-(ethylthio)-4-fluorobenzene (29 g, 80%) as a slightly yellow colored liquid.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Ic1cccs1
Product: Cc1ccc(-c2cccs2)cc1

Procedure:
2-Iodothiophene and 4-methylphenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(4-methylphenyl)thiophene as colorless crystals. APCI-Mass m/Z 175 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1.N1C(C)=C[CH:17]=[CH:16][C:15]=1[CH3:21].BrCCCCBr>CN(C=O)C.C(OCC)(=O)C>[N:1]1([CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:21]1
Reactant: CCOC(=O)c1cc(CCN)c[nH]1
Reactant: Cc1cccc(C)n1
Solvent: BrCCCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(CCN2CCCC2)c[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the product obtained in Step G (1.3 g) in DMF (134 ml) there are added 2,6-lutidine (4.15 ml) and 1,4-dibromo-butane (4.68 ml). The reaction mixture is stirred at 80° C. for 12 hours and at ambient temperature overnight. The reaction mixture is diluted with 600 ml of ethyl acetate. The organic phase is washed with saturated aqueous NaHCO3 solution, with water and with saturated aqueous NaCl solution, dried over magnesium sulphate, filtered and evaporated to dryness. The residue obtained is purified on silica gel (SiO2: gradient CH2Cl2/MeOH with the addition of 1.4N NH3 in the MeOH) to yield the title product, which is used directly in the next Step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.O.C(=O)([O-])O.[Na+].[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>O1CCCC1>[Cl:16][C:17]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1)=[O:20]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2Cl)cc1O
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 2-chloro-3-(trifluoromethyl)benzoic acid (5.26 g, 23.4 mmol) in tetrahydrofuran (50 mL) were added N,N-dimethylformamide (40 μL) and oxalyl chloride (2.8 mL, 31.9 mmol), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give 2-chloro-3-(trifluoromethyl)benzoyl chloride. To a solution of 5-amino-2-methylphenol (2.62 g, 21.2 mmol) in tetrahydrofuran (20 mL) was added water (30 mL) in which sodium hydrogen carbonate (2.68 g, 31.9 mmol) has been suspended, and the mixture was vigorously stirred at room temperature. To the mixture was added dropwise a solution of 2-chloro-3-(trifluoromethyl)benzoyl chloride produced above in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, and filtered through a pad filled with silica gel. The solvent was concentrated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (6.37 g, 91%) as a pale-brown powder. The obtained compound was used for the next reaction without further purification operation.