Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:7])[CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:38]([O-:41])([O-])=[O:39].[Na+].[Na+]>C(Cl)Cl>[O:39]=[S:38]1(=[O:41])[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[O:7])[CH2:2]1
Reactant: O=S([O-])[O-]
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCSC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCS(=O)(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of benzyl 2(S)-(3-thiazolidinecarbonyloxy)-3-phenylpropionate (371 mg) in methylene chloride (7 ml) was added 80% m-chloroperbenzoic acid (431 mg). The mixture was stirred at ambient temperature for 2 days. Then 10% sodium sulfite aqueous solution and methylene chloride were added thereto, and the mixture was separated. The aqueous layer was extracted with methylene chloride. The combined extract was washed with saturated sodium hydrogen carbonate solution 2 times and saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure to give benzyl 2(S)-(1,1-dioxothiazolidine-3-carbonyloxy)-3-phenylpropionate (330 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:35][CH:36]([F:39])[CH2:37]I>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:37][CH:36]([F:39])[F:35])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Reactant: FC(F)CI
Product: FC(F)Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 14.5 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 1,1-difluoro-2-iodoethane, 162 was obtained as a light yellow solid (21 mg, 14.5%) over two steps. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.060-9.062 (d, J=1 Hz, 1H), 8.74 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 8.04 (s, 1H), 7.61-7.64 (t, J=16 Hz, 1H), 7.26-7.28 (t, J=10.5 Hz, 1H), 6.42-6.44 (d, J=8.5 Hz, 1H), 6.04-6.26 (m, 1H), 4.51-4.57 (m, 2H), 3.89-3.93 (m, 4H), 3.17-3.19 (t, J=11 Hz, 2H), 2.92-2.94 (t, J=11 Hz, 2H), 2.02-2.05 (m, 2H); MS (ESI) m/z: 425 [M+H]+.
Reaction SMILES: [NH:1]([CH3:21])[C@H:2]([C:18]([NH2:20])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[N:22]([C:31]([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])([CH3:30])[C@H:23]([C:27](O)=[O:28])[CH:24]([CH3:26])[CH3:25].O>C1COCC1>[N:22]([C:31]([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])([CH3:30])[C@H:23]([C:27]([N:1]([CH3:21])[C@H:2]([C:18]([NH2:20])=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)=[O:28])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
To a solution of N-Me-Tyr(Bzl)-NH2(329 mg, 1.16 mmol) in THF (15 ml), Fmoc-N-Me-Val-OH (533 mg, 1.51 mmol), CMPI (415 mg, 1.62 mmol) and TEA (0.323 ml, 2.32 mmol) were added under cooling with ice, followed by stirring for 4 hours at room temperature. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:1) to give the titled compound (680 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([O:10][CH3:11])=[O:9]>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:12][CH2:13][NH:14]1
Reactant: COC(=O)c1ccnc(Cc2ccccc2F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2ccccc2F)C1
Reaction time: 4 h
Yield: 80.9 %

Procedure:
Methyl 2-(2-fluorobenzyl)isonicotinate (5.42 g, 22.08 mmol) was dissolved in acetic acid (50 mL) and platinum(IV) oxide (0.251 g, 1.10 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator for 4 h at room temperature and 5 bar. The catalyst was filtered off and washed with MeOH and the eluate evaporated. DCM and 10% K2CO3 were added and the phases separated. The water phase was extracted with DCM and the combined organic phase washed with water, passed through a phase separator and evaporated to yield methyl 2-(2-fluorobenzyl)piperidine-4-carboxylate (4.49 g, 81%) MS m/z 252 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2([O:13][CH:12]([CH3:14])[CH:11]([OH:15])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:13][CH:12]([CH3:14])[CH:11]([O:15][CH3:20])[CH2:10]2)[CH2:16][CH2:17]1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)N1CCC2(CC1)CC(O)C(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CC1)CC(OC)C(C)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 93 mg 8-ethoxycarbonyl-3-hydroxy-2-methyl-1-oxa-8-azaspiro[4.5]decane in 1 ml N,N-dimethylforamide was cooled in ice, 16.7 mg oily sodium hydride (60%) was added, and the resulting mixture was stirred for 30 minutes under ice cooling. Methyl iodide (26.2 μl) was then added, and the mixture was stirred at room temperature for about 24 hours and poured into 5 ml ice water. After extraction with chloroform, the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure from the dried solution, and the residue was purified by silica gel column chromatography using, as eluent, a mixed solvent of ethyl acetate/n-hexane (1:1 by volume), giving 47 mg 8-ethoxycarbonyl-3-methoxy-2-methyl-1-oxa-8-azaspiro[4.5]decane as oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[N+:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]>>[F:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:11]([O-:13])=[O:12])[CH:19]=2)=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: N#Cc1cc(F)ccc1Br
Product: N#Cc1cc(F)ccc1-c1cccc([N+](=O)[O-])c1

Procedure:
2-Bromo-5-fluorobenzonitrile and 3-nitrophenylboronic acid were coupled following the procedure in Example 4 to afford 4-fluoro-3′-nitrobiphenyl-2-carbonitrile as a black solid: 1H NMR (360 MHz, CDCl3) δ 7.39-7.48 (2H, m), 7.52-7.64 (1H, m), 7.71 (1H, dd, J 8, 8 Hz), 7.89 (1H, d, J 8 Hz), 8.33-8.37 (2H, m).
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[N:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@H:37]([C:38]([OH:40])=[O:39])[CH2:36][C@@H:35]2[C@H:33]1[CH2:34]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C.C([O-])(O)=O.[Na+]>[C@@H:33]12[CH2:34][C@@H:35]1[CH2:36][C@@H:37]([C:38]([O:40][CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[N:15]=1)=[O:13])=[O:39])[N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
DIPEA (0.21 mL, 1.2 mmol) was added to a solution of 2-bromo-1-(6-bromoquinolin-2-yl)ethanone (268 mg, 0.815 mmol)) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (204 mg, 0.896 mmol) in acetonitrile (8 mL) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with sat. aq. NaHCO3 (5 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by flash silica gel chromatography (used DCM as loading solvent, eluted with Et2O/hexanes, gradient from 10% to 30% Et2O) to yield (1R,3S,5R)-3-(2-(6-bromoquinolin-2-yl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (332 mg) as white solid. LC-MS retention time 4.283 min; m/z 476.88 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N+:7]([C:10]1[S:14]C(C(O)=O)=[N:12][CH:11]=1)([O-:9])=[O:8].CN(C)C=O>C(Cl)Cl>[N+:7]([C:10]1[S:14][C:1]([C:2]([Cl:4])=[O:3])=[N:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ncc([N+](=O)[O-])s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ncc([N+](=O)[O-])s1
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (13 ml) was added dropwise to a stirred suspension of 5-nitrothiazole-2-carboxylic acid (12.9 g; Chem. Ber. 1973, 106, 722) in a mixture of methylene chloride (80 ml and dimethylformamide (20 ml). The mixture was stirred at laboratory temperature for 30 minutes and evaporated to dryness to give 5-nitrothiazole-2-carbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[N:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[N:11]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:12]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)nc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1cc(N)n(-c2ccc(=O)n(CCN3CCOCC3)c2)n1

Procedure:
To a solution of 5-(5-amino-3-(tert-butyl)-1H-pyrazol-1-yl)pyridin-2-ol (Abraham, S. et al., WO 2009/117080, 24 Sep. 2009) (4.04 g, 17.4 mmol) in MeCN (50 mL) was added 4-(2-chloroethyl)morpholine hydrochloride (3.88 g, 20.9 mmol) and K2CO3 (5.29 g, 38.3 mmol)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(Cl)cc4)c3)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (52 mg, 0.158 mmol) (from Example 3 supra) in THF (3 mL) were added diisopropylethylamine (44 mg, 0.35 mmol) and then 4-chlorobenzoyl chloride (30.8 mg, 0.174 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (50 mL), washed with aqueous 1N NaOH (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH, 99/1 to 95/5) to give 3-[3-(4-Chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 41.4 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[C:28]2[C:5]([CH2:6][CH2:7][C:8]3[C:9]2=[N:10][O:11][C:12]=3[C:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:15][N:14]=2)=[CH:4][C:3]=1[CH:30]=C.[O:32]=[O+][O-].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:29]=[C:28]2[C:5]([CH2:6][CH2:7][C:8]3[C:9]2=[N:10][O:11][C:12]=3[C:13]2[C:17]([C:18]([F:21])([F:19])[F:20])=[C:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:15][N:14]=2)=[CH:4][C:3]=1[CH:30]=[O:32]
Reactant: C=Cc1cc2c(cc1C)-c1noc(-c3noc(-c4ccccc4)c3C(F)(F)F)c1CC2
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C=O)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 64E, 0.058 g, 0.137 mmol) in dichloromethane (10 mL) at −78° C. was passed ozone from an ozone generator until the solution turned a deep blue. The reaction mixture then was purged with oxygen until the blue color disappeared, then with nitrogen for five minutes. The reaction mixture was allowed to warm to room temperature and triethylamine (0.019 mL, 0.137 mmol) was added. The reaction mixture was stirred at room temperature for fifteen minutes and then concentrated under vacuum to give 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde as a tan solid (0.043, 0.101 mmol, 74%). The product had an HPLC ret. time=3.43 min (condition B). LC/MS M+1=425.10.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:47])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]OS(C)(=O)=O)[C:25]=1[CH2:41][CH2:42][C:43]([O:45]C)=[O:44]>>[C:43]([CH2:42][CH2:41][C:25]1[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([OH:47])=[O:17])([OH:45])=[O:44]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCCCc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Product: CCCc1c(OCCCCCCc2cccc(CCCCCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 126, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-(3-methoxy-3-oxopropyl)-3-[6-[(methylsulfonyl)oxy]hexyl]benzenehexanoic acid methyl ester from the preceding example, followed by saponification, in 16.8% overall yield. The product was a colorless solid, mp 109°-110° C., recrystallized from acetonitrile.
Reaction SMILES: [Br-].[O:2]=[C:3]1[N:8]2[CH:9]=[N+:10]([CH2:12][CH2:13][CH3:14])[CH:11]=[C:7]2[CH2:6][CH2:5][NH:4]1.[F:15][C:16]1[CH:17]=[C:18]([C:26]2[S:30][C:29]([NH2:31])=[N:28][C:27]=2[CH3:32])[CH:19]=[CH:20][C:21]=1[S:22]([CH3:25])(=[O:24])=[O:23].CCN(CC)CC>CCOC(C)=O>[F:15][C:16]1[CH:17]=[C:18]([C:26]2[S:30][C:29]([NH:31][C:3]([NH:4][CH2:5][CH2:6][C:7]3[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH3:14])[CH:11]=3)=[O:2])=[N:28][C:27]=2[CH3:32])[CH:19]=[CH:20][C:21]=1[S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: CCC[n+]1cc2n(c1)C(=O)NCC2
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCn1cnc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(F)c3)s2)c1
Temperature: 120 °C
Yield: 23.4 %

Procedure:
A stirred mixture of 5-oxo-2-propyl-5,6,7,8-tetrahydro-imidazo[1,5-c]pyrimidin-2-ium bromide (Intermediate DA) (0.214 g, 0.83 mmol) and 5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Intermediate AA) (0.15 g, 0.55 mmol) and Et3N (0.48 ml, 3.3 mmol) is heated at 120° C. for 2 days. After cooling to room temperature the mixture is diluted with EtOAc (50 ml) and washed water followed by brine. The organic extract is dried (MgSO4) and the solvent is removed to give a solid. Purification by chromatography oh silica eluting with DCM:MeOH (95:5) affords the titled compound (0.06 g, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:8]=[C:9]([NH:11][NH2:12])[CH:10]=1)=[O:4].CN([CH:23]=[N:24][C:25](=O)[CH:26]([CH3:28])[CH3:27])C>CC(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:8]=[C:9]([N:11]2[C:25]([CH:26]([CH3:28])[CH3:27])=[N:24][CH:23]=[N:12]2)[CH:10]=1)=[O:4]
Reactant: CC(C)C(=O)N=CN(C)C
Reactant: COC(=O)c1cc(NN)cc(-c2ccc(C)cc2)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2ncnc2C(C)C)c1
Temperature: 90 °C

Procedure:
To a solution of 5-hydrazino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (300 mg, 1.17 mmol) in HOAc (5 mL) was added N-dimethylaminomethylene-isobutyramide (233 mg. 1.4 mmol) in one portion. The mixture was heated to 90° C. for two hours. After removing the excess HOAc, the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO™) to afford 5-(5-isopropyl-[1,2,4]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester a yellow solid (293 mg, 74.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=3)[CH:21]=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[OH:36][N:35]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2cccc(-c3cccc(C(=O)O)c3)c2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(-c3cccc(C(=O)O)c3)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (8.5:1) as an off-white solid, MS (ESI+): m/z=451.20 ([M+H]+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([C:11]2[C:12]3[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=3[S:14][C:15]=2[CH2:16]OS(C)(=O)=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C=O)C.O>[N:1]([CH2:16][C:15]1[S:14][C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[C:11]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
Sodium azide (179 mg, 2.76 mmol) was added to a solution of methanesulfonic acid 3-phenylbenzo[b]thiophen-2-ylmethyl ester (828 mg, 1.84 mmol) in DMF (10 mL) and the mixture stirred at RT for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-35% DCM in cyclohexane) affording the title compound as a clear oil (244 mg, 50%). LCMS (Method C): RT 4.46 min [M+H-N2]+ 237.8
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.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>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]2[N:4]=[N:3][C:2]([C:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=3)=[CH:7][CH:6]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(OCc2ccc(Cl)nn2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nn2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 13.8 %

Procedure:
To a solution of 3-chloro-6-(4-methanesulfonylphenoxymethyl)pyridazine (79 mg, 0.26 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (82 mg, 0.26 mmol) in dry N,N-dimethylformamide (3 mL) was added tetrakis(triphenylphosphine)palladium (9.0 mg, 7.9 μmol) and cesium carbonate (129 mg, 0.397 mmol). The mixture was stirred at 80° C. for 2 hours, allowed to cool to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate=10/1 and hexane/ethyl acetate=1/2) to give the title compound as a white crystal (16 mg, yield 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=2)[CH:7]=1.O.[OH-].[Li+:18]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O-:13])=[O:12])[N:10]=2)[CH:7]=1.[Li+:18]
Reactant: CCOC(=O)c1cn2cc(Cl)ccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cn2cc(Cl)ccc2n1
Reaction time: 1 h

Procedure:
Ethyl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (Japanese Patent Application Laid-Open No. 11-500123 through PCT route) (150 mg) was dissolved in tetrahydrofuran (4 ml), and water (1 ml) and lithium hydroxide (18 mg) were added at room temperature to stir the mixture for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude lithium 6-chloroimidazo[1,2-a]pyridine-2-carboxylate. This product was dissolved in N,N-dimethylformamide (4.0 ml), and (±)-cis-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine hydrochloride (232 mg), 1-hydroxybenzotriazole monohydrate (180 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (256 mg) and triethylamine (371 μl) were added to this solution to stir the mixture at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and water and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to conduct extraction with dichloromethane. The resultant organic layer was then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by column chromatography on silica gel (dichloromethane:acetone=1:1→dichloromethane:acetone:methanol=5:5:1) to obtain a white solid. To this solid, were added dichloromethane, methanol and 1N hydrochloric acid, and the resultant mixture was concentrated to obtain the title compound (224 mg) as a pale brown solid.