Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:25]([N:32]1[C@H:35]([CH:36]=O)[CH2:34][C:33]1=[O:38])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>ClCCl>[Si:25]([N:32]1[C@H:35]([CH:36]=[C:1]([Br:5])[Br:2])[CH2:34][C:33]1=[O:38])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C=O
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C=C(Br)Br
Reaction time: 0.33 h
Yield: 48 %

Procedure:
To a solution of CBr4 (3.11 g) in dichloromethane (15 ml) was added dropwise a solution of triphenylphosphine (4.92 g) in dichloromethane (15 ml) at 0° C. After stirring for 10 minutes a solution of (S)-N-tert-butyldimethylsilyl-4-formyl-2-azetidinone (1.0 g) in dichloromethane (10 ml) was added dropwise at 0° C. and stirred for 20 minutes. The mixture was poured into saturated aqueous NaHCO3 solution and extracted with dichloromethane. The extract was washed with water, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with (diethyl ether:n-hexane=1:5) to give (S)-N-tert-butyldimethylsilyl-4-(2,2dibromoethenyl)-2-azetidinone (0.83 g) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:5]([F:23])=[CH:4][N:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[K+]>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].CCOC(C)=O.O>[F:23][C:5]1[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])=[CH:7][C:2]([N:31]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)[CH3:32])=[N:3][CH:4]=1
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cc(Cl)ncc2F)cc1
Reactant: CNc1ccc(F)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc([C@@H](C)N2CCC[C@H]2c2cc(N(C)c3ccc(F)cc3)ncc2F)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of 1-(2-chloro-5-fluoro-4-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (100 mg, 0.30 mmol) in toluene (25 mL) are added (4-fluoro-phenyl)-methyl-amine (48 mg, 0.39 mmol), 2-(dicyclohexylphosphino)-biphenyl (10 mg, 0.03 mmol), Pd2(dba)3 (14 mg, 0.015 mmol) and potassium tert-butoxide (84 mg, 0.75 mmol). The reaction mixture is stirred at 85° C. for 3 hours and cooled to room temperature. Water and EtOAc are added to the mixture. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by chromatography (EtOAc/hexane: 10%˜40%) to give (5-fluoro-4-{(S)-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-2-yl)-(4-fluoro-phenyl)-methyl-amine (120 mg, 95%). M/Z=424.23 [M+1]
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][O:13][C:14]([CH2:16][S:17][CH2:18]C(OCCC1C=CC2C(=CC=CC=2)C=1)=O)=[O:15].COS(=O)(=O)OC.O.[F:42][P-:43]([F:48])([F:47])([F:46])([F:45])[F:44].[K+]>C(OCC)(=O)C>[F:42][P-:43]([F:48])([F:47])([F:46])([F:45])[F:44].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][O:13][C:14]([CH2:16][SH+:17][CH3:18])=[O:15]
Reactant: O=C(CSCC(=O)OCCc1ccc2ccccc2c1)OCCc1ccc2ccccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: C[SH+]CC(=O)OCCc1ccc2ccccc2c1

Procedure:
2-naphthylethoxycarbonylmethyl sulfide in an amount of 24.63 g and dimethyl sulfuric acid in an amount of 13.24 g were mixed and allowed to a reaction at 80° C. for 10 hours. The reacted-mixture was then dissolved into a mixed solution of distillated water in an amount of 300 ml and ethyl acetate in an amount of 100 ml and stirred. The aqueous layer resulted was taken out, mixed with potassium hexafluorophosphate in an amount of 18.41 g and ethyl acetate in an amount of 300 ml and then stirred. The ethyl acetate layer was then washed with 100 ml of distillated water twice and mixed with anhydrous magnesium sulfate to remove water remained in the ethyl acetate layer. After evaporating ethyl acetate from the ethyl acetate layer, the residue was allowed to dry at 40° C. under reduced pressure to obtain the objective compound. The yield was 36.4 g.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.C(O)C.N>CO.[Ni]>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(Oc2ccccc2F)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCO
Product: NCc1ccc(Oc2ccccc2F)cc1
Temperature: 60 °C
Yield: 78.9 %

Procedure:
Add 4-(2′-fluorophenoxy)-benzonitrile (1.5 g, 7.0 mmol) and ethanol wet Raney® activated nickel (0.4 g) to a Parr pressure vessel. Immediately add a 7N solution of ammonia in methanol (170 mL) and seal the vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (3400 KPa), seal the vessel, agitate the reaction and heat to 60° C. Continue the reaction for 18 h, turn off the heat and allow the reaction mixture to cool to ambient temperature. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the Raney® nickel. Concentrate in vacuo and purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (9:1) to obtain the title compound (1.2 g, 79%). MS (ES+) m/z: 201 M+H−NH3)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Br:27]C1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1>>[Br:27][C:25]1[CH:26]=[C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc2c(c1)CCC(c1cccc(Br)c1)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc(Br)c2)O3)nc1

Procedure:
2-[2-(3-Bromophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 339 mg of 2-(3-bromophenyl)chroman-6-ol. The product was filtered through silica gel using toluene-ethyl acetate as an eluant and then crystallised from 2-propanol. 1H NMR (400 MHz, CDCl3) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.2, 2.9 Hz), 7.66 (bs, 1H), 7.55 (m, 1H), 7.48 (m, 1H), 7.39 (m, 1H), 7.20 (d, 1H, J 9.2 Hz), 7.01-6.93 (m, 3H), 5.17 (dd, 1H, J 10.1, 2.2 Hz), 2.97 (m, 1H), 2.72 (m, 1H), 2.20 (m, 1H), 2.00 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27]([NH2:29])=[O:28])=[CH:18]1)=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CS(C)=O>[CH3:46][O:45][C:43](=[O:44])[CH2:42][O:26][C:23]1[CH:24]=[C:25]2[C:20]([C:19]([C:27](=[O:28])[NH2:29])=[CH:18][N:17]2[CH2:16][C:15]([N:10]2[CH2:11][C@H:12]([F:14])[CH2:13][C@H:9]2[C:7](=[O:8])[NH:6][CH2:5][C:4]2[CH:31]=[CH:32][CH:33]=[C:2]([Cl:1])[C:3]=2[F:34])=[O:30])=[CH:21][CH:22]=1
Reactant: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)COc1ccc2c(C(N)=O)cn(CC(=O)N3C[C@H](F)C[C@H]3C(=O)NCc3cccc(Cl)c3F)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-6-hydroxy-1H-indole-3-carboxylic acid amide Example 578 (140 mg, 0.285 mmol) in DMSO (3 mL) was treated with Cs2CO3 (0.28 g, 0.85 mmol). The mixture was stirred at RT for 5 min, followed by addition of methyl 2-bromoacetate (0.039 mL, 0.428 mmol) and stirring at RT for 4 h. The mixture was partitioned between water and CH2Cl2, and the organic phase was washed twice with brine (the combined aqueous washings were filtered and the solid thus obtained was dried in vacuo to give an aliquot of the title compound), dried (phase separator) and concentrated under reduced pressure. Purification by preparative HPLC (SunFire C18-ODB, 5 μm, 30×100 mm, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) afforded after lyophilization of the purified fractions the title compound as a white solid. MS: 563 [M+H]+; tR (HPLC conditions c): 4.17 min.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:19]2[CH:23]=[CH:22][N:21]=[N:20]2)=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ICCCc1ccc(OCc2ccccc2)cc1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(CCCn3ccnn3)cc2)cc1
Temperature: 70 °C
Reaction time: 18.5 h
Yield: 41.6 %

Procedure:
Benzyl 4-(3-iodopropyl)phenyl ether (2.47 g), 1H-1,2,3-triazole (629 mg), and potassium carbonate (1.26 g) were suspended in DMF (17.5 ml), followed by stirring at 70° C. for 18.5 hours. The reaction mixture was returned to room temperature and extracted with ethyl acetate, after which it was washed with water and saturated saline. Under reduced pressure, the solvent was distilled off; the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to yield 1-[3-(4-benzyloxyphenyl)propyl]-1H-1,2,3-triazole (856 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH:7]=[CH:8][CH:9]=O)([O-:3])=[O:2].[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH:7]=[CH:8][CH:9]=[N:14][NH:15][C:16]([NH2:18])=[S:17])([O-:3])=[O:2]
Reactant: NNC(N)=S
Reactant: O=CC=Cc1cccc([N+](=O)[O-])c1
Product: NC(=S)NN=CC=Cc1cccc([N+](=O)[O-])c1
Yield: 88 %

Procedure:
The compound is prepared according to the method described in Example 1A from 3-nitrocinnamaldehyde (2.2 mmol) (Org. Lett. 5(5), 777-780, 2003) and from thiosemicarbazide (2.2 mmol). Yield 88%.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[C:19]1([S:25][C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[C:19]1([S:25][C:26]2[CH:27]=[C:28]([NH:29][C:3]([C:5]3[CH:6]=[CH:7][N:8]4[C:12]=3[CH2:11][S:10][CH:9]4[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[O:4])[CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Nc1cccc(Sc2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Sc2ccccc2)c1)c1ccn2c1CSC2c1cccnc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 56.2 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (9 g) is added, at a temperature between 60° and 68° C., to a solution of 3-phenylthioaniline (6 g) and triethylamine (6.1 g) in dioxane (200 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 7 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 2N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (11.5 g) is thereby obtained, which is dissolved in boiling acetonitrile (110 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 10° C. for 1 hour. The crystals formed are separated by filtration, washed 3 times with acetonitrile (45 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(3-phenylthiophenyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (7.2 g) in the form of cream-coloured crystals, m.p. 152° C., is thereby obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13](Br)=[C:12]([Br:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:18][C:19]([OH:24])([CH3:23])[CH2:20][CH2:21][OH:22]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:22][CH2:21][CH2:20][C:19]([OH:24])([CH3:23])[CH3:18])=[C:12]([Br:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)CCO
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(F)c(F)c1
Product: CC(C)(O)CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The dibromo-intermediate from Example 471B was reacted according to the procedure described in Example 194B, substituting 3-methyl-1,3-butanediol in place of methanol, to selectively react at the 4-position and provide the title intermediate.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([CH2:16][N:17]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:35](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1)=[O:15])([CH3:3])[CH3:2].[ClH:60]>O1CCCC1>[ClH:60].[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:13][C:14]([CH2:16][N:17]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1)=[O:15])([CH3:12])[CH3:11]
Reactant: CCCCCN(CC(=O)Nc1c(C(C)C)cccc1C(C)C)Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCN(CC(=O)Nc1c(C(C)C)cccc1C(C)C)Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
N-[[[(2,6-Diisopropylphenyl)amino]carbonyl]methyl]-N-pentyl-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (278.3 mg) was dissolved in tetrahydrofuran (10 mL), and after addition of 10% hydrochloric acid (3.0 mL), the resulting mixture was stirred at room temperature. Nineteen hours later, the solvent was distilled off, and to the residue, water (30 mL) was added. The mixture so obtained was extracted twice with chloroform (30 mL, each). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (chloroform/methanol) to afford N-[[[(2,6-diisopropylphenyl) amino]carbonyl]methyl]-N-pentyl-N-[[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl]amine hydrochloride as pale yellow crystals (190.6 mg). Yield: 93%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1O)([O-:3])=[O:2].S(Cl)([Cl:20])=O.CN(C)C=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[Cl:20])([O-:3])=[O:2]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Yield: 86.6 %

Procedure:
180 grams (.75 mole) of 2,6-dinitro-4-t-butylphenol thus prepared was placed in a mixture of 113 grams (.95 mole) thionyl chloride, 55 grams (0.76 mole) dimethylformamide and 300 ml. of dry toluene. The mixture was stirred and heated to reflux temperature for 15 hours, after which time the thionyl chloride, DMF and toluene were removed under reduced pressure until a slush remained. Hexane was then added to the reaction vessel, the mixture cooled and filtered. The product was then recrystallized from boiling hexane to give 168 grams 2,6-dinitro-4-t-butylchlorobenzene in the form of light yellow needles melting at 114°-116° C.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCC(N=C=NC2CCCCC2)CC1.[N+:35]([C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[CH:40][CH:39]=1)([O-:37])=[O:36]>C(Cl)Cl>[N:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([CH2:15][CH2:16][C:17](=[O:19])[S:44][C:41]3[CH:42]=[CH:43][C:38]([N+:35]([O-:37])=[O:36])=[CH:39][CH:40]=3)=[O:14])[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: O=C(O)CCC(=O)N1CCC(N2CCCCC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCC(=O)N1CCC(N2CCCCC2)CC1)Sc1ccc([N+](=O)[O-])cc1
Temperature: 4 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
3-(4-Piperidinopiperidinocarbonyl)propionic acid (0.26 g, 0.97 mmol) and DCC (0.25 g, 1.2 mmol) were dissolved in methylene chloride, followed by the addition of 4-nitrothiophenol (0.23 g, 1.2 mmol). The resulting mixture was stirred for 16 hours at 4° C. and then overnight at room temperature. The reaction mixture was filtered. After the filtrate was concentrated, the residue was purified by chromatography on a silica gel column (chloroform-acetone mixed solvent [10:1→5:1], whereby S-4-nitrophenyl 3-(4-piperidinopiperidinocarbonyl)propanethioate (196 mg, 50%) was obtained.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[CH3:11][O:12][C:13]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:31]=[CH:30][C:24]3[N:25]=[C:26]([S:28][CH3:29])[S:27][C:23]=3[CH:22]=2)[C:16]([NH2:32])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[N:18]=[C:17]2[N:19]([CH2:20][C:21]3[CH:31]=[CH:30][C:24]4[N:25]=[C:26]([S:28][CH3:29])[S:27][C:23]=4[CH:22]=3)[CH:1]=[N:32][C:16]2=[CH:15][CH:14]=1
Reactant: COc1ccc(N)c(NCc2ccc3nc(SC)sc3c2)n1
Reactant: CCOC(OCC)OCC
Product: COc1ccc2ncn(Cc3ccc4nc(SC)sc4c3)c2n1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a solution of triethoxymethane (5 mL) was added 6-methoxy-N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine (332 mg, 1.0 mmol) from Step 6 of this Example at rt. The reaction mixture was heated under reflux overnight. After cooling to rt, the mixture was concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of EtOAc-CH2Cl2 (0 to 100%, v/v) as eluent to give 6-((5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole as a brown solid (180 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J=8.7 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.70 (d, J=1.1 Hz, 1H), 7.41 (dd, J=1.7, 8.3 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H), 5.47 (s, 2H), 3.99 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Ni].[H][H]>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCCCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(OCCCc2ccccc2)cc1

Procedure:
99 g of 4-(3'-phenyl-propoxy)-nitrobenzene is dissolved in 2000 ml of methanol and hydrogenated with Raney nickel until the absorption of hydrogen is completed. The catalyst is filtered off and the filtrate is concentrated by evaporation to obtain, as a crystalline residue, 4-(3'-phenylpropoxy)-aniline having a melting point of 55°- 57°. -
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7](COC)[C:6]([O:19][CH3:20])=[CH:5][CH:4]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[CH3:20][O:19][C:6]1[C:7]([O:10][CH2:9][O:11][CH3:12])=[C:8]([C:3]([CH2:2][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[CH:4][CH:5]=1)[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: COCc1c(OC)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Product: COCOc1c(OC)ccc(COc2ccc(-c3ccc(CC(=O)OC)cc3)cc2)c1C(=O)OC(C)(C)C
Yield: 25 %

Procedure:
According to a method similar to Example (40-2), from tert-butyl 6-(bromomethyl)-3-methoxy-2-(methoxymethyl)benzoate (1.20 g, 2.33 mmol) and methyl (4′-hydroxy-1,1′-biphenyl-4-yl)acetate (619 mg, 2.56 mmol) obtained in Example (6-2), tert-butyl 3-methoxy-2-(methoxymethoxy)-6-[({4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]benzoate was obtained (306 mg, yield: 25%).
Reaction SMILES: [N+:1]([C:4]1[C:9](=O)[NH:8][CH:7]=[C:6]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:23])=O>CN(C=O)C>[Cl:23][C:9]1[N:8]=[CH:7][C:6]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ncccc2C(F)(F)F)cnc1Cl
Yield: 93 %

Procedure:
Heat a solution of 5′-nitro-3-trifluoromethyl-1′H[2,3′]bipyridinyl-6′-one (25 g, 0.088 mol), thionyl chloride (300 mL) and DMF (3 mL) to reflux for 4 hours. Remove the volatiles by rotary evaporation and partition the residue between ethyl acetate (350 mL) and saturated sodium bicarbonate solution (250 mL). Extract the aqueous layer with further ethyl acetate (250 mL) and wash the combined organics with brine (250 mL). Dry (MgSO4) and concentrate under reduced pressure to give the title compound (25 g, 93%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:18][N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)[N:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][N:17]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[N:16]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1/C=C/C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
After a mixture of ethyl(E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazol-4-yl]propenoate (450 mg), 1N sodium hydroxide solution (1.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at 50° C. for 2 hours, 1N hydrochloric acid (1.5 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazol-4-yl]propenoic acid (410 mg, yield: 96%). This was recrystallized from acetone-hexane. Melting point: 210–211° C.