Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])O1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:28][C:29]1[N:38]=[C:37]([C:39]([N:41]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[C:36]2[C:31](=[CH:32][CH:33]=[C:34](I)[CH:35]=2)[N:30]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:28][C:29]1[N:38]=[C:37]([C:39]([N:41]2[CH2:42][C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:49]2)=[O:40])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:9]3[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:35]=2)[N:30]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(I)ccc2n1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 120 °C

Procedure:
11.66 g of ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, 10.29 g of potassium carbonate, 0.67 ml of water and 912.4 mg of [1,1′-bis-(diphenylphosphino)ferrocene]palladium(II)dichloride are added to a solution of 15 g of 2-amino-6-iodo-4-(1,3-dihydroisoindol-2-ylcarbonyl)quinazoline in 200 ml of ethanol under argon. The mixture is heated at 120° C. for min, giving a clear solution. The hot solution is filtered through kieselguhr. On cooling, ethyl 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)-quinazolin-6-yl]benzoate crystallises out.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]([NH2:30])=[O:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[OH:64][C@H:65]([CH3:69])[C:66](O)=[O:67].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CO.O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:66](=[O:67])[C@H:65]([OH:64])[CH3:69])[CH2:24][CH2:25]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]([NH2:30])=[O:29]
Reactant: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1N1CCNCC1
Reactant: C[C@@H](O)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1N1CCN(C(=O)[C@@H](C)O)CC1
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a solution of 4-(2-fluoro-4-methylphenylamino)-7-methoxy-6-(piperazin-1-yl)cinnoline-3-carboxamide (Example 46, 0.395 g, 0.96 mmol) in CH2Cl2 (20 mL) and MeOH (5 mL) was added benzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate (0.551 g, 1.06 mmol), (R)-2-hydroxypropanoic acid (0.079 mL, 1.06 mmol), and N-ethyldiisopropylamine (0.181 mL, 1.06 mmol). After 1 hour, an additional portion of benzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate (1.10 g, 2.12 mmol) was added. After 2 hours, water (100 mL) was added, and the mixture extracted with CH2Cl2. The organic extract was concentrated under reduced pressure, and the residue purified with silica chromatography (Hex/EtOAc, then with CH2Cl2/MeOH). The crude product was triturated with CH3CN and filtered to give 173 mg (37%) yellow solid. 1H NMR: 11.33 (s, 1H), 8.77 (s, 1H), 7.91 (s, 1H), 7.60 (s, 1H), 7.17 (m, 2H), 7.06 (m, 1H), 6.62 (s, 1H), 4.98 (d, 1H), 4.39 (m, 1H), 4.01 (s, 3H), 3.54 (m, 4H), 2.72 (m, 4H), 2.32 (s, 3H), 1.16 (d, 3H); m/z 484.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
1-(4′-Fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (66.0 g) was dispersed in toluene (660 ml) and manganese dioxide (594 g, type HMH, manufactured by Toso) was added over 1 hr at 15-30° C. The mixture was stirred at 20-30° C. for 1 hr. The reaction mixture was filtered and washed with toluene (330 ml). The solvent was evaporated under reduced pressure to give nearly pure 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (57.6 g, 88%) as pale-yellow white crystals. Various spectrum data of the crystals were the same as those obtained in Example 18.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>C(#N)C>[N:6]1([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C1COCCN1
Solvent: CC#N
Product: O=S(=O)(Cl)N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 4.6 g of sulfuryl chloride in acetonitrile was treated dropwise with 996 mg of morpholine at ambient temperature under an atmosphere of nitrogen. After complete addition, the mixture was refluxed for 16 h, cooled to room temperature, and concentrated in vacuo to yield the title product as a red oil. TLC: Rf=0.65 CH2Cl2. (1 H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(O)(=O)C.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]>C(OCC)C>[N+:1]([O-:4])([OH:3])=[O:2].[N+:1]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][NH2:9])([O-:3])=[O:2]
Reactant: NCCCCO
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: NCCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Fuming nitric acid (1.5 mL) was added dropwise to acetic acid (25 mL) which had been cooled to an inner temperature of −8° C. while an inner temperature of 0° C. or lower was maintained. After the mixed solution was stirred for 10 minutes, 4-amino-1-butanol (3.1 mL) was added dropwise while an inner temperature of 0° C. or lower was maintained. After the mixture was stirred for 10 minutes, a temperature was raised to room temperature with a water bath. After the mixture was stirred for 10 minutes, diethyl ether (100 mL) was added, and this was concentrated under reduced pressure. To the resulting concentrated material was added diethyl ether (100 mL), the mixture was stirred, and the supernatant was removed. The resulting residue was concentrated under reduced pressure to obtain a titled compound (6.31 g) having the following physical property values.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]1([C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH:20][C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Product: O=C(Nc1ccccc1N1CCCCC1)c1ccc([N+](=O)[O-])o1
Yield: 100 %

Procedure:
The compound was prepared according to the procedure described in Example 2 from 5-nitro-furan-2-carbonyl chloride and 2-piperidinoaniline. Yield: 100%. MS: 316 (M+1). LC/MS purity: 100%. 1HNMR (CDCl3, 300 MHz): δ 8.2 (d, 1H), 7.85 (d, 1H), 7.55 (m, 1H), 7.4 (m, 3H), 3.8-3.2 (bm, 4H), 2.7-1.9 (bm, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12][C:11]=2[C:19](O)=[O:20])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:19](=[O:20])[C:11]3[S:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:14][C:10]=3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NCc1cc(C(C)(C)C)sc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Br)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A 250-mL single-necked round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 102e (1.12 g, 2.93 mmol) and anhydrous methylene chloride (50 mL). Thionyl chloride (1.25 g, 10.5 mmol) was added and the reaction was stirred at ambient temperature. After 16 h the reaction was concentrated under reduced pressure. Purification of the resulting residue by column chromatography afforded a 65% yield (757 mg) of 102f as a white solid: mp 185-186° C.; 1H NMR (300 MHz, CDCl3) δ 7.56 (dd, 1H, J=6.6, 1.2 Hz), 7.20 (dd, 1H, J=6.3, 1.5 Hz), 7.11 (t, 1H, 7.8 Hz), 6.87 (s, 1H), 4.56 (s, 2H), 2.33 (s, 3H), 1.45 (s, 9H); MS (ESI+) m/z 364.2 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.[C:23](O)(=[O:27])[C:24]([CH3:26])=[CH2:25]>>[C:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1)(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: O=C(O)c1ccc(OCCCCCCCCCCCO)cc1
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)OCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 47 %

Procedure:
4-(11-methacryloyloxyundecanyloxy)benzoic acid (8a) was prepared from 4-(11-hydroxyundecanyloxy)-benzoic acid and methacrylic acid in the same manner as in Step 3 of Example 1. (Yield: 47%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[C:5]([CH2:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=O)=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:7]=1.O>CC(C)=O>[CH3:18][O:17][C:15]([C:13]1[NH:19][C:4]2[C:5]([CH:12]=1)=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:16]
Reactant: COC(=O)C(=O)Cc1c(CCCO)cc(Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc2c(CCCO)cc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 3-chloro-5-(3-hydroxypropyl)-6-methoxalylmethylnitrobenzene (19.91 g, 0.063 mol) in acetone (300 mL) was added dropwise a mixture of 20% TiCl3 (340 g, 0.441 mol), water (300 mL), and acetone (300 mL) at room temperature over a period of 30 min. The mixture was stirred for 30 min at room temperature and extracted with AcOEt. The extracts were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 4:1 to 1:2 hexane/toluene to give 11.39 g of the title compound (68%): 1H NMR (CDCl3) δ8.96 (bs, 1H), 7.27 (s, 1H), 7.26 (d, 1H, J=1.7 Hz), 6.97 (d, 1H, J=1.7 Hz), 3.95 (s, 3H), 3.71 (t, 2H, J=6.3 Hz), 2.98 (t, 2H, J=7.8 Hz), 2.00 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O-].[Na+].Cl>CO.O1CCCC1>[CH:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[CH:2]/[C:1]([C:4]2[N:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:3])=[CH:12][CH:13]=1
Reactant: CC(=O)c1ccccn1
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(/C=C/c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To solution of 2-acetylpyridine 1a (10 mmol, 1 equiv.) and tetrahydrofuran (25 mL) is added benzaldehyde 1b (10 mmol, 1 equiv.). Sodium methoxide (12 mmol, 1.2 equiv.) in methanol (24 mL, 0.5M) is introduced into the reaction and is agitated for 15 hours at room temperature. Hydrochloric acid (1N) is added until a neutral pH is obtained. The solution is extracted with dichloromethane twice, and washed once with water. The combined organic layers are dried over MgSO4, and concentrated under reduced pressure. The residue is purified by flash column chromatography on SiO2 (33% ethyl acetate/hexanes) to give the 3-phenyl-1-pyridin-2-yl-propenone 1c as a pale yellow solid. See Hollinshead, S. P., Tetrahedron Letters, Vol 37, pp. 9157-9160 (1996).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH:13]=[CH2:14].[N+](=[CH2:17])=[N-]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:13]1([C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=2[F:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:17][CH2:14]1
Reactant: C=Cc1cc(C(=O)OCC)ccc1F
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)c1ccc(F)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a mixture of ethyl 4-fluoro-3-vinylbenzoate (Preparation 54, 48 g, 0.25 mol, 1 eq) and palladium (II) acetate (2.5 g, 10 mmol, 0.4 eq) in ether (300 mL) was added diazomethane in ether (1.5 mol, 6.0 eq). Then the mixture was stirred at room temperature overnight. The reaction was quenched with a solution of AcOH (75 mL) in water (100 mL). The mixture was filtrated and the filtrate was added saturated solution of sodium carbonate until pH=10. The organic phase was washed with brine (200 mL) and water (200 mL), dried over sodium sulfate and concentrated in vacuo to give title compound as brown liquid (51 g, 0.248 mol, 99.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:19])[C:7]=2[CH:20]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:19])[C:7]=2[CH:20]=1
Reactant: COc1ccc2oc(C(=O)CCCCSC)c(C)c2c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(CCCCSC)c2oc3ccc(OC)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 67 %

Procedure:
To a mixture of 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentan-1-one (658 mg) synthesized above, methyl 4-aminobenzoate (375 mg), triethylamine (2.50 mL) and methylene chloride (10 mL) was added a 1.0M solution (2.70 mL) of titanium (IV) chloride in methylene chloride at 0° C., and the mixture was stirred under argon atmosphere at room temperature for 3.5 days. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, methylene chloride was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (10 mL) of the obtained oil in tetrahydrofuran were added acetic acid (647 μL) and sodium cyanoborohydride (283 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% ethyl acetate/hexane) to give the so title object compound (645 mg, 67%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[C:13]=2[CH3:14])=[O:17])[CH:20]=[CH:21][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][OH:35])[CH2:31][CH2:32]1)#[N:25]
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)c(F)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCO)CC3)c(C#N)c2)cnn1-c1ccc(F)c(F)c1
Yield: 32.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxylic acid (3 g) and 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (3.7 g), the title compound (1.9 g) was obtained, melting point: 164–165° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:29]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O)([O-:31])=[O:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[N+:29]([O-:31])=[O:30])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=[N+]([O-])c1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-nitrobenzaldehyde. MS (ESI) m/z 512.
Reaction SMILES: C(O)(=O)C.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([O-:7])=[O:6].[BH4-].[Na+]>CS(C)=O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1cccc(OCc2ccccn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1cccc(OCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.3 %

Procedure:
To an acetic acid (2.5 mL) and dimethyl sulfoxide (43 mL) solution of 2-(3-((E)-2-nitro-vinyl)-phenoxymethyl)-pyridine (2.56 g, 10 mmol) described in Manufacturing Example 60-1-2 was added sodium borohydride (605 mg, 16 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1-4:1-1:1) to obtain the title compound (1.66 g, 64%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:22])[CH2:14][C:15](=[O:21])[CH2:16][C:17](=O)[CH2:18][CH3:19])(C)(C)C>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH2:18]([C:17]1[O:16][C:15](=[O:21])[CH:14]=[C:13]([OH:12])[CH:22]=1)[CH3:19]
Reactant: CCC(=O)CC(=O)CC(=O)OC(C)(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(O)cc(=O)o1
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of 25% (v/v) trifluoroacetic acid (TFA) in trifluoroacetic anhydride (TFAA, 1117 mL) was placed in a 2 liter round bottom flask and cooled in an ice bath for 40 minutes. Crude compound U was loaded into an addition funnel and slowly added to the stirred mixture over 2 hours. The reaction was allowed to warm up to room temperature overnight. The TFA/TFAA solution was removed by rotary evaporation. Residual TFA could be removed azeotropically with toluene. The residue was then purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in dichloromethane. The appropriate fractions were collected and concentrated by rotary evaporation to yield compound V (63.15 g, 45%) as a yellow solid. 1H NMR CDCl3 δ: 11.08 (bs, 1H), 6.00 (s, 1H), 5.59 (s, 1H), 2.52 (q, 2H, J=8.0 Hz), 1.22 (t, 3H, J=8.0 Hz). ESMS m/z: 141.0 [M+H+].
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([N:22]3[CH2:26][C@H:25]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])(=[O:29])=[O:28])[CH2:24][C@H:23]3[C:40](=[O:47])[NH:41][C:42]3([C:45]#[N:46])[CH2:44][CH2:43]3)=[CH:20][C:19]([CH3:48])=[N:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C>[C:45]([C:42]1([NH:41][C:40]([C@@H:23]2[CH2:24][C@@H:25]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])(=[O:28])=[O:29])[CH2:26][N:22]2[C:21]2[N:17]([CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)[N:18]=[C:19]([CH3:48])[CH:20]=2)=[O:47])[CH2:43][CH2:44]1)#[N:46]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCN(C(=O)OCc3ccccc3)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.4 %

Procedure:
Palladium on charcoal 10% (5 mg) was added to a solution of 4-{5-[(2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidin-1-yl]-3-methyl-pyrazol-1-yl}-piperidine-1-carboxylic acid benzyl ester (12 mg, 18 umol; example 406c) in ethanol (1 ml). The reaction mixture was put under an hydrogen atmosphere and stirred at ambient temperature for 12 h. After filtration over dicalite the filtrate was brought to dryness to give the title compound (4.4 mg, 8 umol; 46%) as white solid. MS (ESI): m/z=551 [M+H]+.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:33](=[O:35])[NH2:34])=[C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:33]([NH2:34])=[O:35])=[C:19]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]([F:31])([F:32])[F:30])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:39][CH2:38]1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCc1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1
Solvent: ClCCl
Product: CN1CCN(Cc2cc3c(cn2)ncn3-c2cc(OCc3ccccc3C(F)(F)F)c(C(N)=O)s2)CC1

Procedure:
In a similar manner as described for example 6, 58 mg of [1-(5-carbamoyl-4-{[2-(trifluoromethyl)benzyl]oxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (compound A1) and 200 mg of 1-methylpiperazine in 5 ml dichloromethane yield the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:31])[NH:12][C:13]1[S:14][C:15]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)([CH3:10])[CH3:9])(C)(C)C.Cl>CCOC(C)=O>[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C:13]1[S:14][C:15]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:31]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1nc(-c2ccccc2)c(Cc2ccccc2)s1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(N)C(=O)Nc1nc(-c2ccccc2)c(Cc2ccccc2)s1

Procedure:
[1-(5-Benzyl-4-phenyl-thiazol-2-ylcarbamoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (6.4 g) was stirred overnight in freshly prepared HCl (g)/EtOAc solution (150 mL). Evaporation of the solvent gave the title compound as the hydrochloride salt. 1H NMR (400 MHz, DMSO-D6) δ 1.62 (s, 6H) 4.24 (s, 2H) 7.16-7.25 (m, 3H) 7.30 (d, J=7.58 Hz, 2H) 7.37 (s, 1H) 7.41-7.47 (m, 2H) 7.58-7.63 (m, 2H) 8.64 (s, 3H). m/z 352.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([I:14])=[C:5]([C:9]([I:13])=[CH:10][C:11]=1[I:12])[C:6]([OH:8])=[O:7].[Si](C=[N+]=[N-])(C)(C)[CH3:16].N#N>CCOCC.CO>[CH3:1][O:2][C:3]1[C:4]([I:14])=[C:5]([C:9]([I:13])=[CH:10][C:11]=1[I:12])[C:6]([O:8][CH3:16])=[O:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1c(I)cc(I)c(C(=O)O)c1I
Agent: N#N
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c(I)cc(I)c(OC)c1I
Reaction time: 0.5 h

Procedure:
In a 3-neck 250 mL round-bottom flask fitted with a thermometer and a condenser, 3-methoxy-2,4,6-triiodobenzoic acid (10.38 g) was dissolved in a 2:1 mixture of Et2O and methanol at 0° C. A 2.0 M hexanes solution of TMSCHN2 was added dropwise until yellow color persisted and N2 bubbling stopped. The reaction mixture was stirred for 30 minutes and quenched with glacial acetic acid. Solvents and excess AcOH were removed in vacuo for 18 h to give the desired ester as a white solid which was used in the next step without any further purification. Yield 11.07 g (˜100% crude).