Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20](S(C2C=CC=CC=2)(=O)=O)[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH:22]=2)=[O:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH:22]=2)=[O:18]
Reactant: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccc(CN6CCOCC6)cc5n4S(=O)(=O)c4ccccc4)c3N)ccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccc(CN6CCOCC6)cc5[nH]4)c3N)ccc2[nH]1
Temperature: 65 °C
Reaction time: 22 h
Yield: 73.8 %

Procedure:
[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1-benzenesulfonyl-6-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone (132 mg, 0.22 mmol) was dissolved in tetrahydrofuran (THF) (1.0 ml), and then a tetrahydrofuran (THF) solution of 1 M tetrabutylammonium fluoride (0.46 ml, 0.46 mmol) was added thereto. The mixture was heated at 65° C. with stirring for 22 hours. The reaction mixture was then cooled to room temperature, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=100/10) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone as a yellow solid (74 mg, 75%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:2]1.C(=O)([O-])[O-].[Na+].[Na+].C([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O.Cl>O.O1CCOCC1>[C:27]1(=[O:28])[N:23]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: N[C@@H](Cc1ccsc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@H](Cc1ccsc1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
3-(3-Thienyl)-L-alanine (2.45 g., 14.3 mmol.) was suspended in water/p-dioxane (22 ml/11 ml.) at room temperature under argon. Sodium carbonate (1.52 g.) was added and the mixture was stirred until homogeneous. N-Carbethoxyphthalimide (3.14 g.) was added, and the resulting mixture was stirred for 3.0 hours and then cooled to 0° C. The pH was adjusted to 1.5 with 6 N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 10% potassium bisulfate and brine, dried (sodium sulfate), filtered, and concentrated. The crude product was flash chromatographed (Merck silica gel) eluting with 1:1 ethyl acetate/hexane/1% acetic acid. The fractions containing clean desired product were combined, concentrated, azeotroped with ethyl acetate, and washed with water to remove the acetic acid. The organic layer was dried (sodium sulfate), filtered, and concentrated to give 3.22 g. of title compound as a white crystalline product; m.p. 166°-168° C.; [α]D =-146.8° (c=0.46, methylene chloride). TLC (1% acetic acid in 1:1 ethyl acetate/hexane) Rf =0.31.
Reaction SMILES: [O:1]1[CH:12]2[C:2]1([CH3:15])[C:3]1([C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11]2)[O:7][CH:6]([CH3:8])[CH:5]=[CH:4]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:8][CH:6]1[CH:5]=[CH:4][C:3]2([C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:2]2([CH3:15])[OH:1])[O:7]1
Reactant: CC1C=CC2(O1)C(C)(C)CCC1OC12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1C=CC2(O1)C(C)(C)CCCC2(C)O
Yield: 90.5 %

Procedure:
2.08 g (0.01 M) of 6,7-epoxy-2,6,10,10-tetramethyl-1-oxa-spiro[4.5]dec-3-ene -- see method B, letter i -- were reduced by means of 570 mg (0.015 M) of LiAlH4 in accordance with the above process. After the usual treatments of washing, drying and evaporation, the fractional distillation of the obtained residue gave 1.9 g (ca. 90 %) of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]dec-3-ene-6-ol, b.p. 80°-90° /0.1 Torr.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[N+:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[C:22]([CH:6]([C:5]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:4]=2[O:3][CH3:2])[N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:21]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: COc1cccc(C=[N+]2CCOCC2)c1OC
Agent: [Cl-]
Product: COc1cccc(C(c2cc(Cl)c3ccccc3c2O)N2CCOCC2)c1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-(2,3-dimethoxy-benzylidene)-morpholin-4-ium chloride and 4-chloro-1-naphthol.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C1CCCc2cc(-c3cccc(Cl)c3)ccc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-chlorophenyl boronic acid according to the coupling procedure as described in example 6. MS (ES) m/z 257.1.
Reaction SMILES: Br[CH2:2][C:3](=[O:27])[O:4][CH:5]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].Cl>C1COCC1>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][CH2:16][CH2:15][C@H:5]2[O:4][C:3](=[O:27])[CH2:2][C@@:7]([OH:8])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6]2)=[CH:20][CH:21]=1)#[N:26]
Reactant: N#Cc1ccc(CCCCC(CC(=O)c2ccccc2)OC(=O)CBr)cc1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(CCCC[C@@H]2C[C@](O)(c3ccccc3)CC(=O)O2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of the product of step B (2.71 g, 6.35 mmol) in dry THF (50 mL) at -78° C. under an atmosphere of nitrogen was added a 0.1M solution of SmI2 (135 mL, 13.5 mmol) over 10 minutes. The blue solution was stirred at -78° C. for 1 hour, poured into dilute aq. HCl, extracted with EtOAc, washed with sat'd NaHCO3, dried (MgSO4), filtered, and the solvent evaporated under reduced pressure. Silica gel chromatography (35-50% EtOAc/hexane) afforded 1.90 g (86%) of title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH2:8]C2N=C(C(OCC)=O)C=CC=2)[CH:7]=1.Br[C:22]1[CH:23]=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[N:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH2:8][C:22]2[CH:23]=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[N:26][CH:27]=2)[CH:7]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2O)n1
Product: CCOC(=O)c1cncc(Cc2cc(Cl)ccc2O)c1

Procedure:
The title compound was prepared in a similar manner to ethyl 6-[(5-chloro-2-hydroxyphenyl)methyl]-2-pyridinecarboxylate using ethyl 5-bromo-3-pyridinecarboxylate instead of ethyl 6-bromo-2-pyridinecarboxylate. Rt=3.18 [MH+] 292, 294.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=[O:11])[C:7]([NH:13][C:14]([C:16](OCC)=[O:17])=[O:15])=[CH:6][C:5]=1[C:21]#[N:22])(=[O:3])[CH3:2]>CN(C)C=O.[Pt]>[C:1]([C:4]1[CH:9]=[C:8]2[C:7]([NH:13][C:14](=[O:15])[C:16](=[O:17])[N:10]2[OH:11])=[CH:6][C:5]=1[C:21]#[N:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)c(C(C)=O)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(cc1C#N)[nH]c(=O)c(=O)n2O

Procedure:
A solution of 1-acetyl-2-cyano-4-ethoxalylamino-5-nitrobenzene (0.31 g, 1 mmol) in 10 ml of N,N-dimethylformamide was hydrogenated at atmospheric pressure and room temperature for 1 h in the presence of 30 mg of 5% platinum on carbon. The catalyst was filtered off, and the filtrate was evaporated to dryness. The pure product was obtained after recrystallization from water with decolourising charcoal. Yield 0.12 g (49%). M.p. 340.8° C. decomp. (DSC); IR (KBr): 2238 (CN), 1692 cm-1 ; 1H-NMR (DMSO-d6): 2.62 (s, 3H, CH3), 7.43 (s, 1H, ArH), 7.96 (s, 1H, ArH), ca. 12 (very broad s, 2H, NH and OH); MS m/e: 245 (M+, 26%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:18][O:19][CH3:20])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#N.CC(C[AlH]CC(C)C)C.C1C[O:33]CC1>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:18][O:19][CH3:20])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:33]
Reactant: COCN(c1nccs1)S(=O)(=O)c1ccc(C#N)cc1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: COCN(c1nccs1)S(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-cyano-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (4.5 mmol) in THF (50 mL) at −78° C. under argon was added DIBAL (5.0 mmol, 1M in THF) and the solution was allowed to warm to room temperature overnight. After the reaction was quenched with potassium sodium tartrate solution slowly, the mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography to give 4-formyl-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (3.1 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:32]([CH:40]=O)[NH:31][C:30]=2[CH3:42])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[C:32]([CH:40]=[C:13]3[C:12]4[C:16](=[CH:17][C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[CH:10][CH:11]=4)[NH:15][C:14]3=[O:18])[NH:31][C:30]=2[CH3:42])=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCN1CCCC1
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(C(=O)NCCN2CCCC2)c1-c1ccccc1
Yield: 34.8 %

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (50 mg, 0.21 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (70 mg) to give 0.04 g (35%) of the title compound as a yellow-orange solid.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[C@H:2]([C:20](O)=[O:21])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=1.[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:24])[C@H:2]([C:20]([NH:47][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:21])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:5]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1cc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)NCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To the mixture of Fmoc-Trp(Boc)-OH (205 mg, 0.39 mmol) and benzylamine (165 μL, 1.51 mmol) in DMF (5 mL) was added TBTU (249 mg, 0.77 mmol) and N,N-diisopropylethylamine (340 μL, 1.95 mmol). The reaction was stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue was purified by flash column silica gel chromatography (2:1, hexane:ethyl acetate) to yield the Fmoc-Trp(Boc)-NHBn (151 mg, 63%). The solution of Fmoc-Trp(Boc)-NHBn (151 mg, 0.25 mmol) and piperidine (0.5 mL) in DMF (2 mL) was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the crude product was purified by flash column silica gel chromatography (from ethyl acetate to 5% methanol in ethyl acetate) to afford the NH2-Trp(Boc)-NHBn (81 mg, 80%). Compound 16 (23 mg, 0.04 mmol) was dissolved in DMF (2 mL) and NH2-Trp(Boc)-NHBn (72 mg, 0.18 mmol), TBTU (33 mg, 0.10 mmol), and N,N-diisopropylethylamine (37 μL, 0.21 mmol). The mixture was stirred for 4 hours at room temperature before removing the solvent under reduced pressure. The crude product was purified by flash chromatography using ethyl acetate as eluent to afford 17 (24 mg, 63%).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:11](=[O:14])[CH2:12][CH3:13])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CS(C)=O.P([O-])([O-])([O-])=O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:11](=[O:14])[CH2:12][CH3:13])[CH2:8][CH:9]=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(=O)C(CCO)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CCC(=O)C(CC=O)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
Fifteen milligrams of 3,3-diphenyl-4-oxo-hexanol (0.043 mmol) was dissolved in DMSO (1 ml). A 10 mg/ml thyroglobulin solution was prepared by dissolving 170 mg of thyroglobulin in 17 ml 0.05M phosphate buffer, pH 9.0. While stirring, the dissolved hapten was added dropwise to the thyroglobulin solution. The hapten vial was rinsed with an additional 0.5 ml DMSO and added dropwise to the solution. The resultant mixture was stirred at room temperature for 1 hour. Five milligrams of sodium cyanoborohydride was added to the mixture, and the solution was stirred at room temperature for 0.5 hours. The pH of the solution was adjusted to 7.5 with 0.1N HCl. An additional 5.0 mg sodium cyanoborohydride was added, and the solution was again stirred for 0.5 hours. This was repeated once more, for a total addition of 15.0 mg sodium cyanoborohydride. This solution was dialyzed against 0.05M phosphate buffer (pH 7.5). The solution was clarified by centrifuging for 10 min at 4000 rpm to produce a solution of 3,3-diphenyl-4-oxo-hexanal, thyroglobulin immunogen.
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2[S:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][NH:13][C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1)[CH3:2].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH2:1]([C:3]1[S:17][C:6]2[S:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][N:13]([CH3:20])[C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(s1)SCCc1cc(=O)[nH]nc1-2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(s1)SCCc1cc(=O)n(C)nc1-2
Yield: 47.5 %

Procedure:
To a solution of 0.6 g of 9-ethyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in 15 ml of N,N-dimethylformamide is added 0.11 g of 60% sodium hydride with stirring under ice-cooling and the mixture is stirred for 10 minutes at room temperature. To the mixture is added 0.39 g of methyl iodide, and the mixture is further stirred for 20 minutes and then poured into ice-cold water. The precipitated crystals are collected by filtration, washed with water and recrystallized from ethanol to give 0.3 g of 9-ethyl-2-methyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 168°-170° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:22]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCCC1>[C:22]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12])=[O:7])=[CH:14][CH:15]=2)=[O:38])=[CH:40][CH:41]=1)([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(C)COC(=O)c1ccc(OC(=O)c2ccc(OC(=O)OCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A solution of 16 mmol (3.3 g) of the 2-methylbutyl p-hydroxybenzoate obtained in 1.(2) in a solvent mixture of 20 ml of THF (tetrahydrofuran) and 40 ml of pyridine was cooled, and to the solution was added dropwise a THF solution of 10 mmol (2/9 g) of the 4-carbobenzoxyoxybenzoyl chloride obtained in 1.(4). The temperature was gradually returned to room temperature, and then the mixture was stirred for 8 hours. After conclusion of the reaction, the reaction solution and purified by column chromatography to obtain 2.9 g of 2-methylbutyl 4-(4'-carbobenzoxyoxybenzoyloxy)benzoate [m.p.: 64.4°-65.4° C⟧ (Yield: 63%)
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[N:10]=[C:9]([N:22]3[CH:27]4[CH2:28][CH2:29][CH:23]3[CH2:24][O:25][CH2:26]4)[CH:8]=2)[CH2:3][CH2:2]1>ClCCl.CC(O)C.[Pd]>[CH:23]12[N:22]([C:9]3[CH:8]=[C:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[N:12]=[C:11]([C:13]4[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=4)[N:10]=3)[CH:27]([CH2:28][CH2:29]1)[CH2:26][O:25][CH2:24]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(C3=CCOCC3)cc(N3C4CCC3COC4)n2)cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: ClCCl
Product: Nc1ccc(-c2nc(C3CCOCC3)cc(N3C4CCC3COC4)n2)cc1
Reaction time: 72 h
Yield: 98.8 %

Procedure:
In a 250 mL round-bottomed flask was placed 8-(6-(3,6-dihydro-2H-pyran-4-yl)-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (74, 353 mg, 0.895 mmol) in dichloromethane (10 mL) and 2-propanol (10 mL) to give a yellow solution. Pd—C (95 mg, 0.089 mmol) was added. The reaction mixture was stirred for 72 hours under an atmosphere of hydrogen. The reaction mixture was diluted with dichloromethane, filtered through Celite™ and washed with dichloromethane. The mixture was concentrated under reduced pressure to give 324 mg of a yellow solid. HRMS: 367.2130 [M+H+. For [M+H]+ mass error=0.3 mDa or 0.7 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:16](N(CC)CC)[CH3:17].ICC.O>O1CCCC1>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][N:10]([CH2:16][CH3:17])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC1(c2cccc(Cl)c2F)CCNC1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1CCC(OC)(c2cccc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 26 h
Yield: 38.1 %

Procedure:
To a solution of (+)-3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (0.25 g, 1.08 mmol) and triethylamine (0.305 ml, 2.17 mmol) in tetrahydrofuran (20 ml), was added iodoethane (0.13 ml, 1.63 mmol) and the solution was stirred at ambient temperature for 26 h. Water (20 ml) was added and the aqueous phase was extracted with EtOAc (2×50 ml), the combined organic phase was dried (Na2SO4) and the solvent was evaporated. Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 65:35) gave the title compound 0.106 g (38%). [a]D=+16.5° (methanol). The amine was converted to the fumaric acid salt and recrystallized from 2-propanol/diisopropyl ether: M.p. 131-133° C. MS m/z (rel. intensity, 70 eV) 257 (M+, 9), 242 (bp), 227 (44), 157 (44), 71 (89).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH3:20])[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:15]=2)=O)[C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[NH:21][C:9]([C:11]3[N:12]([CH3:20])[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:15]=3)=[N:8][C:6]=2[CH:7]=1
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Nc1cc(Br)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cn1nc(C(C)(C)C)cc1-c1nc2cc(Br)ncc2[nH]1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid (2-bromo-5-nitro-pyridin-4-yl)-amide (79.8 mg, 0.183 mmol, prepared as described in the previous step) in acetic acid (1 mL) was treated with Fe powder (102 mg, 1.82 mmol). The resulting mixture was stirred at 110° C. for 1 h, cooled to room temperature, and treated with EtOAc (10 mL) and saturated NaHCO3 (10 mL). The organic layer was separated, washed with saturated NaHCO3 (10 mL), H2O (10 mL), concentrated, and the resulting residue dried in vacuo to yield 6-bromo-2-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3H-imidazo[4,5-c]pyridine. 1H-NMR (400 MHz, CDCl3) δ: 10.0 (br s, 1H), 8.80 (br s, 1H), 7.60 (br s, 1H), 6.60 (m, 1H), 4.40 (s, 3H), 1.30 (s, 9H).
Reaction SMILES: C(Cl)CCl.Cl.[NH2:6][C:7]1[N:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([OH:17])=O)=[CH:9][C:8]=1[C:18]([OH:21])([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.[CH3:32][NH:33][CH2:34][C:35]1[O:36][C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[C:39]=1[CH3:40].C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[NH2:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:33]([CH3:32])[CH2:34][C:35]2[O:36][C:37]3[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=3[C:39]=2[CH3:40])=[O:17])=[CH:9][C:8]=1[C:18]([OH:21])([CH3:20])[CH3:19]
Reactant: CNCc1oc2ccccc2c1C
Reactant: CC(C)(O)c1cc(C=CC(=O)O)cnc1N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCCl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc(N)c(C(C)(C)O)c2)oc2ccccc12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
EDC (98 mg, 0.51 mmol) was added to a suspension of 3-[6-Amino-5-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-acrylic acid hydrochloride (110 mg, 0.43 mmol), HOBt (63 mg, 0.47 mmol), methyl-(3-methyl-benzofuran-2-ylmethyl)-amine (110 mg, 0.47 mmol) and (i-Pr)2EtN (0.36 mL, 2.1 mmol) in DMF (7 mL). The mixture was allowed to stir overnight at 40° C. The mixture was cooled to 0° C. and diluted with H2O (60 mL) with rapid stirring. Only a small amount of precipitate was formed, therefore the product was extracted using EtOAc (2×50 mL), the combined organic layers washed with brine (60 mL), dried over MgSO4 and dried under high vacuum. The solid was then subjected to flash chromatography on silica gel using 10% methanol:dichloromethane. Yield: 77.6 mg (48%); 1H NMR (300 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.70 (s, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.44 (s, 1H), 7.23-7.32 (m, 2H), 6.98 (d, J=17.7 Hz, 1H), 6.59 (s, 2H), 5.51 (s, 1H), 5.00 and 4.80 (2×s, 2H), 3.20 and 2.99 (2×s, 3H), 2.28 (s, 3H), 1.54 (s, 6H); ESI MS m/z 380.2 [C22H25N3O3+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2=[CH2:14])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]32[O:26][CH2:14]3)=[CH:4][CH:3]=1
Reactant: C=C1C(C)(C)CCC1(C)Cc1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1(C)CCC(C)(Cc2ccc(Cl)cc2)C12CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
2-(4-Chlorobenzyl)-2,5,5-trimethyl-1-methylenecyclopentane (6.1 g) was dissolved in 60 ml of chloroform, followed by the addition of 8.5 g of m-chloroperbenzoic acid. The resultant mixture was stirred for 5 hours under ice cooling. Calcium hydroxide (4.0 g) was added, followed by stirring at room temperature for 30 minutes. A solid thus precipitated was filtered off. From the chloroform layer as the filtrate, chloroform was distilled off under reduced pressure to obtain a colorless oily substance. The substance was subjected to and purified by chromatography on a silica gel column (eluent: 6:1 mixed solvent of n-hexane and methylene chloride), thereby obtaining 2.0 g of 4-(4-chlorobenzyl)-4,7,7-trimethyl-1-oxaspiro[2.4]heptane used in the above Preparation Example.