Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:27]([CH2:29][C@@H:30]([OH:37])[CH2:31][C:32](OCC)=[O:33])#[N:28].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:27]([CH2:29][C@@H:30]([OH:37])[CH2:31][C:32](=[O:33])[CH2:10][C:9]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:11])#[N:28]
Reactant: CCOC(=O)C[C@H](O)CC#N
Reactant: CC(=O)N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: N#CC[C@@H](O)CC(=O)CC(=O)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-bis(phenylmethyl)acetamide (prepared from N,N-bis(phenylmethyl)amine and acetyl chloride by refluxing for 2 hours in toluene) (120 g, 0.5 mol) in tetrahydrofuran (0.5 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.25 L of 2M) while maintaining the temperature between -30° C. to -45° C., and the mixture is stirred at -20° C. to -30° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (20 g, 0.125 mol) as a solution in 200 mL of tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -35° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (0.5 L). The aqueous layer is extracted with 300 mL of ethyl acetate, the aqueous layer is separated and reextracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6-cyano-5-hydroxy-3-oxo-N,N-bis(phenylmethyl)hexanamide as an oil. This oil, approximately 0.1 mol, is dissolved in tetrahydrofuran (200 mL) and methanol (100 mL) under a nitrogen atmosphere. The solution is cooled to -20° C., and a 50% solution of methoxydiethylborane in tetrahydrofuran (50 mL) is added. The reaction is cooled to -78° C., and sodium borohydride (12 g, 0.32 mol) is added over 30minutes. The reaction is maintained at -78° C. for 5 hours and allowed to warm to room temperature and stand for 10 hours under a nitrogen atmosphere. The reaction is quenched by the addition of acetic acid (20 mL) and concentrated by vacuum distillation to an oil. The residue is dissolved with methanol (300 mL), concentrated by vacuum distillation, redissolved with methanol (300 mL), and reconcentrated by vacuum distillation to give a yellow oil. The oil is taken up in ethyl acetate (300 mL) and washed with deionized water (300 mL). The ethyl acetate solution is concentrated by vacuum distillation to give crude R-(R*,R*)!-6-cyano-3,5-dihydroxy-N,N-bis(phenylmethyl)hexanamide as an oil which is used without further purification;
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:17]=[C:18]([C:21]([OH:23])=O)[NH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:21]([C:18]1[NH:19][CH:20]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=1)=[O:23]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccccc2)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 87.59 %

Procedure:
DIPEA (155 mg, 0.2 mL, 1.19 mmol) was added to a stirred solution of 4-Phenyl-1H-pyrrole-2-carboxylic acid (50 mg, 0.26 mmol) in DMF (4 mL). HOBT (40 mg, 0.29 mmol) and EDCI (153 mg, 0.79 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method as described above) (103 mg, 0.29 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and filtered the solid precipitated to afford 113 mg (87.59% yield) of 4-phenyl-1H-pyrrole-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 92.52%. 1H NMR (DMSO-d6): δ 11.6 (s, 1H), 8.2-8.1 (bs, 1H), 7.9-7.72 (m, 2H), 7.7-7.64 (t, 1H), 7.6-7.5 (d, 3H), 7.38-7.28 (t, 3H), 7.24-7.1 (m, 2H), 4.2-4.04 (bd, 2H), 3.82-3.56 (m, 4H), 3.5-3.4 (bs, 2H), 3.2-3.1 (bd, 2H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].S(=O)(=O)(O)O.[CH2:11]=[C:12]1[CH:19]2[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]3)[CH2:18]2.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:12]1([CH3:11])[CH:13]2[CH2:21][CH:17]3[CH2:16][CH:15]([CH2:20][CH:19]1[CH2:18]3)[CH2:14]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=C1C2CC3CC(C2)CC1C3
Reactant: C=CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 20 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A 500 ml flask was flushed with nitrogen to displace the air with nitrogen, and was charged with 36.0 g (0.50 mol) of acrylic acid, 0.5g (5mmol) of sulfuric acid and 100 g of toluene. Separately 88.8 g (0.60 mol) of 2-methyleneadamantane, prepared by the same procedures as described in Reference Example 1, was dissolved in 100 g of toluene. The obtained solution of 2-methyleneadamantane in toluene was dropwise added to the content in the flask over a period of about 3 hours, while the content was maintained at a reaction temperature of about 20° C. Then the content was stirred for 5 hours at the same temperature. After completion of the reaction, the residual catalyst was neutralized by adding 40.0 g (50 mmol) of a 5% aqueous sodium hydroxide solution, and the neutralized liquid was washed with an aqueous saturated sodium chloride solution. The thus-obtained organic phase was subjected to column chromatography, and further, analyzed by NMR and mass spectrometry. Thus, 100.7 g (yield: 91.5%) of the object 2-methyl-2-adamantyl acrylate was obtained.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:7]=1.[Zn](C)[CH3:29]>O1CCOCC1.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]>[CH2:23]([CH:22]([CH2:25][CH3:26])[CH2:21][O:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:29])=[CH:18][C:13]=1[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:27])=[N:7]1)[CH3:24]
Reactant: C[Zn]C
Reactant: CCC(CC)COc1ccc(Br)cc1Cn1nc(CCC(=O)OC)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCC(CC)COc1ccc(C)cc1Cn1nc(CCC(=O)O)cc1C
Temperature: 105 °C

Procedure:
A mixture of 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.1363 g, 0.31 mmol), Pd(dppf)Cl2 (0.00506 g, 0.00621 mmol), Zn(CH3)2 (0.31 mlg, 0.62 mmol in 1,4-dioxane (0.93 ml) heated at 105° C. under a N2 atmosphere for 1 h 50 min. The mixture was cooled to RT, quenched with MeOH (0.2 ml) and partitioned between 1M HCl and EtOAc. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was converted to the title compound following the method in Example 1, Step 8.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1.[C:13](O)(=O)[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([OH:12])=[O:11])[C:5]2[N:6]([C:13]([CH3:14])=[N:9][N:8]=2)[N:7]=1
Reactant: CC(=O)O
Reactant: NNc1nnc(Cl)cc1C(=O)O
Product: Cc1nnc2c(C(=O)O)cc(Cl)nn12
Temperature: 100 °C
Yield: 72.5 %

Procedure:
A suspension of starting material 6-chloro-3-hydrazinylpyridazine-4-carboxylic acid (4.80 g, 26 mmol) in acetic acid (100 mL) was heated at 100° C. for 3 hours. The mixture was cooled to room temperature, concentrated in vacuum to give the crude product, which was washed by PE (50 mL) first, then recrystallized from MeOH to give product 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylic acid as a yellow solid (4.00 g, 72.5%). 1H NMR (300 MHz, DMSO) δ: 7.2 (s, 1H), 2.66 (s, 3H). LRMS (M+H+) m/z: calcd 213; found 213.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(F)c(Cl)c4)cc3CC[C@@H]12
Yield: 73.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3-chloro-4-fluorophenylboronic acid (136 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 170 mg (73%) of the title compound as a white solid. mp 114°-116°. FDMS: m/e=357. α[D]589 =+86.00 (c=1.00, methanol).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=1)=O>CO>[CH3:2][O:3][N:4]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=1)[CH3:12]
Reactant: CC(=O)c1cccc(I)c1
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=C(C)c1cccc(I)c1
Temperature: 60 °C

Procedure:
To a solution of O-methyl hydroxylamine hydrochloride (2.5 g, 30.48 mmol) in methanol (25 ml), was added triethylamine (30.48 mmoles) followed by 3-iodo acetophenone (5 g, 20.3 mmol) and the mixture was heated at 60° C. for 3 hours. On completion of the reaction, the mixture was concentrated to remove methanol, to give 1-(3-iodo-phenyl)-ethanone O-methyl-oxime (crude), which was dissolved in glacial acetic acid (50 ml). Sodium cyanoborohydride (2.5 g, 40 mmol) was added portion wise. The mixture was allowed to stirr overnight at ambient temperature. The reaction mixture was concentrated to remove acetic acid and diluted with water. The aqueous layer was extracted with ethyl acetate (3×80 ml), the combined organic layer is washed with brine (40 ml) and dried over sodium sulphate. Organic layer was concentrated under vacuum to obtain 5.6 g crude material, which was subjected to column purification (60-120μ mesh silica gel, 15% ethyl acetate in hexane) to give 3.4 g (54% of theory) of N-[1-(3-Iodo-phenyl)-ethyl]-O-methyl-hydroxylamine.
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[Cl:25])=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:25].[ClH:34].[Cl:25][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)=[CH:16][C:11]=1[NH:10][C:9]([NH2:26])=[NH:8]
Reactant: COc1ccnc(-c2ccc(Cl)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccnc(-c2ccc(Cl)c(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(2-chloro-5-(4-methoxypyridin-2-yl)phenyl)guanidine (133 mg) in dichloromethane (1 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 3 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the resultant precipitate was collected by filtration and dried under reduced pressure to give (2-chloro-5-(4-methoxypyridin-2-yl)phenyl)guanidine dihydrochloride (83 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:37][C:36]([F:39])([F:38])[CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:37][C:36]([F:39])([F:38])[CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CC(F)(F)C2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CC(F)(F)C2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
175 mg (0.29 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3,3-difluorocyclobutyl)propanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 122 mg (77% of theory)
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH3:11])[N:3]=1.[CH3:12][NH2:13].O>C(O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:13][CH3:12])[N:4]([CH3:11])[N:3]=1
Reactant: CN
Reactant: Cn1nc(Br)c([N+](=O)[O-])c1Br
Solvent: CCO
Solvent: O
Product: CNc1c([N+](=O)[O-])c(Br)nn1C
Yield: 88 %

Procedure:
2 g (7.02 mmoles) of 3,5-dibromo-1-methyl-4-nitropyrazole are heated in 50 ml of a 40-percent solution of methylamine in ethanol for 4 hours at boiling temperature. After cooling, 100 ml water are added to the reaction mixture, the separated product is filtered out and washed with a small amount of water (20 ml). After vacuum drying, 1.45 g (88 percent of theory) of 3-bromo-1-methyl-5-methylamino-4-nitropyrazole are obtained in the form of yellow crystals with a melting point of 185° C.
Reaction SMILES: [CH:1]1([CH:4]([C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[O:5][C:6]2[CH:26]=[CH:25][C:9]([CH2:10][NH:11][C:12]3[C:17]([NH2:18])=[CH:16][C:15]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:27][CH3:28])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:44]([N:49]=[C:50]=S)(=[O:48])[O:45][CH2:46][CH3:47].C1(S(Cl)(=O)=O)C=CC=CC=1>O1CCCC1>[CH2:46]([O:45][C:44](=[O:48])[NH:49][C:50]1[N:11]([CH2:10][C:9]2[CH:25]=[CH:26][C:6]([O:5][CH:4]([CH:1]3[CH2:3][CH2:2]3)[C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[C:7]([O:27][CH3:28])[CH:8]=2)[C:12]2=[N:13][CH:14]=[C:15]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[CH:16]=[C:17]2[N:18]=1)[CH3:47]
Reactant: CCOC(=O)N=C=S
Reactant: COc1ccc(C(Oc2ccc(CNc3ncc(-c4cnn(C)c4)cc3N)cc2OC)C2CC2)cn1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(OC(c2ccc(OC)nc2)C2CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
To a stirred solution of N2-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.55 g, 1.13 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.799 g, 7.90 mmol). The resulting mixture was allowed to stir at room temperature. After 15 min, the mixture was treated with ethyl carbonisothiocyanatidate (0.444 g, 3.39 mmol), and the resulting mixture was allowed to stir at room temperature. After 30 min, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (5 mL) and was treated with triethylamine (0.799 g, 7.90 mmol) and benzenesulfonyl chloride (0.259 g, 1.43 mmol). The resulting mixture was allowed to stir at room temperature. After 16 h, the mixture was concentrated. Chromatographic purification of the residue (neutral alumina, 50% ethyl acetate in petroleum ether elute) afforded 0.45 g (68%) of ethyl(3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a brown oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[N+:26]([C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][C:33](=[O:42])[N:34]2[CH2:39][CH:40]=O)([O-:28])=[O:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:40][CH2:39][N:34]4[C:35]5[C:30](=[C:29]([N+:26]([O-:28])=[O:27])[CH:38]=[CH:37][CH:36]=5)[CH:31]=[CH:32][C:33]4=[O:42])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2c([N+](=O)[O-])cccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c([N+](=O)[O-])cccc32)CC1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To 1 mL of a chloroform solution containing 0.20 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.14 g of (5-nitro-2-oxoquinolin-1(2H)-yl)acetaldehyde, 10 μL of acetic acid and 0.18 g of sodium triacetoxyborohydride were added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography[Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-nitro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[CH:4][C:3]=1[CH3:13].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1.C(OCC)(=O)C.CS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[CH:11]=[N:10][N:9]=2)=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(-c2nnc[nH]2)ccc1Br
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nncn2C2CCCCO2)ccc1Br
Temperature: 50 °C
Yield: 97.9 %

Procedure:
3-(4-Bromo-3-methylphenyl)-4H-1,2,4-triazole (2.00 g, 8.40 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature with stirring under nitrogen. 3,4-Dihydro-2H-pyran (3.80 mL, 42.0 mmol) and methanesulfonic acid (0.027 mL, 0.42 mmol) were added and the resulting mixture heated at 50° C. under a reflux condenser under nitrogen for 20 h. The resulting mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (10-30-50% ethyl acetate in hexanes) gave the desired product (2.64 g, 8.22 mmol, 98% yield) as a yellow oil. MS (ESI) m/z 322 [M]+, 324 [M+2]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20](F)[C:19]([N+:23]([O-:25])=[O:24])=[C:18]([F:26])[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[F:30][C:31]([F:36])([F:35])[C@@H:32]([OH:34])[CH3:33]>CCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:34][C@@H:32]([CH3:33])[C:31]([F:36])([F:35])[F:30])[C:19]([N+:23]([O-:25])=[O:24])=[C:18]([F:26])[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Reactant: C[C@H](O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](Oc1cc(C[C@@H]2CSC[C@H](NC(=O)OC(C)(C)C)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as described for example 24j, starting from [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (0.409 g, 1 mmol), KOH (0.06 g, 1.05 mmol) and (S)-1,1,1-trifluoro-propan-2-ol (0.583 g, 5 mmol) and was obtained as a yellow oil, which was used as such in the next step: TLC (hexane-EtOAc 1:1) Rf=0.37; HPLC RtA=2.36 min; ESIMS [M+H-isobutylene]+=443.
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17]>>[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[N:17]=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)cc1C
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Product: Cc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 3,4-dimethylaniline as starting materials, the title compound was obtained as a yellow powder (yield 60%).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](OS(C2C=CC=CC=2)(=O)=O)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.[OH-].[Li+]>C(O)C.CO.O>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:3]([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9])[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(OCc1ccccc1)N1CCC(OS(=O)(=O)c2ccccc2)CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: O=C(O)C(C(=O)O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
Sodium metal (3.2 g) was dissolved in ethanol (50 ml) under a nitrogen atmosphere at room temperature. A solution of diethyl malonate (56.4 ml) in ethanol (50 ml) was added dropwise, followed by a solution of 4-benzenesulfonyloxy-piperidine-1-carboxylic acid benzyl ester (31.88 g) in ethanol (50 ml), also added dropwise. The mixture was heated to reflux for 16 h then the solvent was removed under reduced pressure. The residue was partitioned between water (100 ml) and diethyl ether (100 ml) and the aqueous washed with further diethyl ether (60 ml). The combined organics were washed with 10% citric acid solution (50 ml), water (50 ml) and brine (50 ml). After drying (Na2SO4) and filtering the solvent was removed under reduced pressure to leave a yellow liquid. Half of this crude diester was taken and dissolved in methanol (150 ml) and water (50 ml). Lithium hydroxide monohydrate (18.14 g) was added slowly and the reaction left to stir at room temperature for 16 h then the methanol was removed under reduced pressure. The aqueous was washed with diethyl ether (3×40 ml), acidified to pH=3 with citric acid and extracted with ethyl acetate (2×40 ml). The combined organics were washed with water (2×40 ml) and brine (40 ml), dried (Na2SO4), filtered and evaporated under reduced pressure to give the title compound (8.29 g, 56%) as a white crystalline solid.