Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:14]CC1.[Br:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:38]=[C:26]3[N:27]=[C:28]([CH3:37])[C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:30]([I:31])[N:25]3[N:24]=2)[CH:20]=[CH:21][CH:22]=1.C1(C2ON2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:38]=[C:26]3[N:27]=[C:28]([CH3:37])[C:29]([CH:32]([OH:14])[C:33]([O:35][CH3:36])=[O:34])=[C:30]([I:31])[N:25]3[N:24]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [K+]
Product: COC(=O)C(O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a stirred solution of 0.9M KHMDS/THF (2.55 mL, 2.297 mmol) in THF (8 mL) at −78° C. was added dropwise a THF (10 mL) solution of methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (859 mg, 1.767 mmol) over 5 min. After 30 min, a THF (10 mL) solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (600 mg, 2.297 mmol) was added to the resulting red reaction mixture and stirred for additional 30 min at −78° C. Then, the resulting orange reaction mixture was quenched with sat. NH4Cl (50 mL), diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to give light solid. This solid was triturated with small amount of ethyl acetate and solids were filtered, washed with hexanes and dried under high vacuo to afford methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (600 mg, 1.195 mmol, 67.6% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 8.21 (t, J=1.7 Hz, 1H), 7.96 (dt, J=7.8, 1.2 Hz, 1H), 7.59-7.55 (m, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.09 (s, 1H), 5.78 (s, 1H), 3.87 (s, 3H), 3.54 (br. s., 1H), 2.61 (s, 3H). LCMS (M+H)=504.05.
Reaction SMILES: [BH4-].[Na+].CCO.[CH2:6]([O:8][C:9](=[O:35])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1/[CH:23]=[CH:24]/[C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:35])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1/[CH:23]=[CH:24]/[CH:25]([OH:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH3:7]
Reactant: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Yield: 80.4 %

Procedure:
Sodium borohydride (10 mg, 0.26 mmol) followed by EtOH (0.25 mL) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid ethyl ester (110 mg, 0.25 mmol) in CH2Cl2 (1.0 mL) at 0° C. After 1 h at 0° C. the reaction was quenched with 1 N aqueous HCl. The reaction mixture was extracted with CH2Cl2 (3×10 mL), then the combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2) afforded 88 mg (80%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid ethyl ester.
Reaction SMILES: CS(O[CH2:6][CH:7]1[S:11][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]([CH3:31])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=[O:24])=[O:23])=[N:9][CH2:8]1)(=O)=O.[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][N:21]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([C:10]1[S:11][CH:7]([CH2:6][N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)[CH2:8][N:9]=1)=[CH:20]2)[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=[O:24])=[O:23]
Reactant: c1nc[nH]n1
Reactant: CN(c1cccc2cc(C3=NCC(COS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C3=NCC(Cn4cncn4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 60 °C
Reaction time: 15 h
Yield: 59.3 %

Procedure:
A mixture of (2-{7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)methyl methanesulfonate (1.0 g), 1H-1,2,4-triazole (290 mg), potassium carbonate (580 mg) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate-methanol (50:50:0-0:100:0-0:95:5, volume ratio) to give N-methyl-N-{2-[5-(1H-1,2,4-triazol-1-ylmethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}pyridine-2-sulfonamide (560 mg, yield 59%) as a pale-yellow amorphous solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[S:6]([C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:8])=[O:7])[C:2]([CH3:4])=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[NH2:31][CH:2]([CH3:4])[CH2:1][N:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[S:6]([C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:8])=[O:7]
Reactant: CCCCCCN(CC(C)=O)S(=O)(=O)c1cccc2cnccc12
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCN(CC(C)N)S(=O)(=O)c1cccc2cnccc12
Reaction time: 19 h

Procedure:
To 75 ml of an anhydrous methanol solution containing 5.89 g of the thus obtained N-acetonyl-N-hexyl-5-isoquinolinesulfonamide were added 13.03 g of ammonium acetate and 0.75 g of sodium cyanoborohydride, followed by stirring at 15° to 20° C. for 19 hours. Then, the methanol was removed at 30° C. under reduced pressure. To the resultant reaction product were added 50 ml of chloroform and 50 ml of 1N sodium hydroxide solution. The chloroform layer was dried with anhydrous magnesium sulfate, and the chloroform was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, 100 g; solvent: chloroform) to obtain 2.75 g of N-(2-aminopropyl)-N-hexyl-5-isoquinolinesulfonamide [Compound (11)]. Compound (11) was analyzed to give the following data.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=3)[S:10][C:3]=12.[F:27][C:28]1[CH:48]=[C:47]([N+:49]([O-:51])=[O:50])[CH:46]=[CH:45][C:29]=1[O:30]C1C=CN=C2C=C(C3SC=CN=3)SC=12>>[F:27][C:28]1[CH:48]=[C:47]([N+:49]([O-:51])=[O:50])[CH:46]=[CH:45][C:29]=1[O:30][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=3)[S:10][C:3]=12
Reactant: CN(CCn1cc(-c2cc3nccc(Cl)c3s2)cn1)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: CN(CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1)C(=O)OC(C)(C)C
Yield: 37 %

Procedure:
Starting from the chloride 180 and following the procedure described above for the synthesis of compound 11 (scheme 2, example 12), title compound 181 was obtained in 37% yield. LRMS (M+1) 514.1 (100%).
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](=[NH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].C([Li])CCC.Cl[P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[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](=[N:21][P:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=N)c1ccccc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: CC(C)c1cccc(C(C)C)c1NC(=NP(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 4.20 g N1-(2,6-diisopropylphenyl)benzamidine (15.0 mmol), 7.50 mL of 2.0 M butyllithium (15.0 mmol), 2.70 mL of chlorodiphenylphosphine (15.0 mmol). Following removal of lithium chloride via filtration and removal of solvent in vacuo, the sticky residue was dissolved in 20 mL of pentane, reduced in volume to 5 mL (cold), producing a while solid that was filtered and dried (5.33 g, 76%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=N)[O-:4].[C:18](OCC)(=[O:20])C>O>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([O:20][CH3:18])=[O:4]
Reactant: CCOC(C)=O
Reactant: N=C([O-])C(O)CCCCCCc1ccccc1
Solvent: O
Product: COC(=O)C(O)CCCCCCc1ccccc1

Procedure:
A two-phase solution of the 2-hydroxy-8-phenyloctanimidate, ethyl acetate (50 mL), and water (50 mL) was stirred overnight. The layers were separated and the organic phase was dried (Na2SO4), filtered and concentrated to yield methyl 2-hydroxy-8-phenyloctanoate as an oil. The oil was dissolved in 9:1 dioxane-water (50 mL) containing LiOH (1.7 g). After 2 h of stirring, the mixture was acidified with 2N HCL to pH˜3. The resulting mixture was extracted twice with EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated to yield 2-hydroxy-8-phenyloctanoic acid as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[N:9][CH:10]=1)=[O:4].Cl.O1CCOCC1>ClCCl>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)c1cnc(Oc2ccc3c(c2)CCNCC3)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A solution of 1,1-dimethylethyl 7-({5-[(methylamino)carbonyl]-2-pyrazinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D49, Step 3) (44.26 g, 0.11 mol) in dichloromethane (800 ml) was added dropwise to a stirring solution of 4M hydrogen chloride in dioxane (270 ml, 1.1 mol). The resulting mixture was stirred at room temperature for 60 minutes. A further quantity of 4M hydrogen chloride in dioxane (30 ml, 0.12 mol) was added and the mixture stirred for 60 minutes. The resulting white solid was collected by filtration and washed with dichloromethane. The solid was dissolved in water (2 L) and basified by addition of saturated sodium carbonate solution. The water layer was extracted with dichloromethane and the extracts filtered through celite. The celite was washed with methanol and the combined dichloromethane and methanol washings were evaporated in vacuo to give the title compound (25.1 g); MS (ES+) m/e 299 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:25])[N:14]([CH2:17][O:18]CC[Si](C)(C)C)[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[ClH:43].[Cl:44][CH2:45][C:46]1[N:47]=[C:48]([CH3:51])[S:49][CH:50]=1.FC(F)(F)C(O)=O.Cl>CN(C=O)C.C(Cl)Cl.CC(O)C.O>[ClH:44].[ClH:43].[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:45][C:46]3[N:47]=[C:48]([CH3:51])[S:49][CH:50]=3)[C:13](=[O:25])[N:14]([CH2:17][OH:18])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(COCC[Si](C)(C)C)C2=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(C)O
Product: CCCCc1ncc(/C=C2/C(=O)N(CO)C(=O)N2Cc2csc(C)n2)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 16 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[[2,5-dioxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-4-imidazolidinylidene]methyl]-1H- imidazol-1-yl]methyl]benzoate (0.390 g, 0.760 mmol) in DMF (5 mL) is added K2CO3 (0.525 g, 3.80 mmol). After stirring for 5 minutes 4-chloromethyl-2-methylthiazole hydrochloride (0.275 g, 1.49 retool) is added. The mixture is stirred for 16 hours. Water is added and the gum that precipitates is separated. This gum is dissolved in ethyl acetate, washed with water and brine, and then dried over MgSO4. Chromatography eluting with 0.5% methanol in chloroform and evaporation in vacuo affords a viscous oil. This oil is dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (5 mL). After stirring for 90 minutes the mixture is concentrated in vacuo and then extracted into methylene chloride from pH 7 buffer. The organic phase is dried over MgSO4 and then evaporated in vacuo to afford an oil. This oil is disssolved in 2-propanol and treated with ethereal HCl (1M, 2mL). The white gummy solid that results is crystallized from methanol/2-propanol/ether.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.S(O)(O)(=O)=O.[NH2:60][C:61]1[NH:62][CH:63]=[CH:64][N:65]=1>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:60][C:61]2[NH:62][CH:63]=[CH:64][N:65]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncc[nH]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc[nH]1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 33 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 200 mg, 0.70 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (310 mg, 0.70 mmol), N,N-diisopropylethylamine (244 μL, 1.40 mmol), and 2-aminoimidazole sulfate (140 mg, 1.05 mmol) in dry N,N-dimethylformamide (5 mL) was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide (81.4 mg, 33%) as a white solid: mp 58-60° C.; EI-HRMS m/e calcd for C17H19Cl2N3O (M+) 351.0905, found 351.0901.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[N:12][CH:13]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[N:12][CH:13]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCOC(=O)c1cncc(N2CC[C@H](N)[C@H](OC)C2)c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1cncc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)c1

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)pyridine-3-carboxylate obtained in Example (162b) (137.5 mg, 0.49 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (82 mg, 0.47 mmol), WSC hydrochloride (270 mg, 1.41 mmol) and HOBt (63.4 mg, 0.47 mmol), to obtain 132 mg of the title compound as a pale yellow oily substance (65%).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])([CH3:5])[CH3:4].[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+]([O-])=O)[C:16]=1[C:17]#[N:18])([O-:14])=[O:13]>>[C:17]([C:16]1[C:15]([N+:12]([O-:14])=[O:13])=[CH:22][CH:21]=[CH:20][C:19]=1[O:1][CH2:2][C:3]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])([CH3:5])[CH3:4])#[N:18]
Reactant: CCCC(=O)NC(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCCC(=O)NC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 72 %

Procedure:
Prepared as in Example 215c from N-(1-hydroxy-2-methylpropan-2-yl)butyramide (Example 229d) and 2,6-dinitrobenzonitrile in 72% yield. MS 306 (MH+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13]>>[CH3:11][C:1]1[CH:2]=[CH:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)c1ccc(C)cc1
Product: CCC(=O)c1ccc(C)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A solution of fuming nitric acid (100 mL) at 0° C. is added dropwise 1-p-tolylpropan-1-one (Sigma-Aldrich, 121 mmol) while maintaining the reaction temperature below 10° C. The reaction mixture is stirred at 0° C. for 1 hour then poured into excess ice water. The mixture is placed in a freezer overnight and precipitate collected by filtration, washed with ice water, and taken up in CH2Cl2. The organic solution is washed with sat. aqueous NaHCO3 (100 mL), organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude is purified via chromatography (hexanes to EtOAc) to afford the title compound (14.8 g, 63%) as a light yellow solid: Rf 0.5 (1:4 EtOAc:hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]([C:8]2[N:12]([CH3:13])[CH:11]=[C:10]([C:14](=[O:40])[CH2:15][C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3)[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl>CO>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]([C:8]2[N:12]([CH3:13])[CH:11]=[C:10]([C:14]([C:15]3[NH:19][CH:18]=[N:17][CH:16]=3)=[O:40])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Product: Cn1cc(C(=O)c2cnc[nH]2)cc1C(=O)c1ccc(Cl)cc1

Procedure:
A 2.0 g sample of 1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-2-(1-trityl-1H-imidazol-4yl)ethanone was stirred in 50 mL of MeOH and 35 mL of 2 N HCl for 5 h. The solvent was evaporated in vacuo and the resulting residue was passed through a Biotage Flash 40L (silica gel; CH2Cl2:MeOH) to give 0.14 g of (4-chlorophenyl)-[4-(3H-imidazole-4-carbonyl)-1-methyl-1H-pyrrol-2-yl]methanone: mp.198-200° C. CI-MS m/z=314 (M++H). 1HNMR (CD3CN) δ 8.4 (ar, 1H); 7.9-7.8 (ar, 4H); 7.7 (ar, 1H); 7.6 (ar, 3H); 7.5 (ar, 1H); 4.0 (s, 3H); 2.0 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([Br:21])=[CH:10][CH:11]=3)[N:6]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:33](I)[C:34]([CH3:37])([CH3:36])[CH3:35]>O.C(OCC)(=O)C>[Br:21][C:9]1[CH:8]=[C:7]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1ncc(O)cc12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2′-amino-7-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-3-ol (390 mg, 1.120 mmol) in DMF (4481 μL, 1.120 mmol) in a sealed tube was added cesium carbonate (912 mg, 2.80 mmol). After stirring for 1 minute neopentyl iodide (223 μL, 1.680 mmol) was added, the reaction vessel was sealed and heated at 100° C. for 2.5 hours. Reaction was cooled to RT to prevent over alkylation. The reaction was diluted with water (25 mL) and 10 mL of ethyl acetate and stirred for 30 minutes before being poured into a separatory funnel containing ethyl acetate (100 mL) and water (250 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The aqueous layer was then extracted with DCM (3×50 mL). The organic layers were each washed with water and then brine, at which point all the organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown foam that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-7-bromo-3-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a yellow solid. Step 2: A sealable tube was charged with (S)-7-bromo-3-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (75 mg, 0.179 mmol), copper iodide (3.38 mg, 0.018 mmol), tetrakis(triphenylphosphine)palladium (20.53 mg, 0.018 mmol). To this mixture was added DMF (355 μL, 0.178 mmol), diisopropylamine (498 μL, 3.55 mmol) and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (90 mg, 0.533 mmol). The tube was flushed with argon, sealed and heated to 90° C. for 12 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-7-((3-methyloxetan-3-yl)ethynyl)-3-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a yellow solid.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][CH3:7])([CH3:4])[CH3:3].C([Li])CCC.[Si:13]([O:20][CH:21]1[CH2:25][C:24](=[O:26])[CH:23]=[CH:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>O1CCCC1.CCCCCC>[Si:13]([O:20][CH:21]1[CH2:25][C:24]([OH:26])([CH2:7][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:23]=[CH:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Reactant: CC#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC1C=CC(O)(CC#C[Si](C)(C)C)C1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution mixture of 6.5 g of trimethylsilyl-1-propyne and 50 ml of tetrahydrofuran was added under nitrogen stream and at -30° C. 17.4 ml of 1.56 M hexane solution of n-butyllithium and the resulting mixture was stirred at the same temperature for 1 hour. Then, a solution mixture of 10 g of (RS)-4-oxo-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether and 100 ml of tetrahydrofuran was added by drops to the reaction solution obtained above, and the resulting mixture was stirred for further one hour. The reaction liquid thus obtained was after-treated and purified in the same manner as in (2) of the intermediate preparation example 1 to obtain 8.9 g of (1RS,4RS)-4-hydroxy-4-(3-trimethylsilyl-2-propynyl)-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 59%