Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[S:2](=[CH:5][CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)(=[O:4])=[O:3].[CH3:13]I>>[CH3:13][N:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][CH:5]=[S:2](=[O:4])=[O:3])[CH2:12]1
Reactant: O=S(=O)=CCc1cnccn1
Reactant: CI
Agent: [Na]
Product: CN1C=CN=C(CC=S(=O)=O)C1

Procedure:
5.0 g of 2-(2-sulfonylethyl)pyrazine sodium salt (2500) was added to a solution of 10 ml methyl iodide/50 ml methanol and the mixture refluxed for 4 days. It was then concentrated and purified by gel permeation chromatography (Biogel P-2/water). Freeze-drying gave 4.5 g of product (2600). It was recrystallized from ethanol/water, m.p. 255-60 (dec.). UV H2O max: 281 (3.87). 13C NMR: 162.99, S (C3); 150.63, D (C5); 138.51, D, 136.24, D (C2, C6); 49.66, Q (NCH3); 49.56, T (CH2SO3); 31.44, T (ArCH2). 1H NMR: 9.33, D,T (H6); 8.99, S (H2); 8.82, D (H5); 4.48, S (NCH3); 3.58-3.43, M (--CH2 --).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(N1CC[O:41][CH2:40][CH2:39]1)C.C(Cl)(=O)C>ClCCl>[C:1]([O:5][C:6](=[O:35])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:40](=[O:41])[CH3:39])=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN1CCOCC1
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 100.5 %

Procedure:
A mixture of 11.2 g (21.7 mmol) (S)-3-(4-amino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester and 50 mL dichloromethane and cooled to 0° C. in an ice/water bath. 3.2 mL (25 mmol) N-ethylmorpholine was added, followed by dropwise addition of 1.71 mL (24 mmol) acetyl chloride. After 10 min reaction time, TLC analysis showed complete reaction. The mixture was transferred to a separatory funnel and washed with 50 mL water, 50 mL brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 12 g (21.8 mmol, 100%) of (S)-3-(4-acetylamino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester as a brown oil. MS (APCI) m/z 549.1 (M−1), 459.1 (M-CH2Ph).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]1[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O.O>[CH3:25][O:24][C:22]([N:9]1[CH2:10][CH2:11][C@@H:12]([C:14]2[O:21][NH:29][C:16](=[O:17])[CH:15]=2)[CH2:13][C@@H:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
A solution of trans-methyl 2-benzyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (6.35 g, 18.3 mmol) in MeOH (2 mL) was added to a solution of NaOH (0.77 g, 19.4 mmol) in MeOH/H2O (15 mL/0.9 mL) at −30° C. After 10 minutes was added a solution of hydroxylamine hydrochloride (2.54 g, 36.6 mmol) and NaOH (1.46 g, 36.6 mmol) in MeOH (18 mL) and H2O (18 mL). Stirring was continued at −30° C. for 30 minutes. The reaction mixture was then poured into concentrated HCl (20 mL) held at 80° C. The solution was stirred for 30 minutes. The organic solvent was evaporated and the aqueous phase extracted with DEE (×3). The organic phase was dried over Na2SO4 and evaporated to give a solid, 3.68 g, which was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 20-70% acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer, over 18 minutes with a flow of 19 mL/minutes. Trans-methyl-2-benzyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (2.54 g, 54.6%) was isolated as a solid. 1H NMR (600 MHz, cdcl3) δ 1.50-2.21 (m, 4H), 2.91 (m, 2H), 3.10 (m, 2H), 3.58 (d, 3H), 4.04-4.41 (m, 1H), 4.43-4.82 (m, 1H), 5.55-5.84 (m, 1H), 7.15-7.30 (m, 5H); MS m/z 317 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH:28]([O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:17]([CH2:16][N:7]1[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5])=[CH:18][CH:19]=[CH:20]2)([CH3:30])[CH3:29]
Reactant: CC(C)Oc1ccc2c(CBr)cccc2c1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: CC(C)Oc1ccc2c(Cn3c(C(=O)O)cc4ccccc43)cccc2c1

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-6-isopropoxy-naphthalene and the product obtained was hydrolyzed to give 1-(6-isopropoxy-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. MS: 358.0 ([M−H]−).
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:10]=[N:11][NH:12][CH:13]=1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]([CH3:24])[CH3:23]>O>[CH3:21][CH:22]([CH3:24])[CH2:23][N:11]1[CH:10]=[C:9]([N+:6]([O-:8])=[O:7])[CH:13]=[N:12]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1cc([N+](=O)[O-])cn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 276 %

Procedure:
To a DMF solution (30 ml) of 4-nitro-1H-pyrazole (1.00 g) were added potassium carbonate (3.67 g) and 1-bromo-2-methylpropane (1.82 g), and the mixture was stirred at 70° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (4.13 g, containing DMF).
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[CH3:15][C:16]1[CH:29]=[C:19]2[CH:20]=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:22]=[CH:23][N:18]2[N:17]=1.[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[CH:33]=O>ClCCl>[Cl:30][C:31]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:32]=1[CH2:33][C:29]1[C:16]([CH3:15])=[N:17][N:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][C:19]=12
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1ccn2nc(C)cc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccn2nc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.5 %

Procedure:
To a solution of trifluoroacetic acid (558 mg) and triethylsilane (1.14 g) in dry dichloromethane (2.0 ml) were added ethyl 2-methylpyrazolo[1,5-a]pyridine-5-carboxylate (200 mg) and 2,4-dichlorobenzaldehyde (189 mg), and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added 2,4-dichlorobenzaldehyde (189 mg) and the mixture was stirred at room temperature for one day. This step was repeated three times. The reaction mixture was diluted with dichloromethane and washed with a saturated aqueous sodium hydrogencarbonate solution. The aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) and washed with isopropyl ether to give the objective compound (233 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]([CH2:23][CH3:24])[N:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:23]([N:22]1[C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:19][CH:20]=[N:21]1)[CH3:24]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCn1nccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nccc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (927 mg, 6.5 mmol) was dissolved in anhydrous DMF (30 mL), then potassium carbonate (2.70 g, 19.6 mmol) and 5-(bromomethyl)-1-ethyl-1H-pyrazole (8.5 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM/MeOH to afford 2-{[(1-ethyl-1H-pyrazol-5-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (265 mg, 16% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.32 (t, J=7.0 Hz, 3H), 2.21 (s, 3H), 4.15 (q, J=7.2 Hz, 2H), 4.50 (s, 2H), 6.04 (bs, 1H), 6.22 (d, J=1.7 Hz, 1H), 7.33 (d, J=1.7 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]=1[C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].F[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1>CS(C)=O>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][O:15][C:4]1[CH:5]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[C:2]([O:1][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)[C:3]=1[C:22](=[O:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COCCOCOc1cc(O)c(C(C)=O)c(OCOCCOC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCOCOc1cc(OCOCCOC)c(C(C)=O)c(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 80 °C
Yield: 57.3 %

Procedure:
A stirred suspension of 1-{2-hydroxy-4,6-bis[(2-methoxyethoxy)methoxy]phenyl}ethanone (2.1 g, 6 mmol), potassium carbonate (0.85 g, 6 mmol) and 1-fluoro-4-nitrobenzene (0.86 g, 6.1 mmol) in DMSO (5 mL) was heated at 80° C. overnight. After dilution with ethyl acetate, the suspension was washed with brine and dried. After removal of the solvent, the residue was chromatographed on silica gel eluting with hexane/ethyl acetate 6/4 to afford the title compound (1.6 g, 54% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][C:7]=1[CH:8]=[O:9].C(O)C.[BH4-].[Na+].O.[O:22]1[CH2:26]CC[CH2:23]1>>[CH3:23][O:22][CH2:26][O:1][CH2:2][C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][C:7]=1[CH2:8][OH:9]
Reactant: C1CCOC1
Reactant: O=Cc1oc(-c2ccccc2)nc1CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCOCc1nc(-c2ccccc2)oc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 4-hydroxymethyl-2-phenyloxazole-5-carbaldehyde (0.25 g) in tetrahydrofuran (5 mL)-ethanol (3 mL) was gradually added sodium borohydride (0.04 g) at 0° C. After stirring at room temperature for 1 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 over anhydrous magnesium sulfate and concentrated to give (4-methoxymethoxymethyl-2-phenyl-1,3-oxazol-5-yl)methanol as colorless crystals (0.19 g, yield 76%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 70-71° C.
Reaction SMILES: C(N1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])C1)C.C[C@H](OC1N=[C:42]2[C:38](N=[C:40](OC)[N:41]2[CH2:44][CH2:45]CCC2CCNCC2)=C(N)N=1)CCC.ICC>>[CH2:42]([N:41]1[CH2:40][CH2:8][CH:7]([CH2:6][CH2:5][CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])[CH2:45][CH2:44]1)[CH3:38]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CCI
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and 2-iodoethane.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2Cl)[CH2:7]3)=[CH:4][CH:3]=1.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19]>CC(O)(C)C>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[NH:19][CH2:18][CH:17]([O:20][CH3:21])[O:16][CH3:15])[CH2:7]3)=[CH:4][CH:3]=1
Reactant: ClC1=NC2CC(C2)c2ccc(Br)cc21
Reactant: COC(CN)OC
Solvent: CC(C)(C)O
Product: COC(CNC1=NC2CC(C2)c2ccc(Br)cc21)OC
Temperature: 85 °C
Reaction time: 5 h
Yield: 104.3 %

Procedure:
Into a 10-L 4-necked round-bottom flask was placed 5-bromo-8-chloro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene (260 g, 960.99 mmol, 1.00 equiv), 2-methylpropan-2-ol (6000 mL), and 2,2-dimethoxyethan-1-amine (600 g, 5.71 mol, 6.00 equiv). The resulting solution was stirred at 85° C. for 5 h, cooled to room temperature and concentrated under vacuum. The residue was washed with 2×500 mL water and extracted with 3×500 mL of ethyl acetate. The organic layers were combined and concentrated under vacuum to afford 340 g (crude) of 5-bromo-N-(2,2-dimethoxyethyl)-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraen-8-amine as a black oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=1.Cl.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[NH:29][NH2:30]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:8]2[N:29]([C:23]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=3[F:21])[N:30]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:7]=1
Reactant: NNc1ccc(F)cc1F
Reactant: O=C(C=Cc1cc(Br)ccc1F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccc2F)c(F)c1
Temperature: 125 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
1-(5-Bromo-2-fluoro-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (620.0 mg, 1.8 mmol) prepared in Step 4 and 2,4-difluorophenylhydrazine hydrochloride (390.0 mg, 2.1 mmol) were added to acetic acid (30.0 mL). The reaction mixture was stirred at 125° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30) to give 250.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]([N+:14]([O-:16])=[O:15])=[CH:5][C:4]=3[C:3]=1[CH2:17][C:18]([OH:20])=[O:19].S(=O)(=O)(O)O.[CH2:26](O)[CH3:27]>>[CH3:1][C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]([N+:14]([O-:16])=[O:15])=[CH:5][C:4]=3[C:3]=1[CH2:17][C:18]([O:20][CH2:26][CH3:27])=[O:19]
Reactant: CCO
Reactant: Cc1c(CC(=O)O)c2cc([N+](=O)[O-])cc3c2n1CCC3
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1c(C)n2c3c(cc([N+](=O)[O-])cc13)CCC2

Procedure:
44.5 g of 5,6-dihydro-2-methyl-8-nitro-4H-pyrrolo[3,2,1-ij]quinoline-1-acetic acid (preparation see Example 20 A) were heated under reflux for 1 hour in 450 ml of ethanol after addition of 8.63 ml of sulfuric acid. To work up the reaction mixture the ethanol was removed by evaporation, the residue was taken up in a mixture of water and dichloromethane, and the organic phase was separated, washed with water until neutral, dried and evaporated. Some diethyl ether was added to the oily crude product which remained as a residue, and the resulting precipitate was filtered out. 32.4 g of ethyl 5,6-dihydro-2-methyl-8-nitro-4H-pyrrolo[3,2,1-ij]quinoline-1-acetate were obtained as a greenish-ochre-colored powder.
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].C([O:15]O)(C)(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(OCC)C>C1(C)C=CC=CC=1>[O:15]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])[CH:2]1[CH2:1][OH:10]
Reactant: C=CCCCC/C=C/CO
Reactant: CC(C)(C)OO
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCCCCC1OC1CO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
2.72 g (19.4 mM) (E)-nona-2,8-diene-1-ol (11) is added into the reaction mixture after another 5 minutes. Then, after yet another 5 minutes, 6.9 ml of a 3.39 molar solution in toluene (23.4 mM) of tertiary butyl hydroperoxide is added. The reaction mixture is allowed to react for 3 days at -25° C. Subsequently, the reaction vessel is put into an ice bath and 10 ml (1 ml per mM tetraisopropyl titantate added) saturated aqueous sodium sulfate solution and another 100 ml diethyl ether are added to the reaction mixture. The reaction solution is vigorously agitated for approximately 1 hour until the solution has warmed up to room temperature. The gelatinous orange-colored precipitation is separated out by means of a glass filter, washed twice with 100 ml quantities of ether and dried by suction. The solvent is evaporated from the combined filtrates and the residue is mixed with 100 ml ether and 2 ml dimethyl sulfide in order to destroy excess tertiary butyl hydroperoxide. The solution is agitated for one hour. Then, 50 ml 1 molar sodium hydroxide is added and the mixture is agitated another 3-4 hours. The ether phase is separated out, washed with 2×40 ml water, dried over magnesium sulfate and, after evaporation of the solvent in a vacuum, 2.48 g (15.9 mM) 2S, 3S-2-epoxy-1-hydroxynon-8-ene (III) is obtained by bulb tube distillation at 110° C./0.5 mm pressure. This corresponds to a yield of 82%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]([C:18]([O-])=[O:19])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:10]=1[CH3:11])=[O:4].CN(C1C=CC=CN=1)C.[C:39]([O:43][C:44](=[O:47])[CH2:45][NH2:46])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]([C:18]([NH:46][CH2:45][C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:47])=[O:19])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COC(=O)C1=C(C)NC(c2ccccc2)=C(C(=O)[O-])C1c1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(c2ccccc2)=C(C(=O)NCC(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
More specifically, a dried methylene chloride solution containing 394 mg (1 mmol) of 1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3-carboxylate, 309 mg (1.5 mmol) of dicyctohexylcarbodiimide and 134 mg (1.1 mmol) of dimethylaminopyridine was stirred for one hour. To this reaction mixture, 157 mg (1.2 mmol) of glycine t-butyl ester was added and the reaction mixture was refluxed for 2 hours. Insoluble components were removed from the reaction mixture by filtration and the reaction mixture was chromatographed on a silica gel column for purification, whereby 508 mg (100%) of the captioned compound was obtained as an oily material.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:18])=[N:4][C:5]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[N:6][C:7]=1Cl.[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1.O>CS(C)=O>[Br:1][C:2]1[C:7]([NH:23][CH2:22][CH:19]2[CH2:21][CH2:20]2)=[N:6][C:5]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[N:4][C:3]=1[NH2:18]
Reactant: NCC1CC1
Reactant: Nc1nc(-n2ncc3ccccc32)nc(Cl)c1Br
Solvent: O
Solvent: CS(C)=O
Product: Nc1nc(-n2ncc3ccccc32)nc(NCC2CC2)c1Br
Temperature: 65 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
A mixture of 0.1 g (0.31 mmol) of 5-bromo-6-chloro-2-(1H-indazol-1-yl)pyrimidine-4-amine (intermediate 5) and 160 μl (1.85 mmol) of cyclopropylmethylamine in 0.5 ml of DMSO in a closed glass tube was stirred for 5 h at 65° C. The reaction mixture was poured onto 20 ml of cold water. The formed white precipitate was filtered, washed several times with water and dried. 0.088 g (79.7%) of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([OH:18])[C:15]([Cl:19])=[CH:14][C:13]=2[F:20])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[Cl:19][C:15]1[CH:14]=[C:13]([F:20])[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([C:7]([F:8])([F:10])[F:9])[N:5]([CH3:11])[N:4]=2)=[CH:17][C:16]=1[O:18][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CBr
Reactant: Cn1nc(-c2cc(O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
At 25° C., 13.16 g (0.04 mole) 4-chloro-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, 6.1 g (0.044 mole) K2CO3, and 4.8 mL (0.044 mole) ethyl bromoacetate were slurried in 25 mL acetone. The reaction mixture was stirred at 25° C. for 16 hours. The reaction solution was poured into 150 mL ice water, filtered, washed with water and air dried. The residue was recrystallized from hexane to give 16.6 g (100%) of (2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorophenoxy)acetic acid, ethyl ester as a white solid, mp 130°-131° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH:3]1[OH:12].[NH2:13][C:14]1[C:19]([C:20]([C:22]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]([F:30])[C:23]=2[F:31])=[O:21])=[CH:18][N:17]=[C:16](Cl)[N:15]=1.C(N(C(C)C)CC)(C)C>C(O)C>[NH2:13][C:14]1[C:19]([C:20]([C:22]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]([F:30])[C:23]=2[F:31])=[O:21])=[CH:18][N:17]=[C:16]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH:3]2[OH:12])[N:15]=1
Reactant: CS(=O)(=O)N1CCC(N)C(O)C1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(Cl)nc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2O)nc1N

Procedure:
The amine (44 mg, 0.22 mmol, Example 305) and chloropyrimidine (55 mg, 0.18 mmol, Example 289) were dissolved in ethanol (5 mL). To the stirred mixture at reflux, diisopropylethylamine (64 uL, Aldrich) was added and the mixture was refluxed for 20 hours. The solvent was removed and the residue was purified by HPLC (10-60%, acetonitrile/water) to give a white solid, 25 mg, 30%. MS (ES) MH+=458.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[CH:30][C:31]([C:33]3[N:34]=[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]4[CH:41]=3)=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[CH:30][C:31]([C:33]3[N:34]=[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]4[CH:41]=3)=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cc(-c3cn4ccccc4n3)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2cc(-c3cn4ccccc4n3)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[[2-n-propyl-5-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.