Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9](Br)[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:24]1([C:2]2[CH:10]=[C:9]([C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=3)[CH:8]=[C:7]3[C:3]=2[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(Br)cc(Br)c12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(-c3ccccc3)cc(-c3ccccc3)c12
Temperature: 25 °C

Procedure:
Ethyl 4,6-dibromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (0.244 g, 0.5 mmol), phenylboronic acid (0.147 g, 1.2 mmol, 2.4 equiv.) and potassium phosphate trihydrate (0.400 g, 1.5 mmol, 3.0 equiv.) were mixed together in a 10 ml microwave vial. The vial was purged with Argon and trans-dichlorobis(triphenylphosphine)-palladium (II) (0.021, 0.03 mmol, 6 mol %) and 5 ml of dry dioxane were added to the mixture. The microwave vial was capped and irradiated at 100 watt, 150° C., under pressure up to 10 bars. Then it was allowed to cool down to rt, and toluene was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography using 20% of ethyl acetate/cyclohexane as eluent to yield a light-beige-colored solid in 60-70%. 1H-NMR (DMSO-d6) δ 1.09, 1.32 (each t, 3H, 3J=7.1 Hz, CH3); 2.11 (m, 2H, 2′-H); 2.84 (m, 2H, 1′-H); 3.89, 4.33 (each q, 2H, 4J=7.1 Hz, CH2); 7.12 (d, 1H, 2J=1.6 Hz, 7-H); 7.35 (t, 1H, 3J=7.4 Hz, Ph-ring); 7.43 (m, 7H, Ph-ring); 7.67 (d, 1H, 2J=0.9 Hz, 5-H); 7.68 (d, 1H, 2J=1.6 Hz, Phenyl-ring); 11.84 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 14.2, 14.3 (2CH3, each C═OOCH2CH3); 20.5 (C-2′); 34.8 (C-1′); 59.5, 60.5 (2CH2, each C═OOCH2CH3); 109.6 (C-5); 121.1 (C-7); 121.8 (C-3); 123.6 (C-2); 124.7 (C-3a); 127.0 (C-2″, C-6″); 127.4 (C-4″′); 127.5 (C-4″); 128.0 (C-3′″, C-5″′); 129.0 (C-3″, C-5″); 129.1 (C-2′″, C-6″′); 136.7 (C-7a); 137.4 (C-4), 137.6 (C-6); 140.7 (C-1″); 140.8 (C-1′″); 161.5 (2′-CO2Et); 171.7 (2-CO2Et). LC-MS (m/z): 442 [M]+, 440 [M]−. Purity (LC-MS): 96%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1.C([O-])(O)=O.[Na+].[I:16]I.OS([O-])(=O)=O.[Na+]>O>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:16])[CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1
Reactant: OCc1ccc(O)c(Cl)n1
Reactant: II
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: OCc1cc(I)c(O)c(Cl)n1
Yield: 62 %

Procedure:
C1 (11.6 g, 72.7 mmol) and NaHCO3 (18.3 g, 218 mmol) are added to 200 mL H2O. The mixture is stirred until homogeneous, the flask is placed in an ice bath, iodine (19.4 g, 76.3 mmol) is added, and the reaction is stirred over the weekend at rt. The pH of the mixture is adjusted to 3 with 2N NaHSO4, and the mixture is extracted with 4×50 mL EtOAc. The combined organic layer is dried over MgSO4, is filtered, and the filtrate is concentrated in vacuo to a yellow solid. The crude solid is washed with EtOAc to provide 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C2) as an off-white solid (62% yield), and the filtrate is concentrated to a small volume and is chromatographed over 250 g silica gel (230-400 mesh) eluting with 2.5:4.5:4:0.1 EtOAc/CH2Cl2/hexane/acetic acid to afford additional pure C2 (12% yield). MS (EI) for C6H5Cl/NO2, m/z: 285(M)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:11]=2[O:10]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][C:11]=2[O:10]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCC(COC1CCCCO1)O2
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)CCC(COC1CCCCO1)O2
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a stirred mixture of 5.3 parts of 3,4-dihydro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran-6-amine and 50 parts of pyridine were added dropwise 2.25 parts of acetic acid anhydride at a temperature below 10° C. Upon completion, stirring was continued for 10 minutes in an ice bath. The whole was stirred for 3 hours at room temperature. The reaction mixture was evaporated. Water was added to the residue. The product was extracted with 1,1'-oxybisethane. The organic layer was washed with water, dried, filtered and evaporated, yielding 5 parts (82%) of N-[3,4-dihydro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran-6-yl]-acetamide as an oily residue (intermediate 11).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[CH:8]1[O:16][CH:7]21)(=[O:3])[CH3:2].[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[C@@H:8]([OH:16])[C@@H:7]2[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]1=[O:17])(=[O:3])[CH3:2]
Reactant: Oc1ccccn1
Reactant: CC(=O)c1ccc2c(c1)C1OC1C(C)(C)O2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)[C@@H](n1ccccc1=O)[C@H](O)C(C)(C)O2
Yield: 49.8 %

Procedure:
A mixture containing 2.1 g of 6-acetyl-2,2-dimethyl-3,4-epoxychromane and 1.7 g of 2-hydroxypyridine in 40 ml of tetrahydrofuran is refluxed for 16 hours in the presence of 0.4 ml of benzyltrimethylammonium hydroxide. The mixture is cooled and the crystals formed are filtered off and washed with tetrahydrofuran. After drying under vacuum at 60° C., 1.5 g of the expected product are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[OH:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:22]1[C:21]2[C:25](=[CH:26][C:18]([OH:17])=[CH:19][CH:20]=2)[NH:24][C:23]1=[O:27])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccc(O)cc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(O)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-hydroxy-2-oxindole to give 0.3 g of 3-(3,5-Diisopropyl-4-methoxybenzylidene)-6-hydroxy-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1.[CH3:18][CH:19]([SH:23])[CH:20]([SH:22])[CH3:21].[C:24]1([CH2:30][CH:31]=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:30]([CH:31]1[S:23][CH:19]([CH3:18])[CH:20]([CH3:21])[S:22]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=CCc1ccccc1
Reactant: CC(S)C(C)S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CC1SC(Cc2ccccc2)SC1C
Reaction time: 0.5 h

Procedure:
Into a 100 ml flask equipped with reflux condenser and magnetic stirring bar and hot plate equipped with magnetic stirring apparatus is placed 0.2 grams of para-toluenesulfonic acid, 5 ml cyclohexane and 6.1 grams (0.05 moles) of 2,3-butanedithiol. With stirring, over a period of 30 minutes, 6.0 grams (0.05 moles) of phenylacetaldehyde is added to the reaction mass. The reaction mass is then heated to reflux and refluxed for a period of 10 hours during which time water of formation is removed. After the 10 hour period, the reaction mass is cooled and transferred to a separatory funnel. The reaction mass is washed with one 50 ml portion of saturated sodium chloride, dried over anhydrous sodium sulfate and filtered. The resulting filtrate is then distilled on a Microvigreux column yielding the following four fractions:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2
Reactant: Nc1ccc2ncccc2c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc2ncccc2c1
Temperature: 110 °C
Yield: 85.7 %

Procedure:
A mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (141 mg, 0.5 mmol), 6-aminoquinoline (72.2 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 0.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide (DMF) and ether to give 169 mg (85%) of yellow solid. MS (ESI) m/z 394.0, 396.0 (M+H)+1
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=O)[C:7](=[CH:11][CH:12]=1)[C:8](O)=[O:9])([O-:3])=[O:2].P([O-])([O-])([O-])=O.[OH:21][NH3+:22].O[NH3+].O[NH3+]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:15])[N:22]([OH:21])[C:8](=[O:9])[C:7]2=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: [NH3+]O
Agent: O=P([O-])([O-])[O-]
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1O

Procedure:
Analogous to Example 4, but from 500 mg (2.37 mmol) of 4-nitrophthalic acid (tech., contaminated with approximately 10% of 3-nitrophthalic acid) and 187 mg (0.974 mmol) of hydroxylammonium phosphate at a bath temperature of 130° C. The yield was 332 mg (67%, approximately 5% contaminated).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH3:19])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH3-]C#N.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH3:19])[CH:11]=2)[CH2:29][CH2:28]1
Reactant: CCCc1cc(CCC=O)n(-c2cccc(Cl)c2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2cccc(Cl)c2)n1

Procedure:
91.87 mg (46.19%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(3-chlorophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (124.75 mg, 0.451 mmol), 1-(2-fluorophenyl)piperazine (92 mL, 0.586 mmol), and NaCNBH3 (85.02 mg, 1.353 mmol).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([CH2:8]C(O)=O)[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])[CH2:3]1.C([N:25](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1>[NH2:25][CH2:8][C@H:7]1[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])[CH2:3][C@H:2]1[F:1]
Reactant: Cc1ccc(COC(=O)N2CC[C@H](CC(=O)O)[C@H](F)C2)cc1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(COC(=O)N2CC[C@H](CN)[C@H](F)C2)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a suspension of crude acid (±)-((cis)-3-fluoro-1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)acetic acid (9.1 g, 29.4 mmol) in toluene (80 mL) was added triethylamine (10.2 mL, 73.5 mmol) and diphenylphosphoryl azide (9.52 mL, 44.1 mmol). The reaction mixture was heated to 70° C. and stirred for 20 min. A mixture of dioxane (80 mL) and 1 M NaOH (80 mL) was added and the reaction mixture was cooled to RT. The reaction mixture was concentrated to remove the dioxane and extracted with EtOAc three times, dried over Na2SO4, filtered and concentrated. The residue was suspended in CH2Cl2, stirred for 30 min, and the white preciptate filtered off. The filtrate was concentrated to give crude product (7.5 g) as a yellow oil, used directly in the next step. An analytical sample was purified by silica gel chromatography (gradient elution: CH2Cl2 to 80:20:2 CH2Cl2:MeOH:NH4OH) for characterization:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.N1C=CC=CC=1>O>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:31]([C:28]4[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=4)(=[O:33])=[O:32])=[CH:3][CH:4]=3)[CH:10]=2)=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n(C)n1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 102 %

Procedure:
A mixture of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (750 mg, 2.32 mmol), p-toluenesulfonyl chloride (486 mg, 2.55 mmol) and pyridine (6 mL) was stirred at 80° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure and dried to give the title compound (1.13 g, 99%) as a colorless oil.
Reaction SMILES: O.[ClH:2].Cl.C([N:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)C1C=CC=CC=1.O>C(O)C.[Pd]>[ClH:2].[ClH:2].[CH3:19][N:18]1[CH:13]2[CH2:14][CH2:15][CH:16]1[CH2:17][NH:11][CH2:12]2
Reactant: CN1C2CCC1CN(Cc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C2CCC1CNC2
Reaction time: 2 h
Yield: 152.9 %

Procedure:
A mixture of 3-benzyl-8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride monohydrate (18.1 g, 0.059 mole) in absolute ethanol (200 ml) and 10% palladium on charcoal (3.0 g) was hydrogenated for 2 hours at atmospheric pressure. Sufficient water was added to dissolve the insoluble hydrochloride salt that had formed, and the reaction was filtered. The filtrate was evaporated in vacuo, the residue was triturated in hot absolute ethanol, and the mixture was filtered to yield 8.98 g of 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride, melting point 315°C (dec.). The mother liquor was treated with ethanolic dry hydrogen chloride to afford an additional 2.28 g. Yield: 12.26 g (96%).
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH:2]1([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH2:31])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: NCCCCCCCCCCCCCCCCCCC1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O

Procedure:
The preparation is analogous to Example 1, starting from 22 g of mannose and 40 g of octadecylamine.
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(OC(Cl)=O)C.Cl.C(N(CC)CC)C.N>C1COCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][CH2:26][CH2:27][C:28]([NH2:3])=[O:29])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCCOc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)CCCOc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution cooled to -10° C. of 100 ml abs. THF, 4.32 g (43 mmol)triethylamine and 14.4 g (36 mmol) 4-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxy]butyric acid one slowly adds dropwise a mixture of 4.02 g (37 mmol) chloroformic acid ethylester and 30 ml abs. THF. One allows to come to room temperature, stirs a further 30 min and filters off with suction the precipitated triethylaminehydrochloride. The filtrate is then gassed with ammonia with ice cooling. It is then stirred for 6 hrs. at room temperature, evaporated and mixed with 2N HCl. One adds ethyl acetate thereto, mixes up very vigorously and separates the phases. The ethyl acetate phase is shaken out twice with bicarbonate solution and twice with water, then dried with Na2SO4 and evaporated. After recrystallisation from ethyl acetate, one obtains colourless crystals. Yield: 12.8 g (89% of theory); m.p. 110°-112° C.
Reaction SMILES: [N+:1]([O-:7])([O:3][CH2:4][CH2:5][OH:6])=[O:2].[C:8]([NH:15][C@H:16]([C:20](O)=[O:21])[CH:17]([CH3:19])[CH3:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:8]([NH:15][C@H:16]([C:20]([O:6][CH2:5][CH2:4][O:3][N+:1]([O-:7])=[O:2])=[O:21])[CH:17]([CH3:18])[CH3:19])([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: O=[N+]([O-])OCCO
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCO[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 5 h

Procedure:
To the reactor 2-hydroxyethyl nitrate (8 kg) was added, followed by dichloromethane (25 L). Then, boc-L-valine (12.5 kg) was added slowly under stirring, and the reaction mixture was cooled down to −10° C. Afterwards, DMAP (50 g) was added as the catalyst, and DCC (12.5 kg dissolved in 5 L of dichloromethane) was slowly added dropwise to the mixture under −10° C. The reaction was continued for another 5 hours at temperature between −10 and 0° C. under continuous stirring, while insoluble white solid was gradually formed. The reaction mixture was then warmed up slowly to room temperature, and the reaction was continued for another 12 hours at room temperature. At the end, the reaction mixture was filtered, and the filtrate was washed with water and dried to yield the crude nitrooxyethyl boc-valinate that was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:27]([NH2:29])=[O:28])[CH3:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][CH:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:33])=[O:32]
Reactant: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example 49 (step 1), 1.06 g of 3-[(1-(2-fluorophenyl)ethoxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 586 mg of methanesulfonyl chloride, and 518 mg of triethylamine in 19 ml dichloromethane give ((1-{5-carbamoyl-4-[1-(2-fluorophenyl)ethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:19]([O:21]CC)=[O:20])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]([CH:16]4[CH2:18][CH2:17]4)[CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([C:4]2[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]([CH:16]4[CH2:17][CH2:18]4)[CH3:15])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)C2CC2)c2nc(C3CC3)cc(C(=O)O)c12
Temperature: 70 °C

Procedure:
To an EtOH (10 mL) solution of ethyl 6-cyclopropyl-1-(1-cyclopropylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (720 mg, 2.297 mmol) was added sodium hydroxide (6.89 mL, 6.89 mmol) and the mixture heated at 70° C. for 1 hour. The solvent was removed in vacuo and the residue was dissolved in 20 mL of water. The contents were acidified with acetic acid, and extracted with EtOAc (4×30 mL). The combined organic extracts were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The final product was collected as a solid, 0.560 g (85%). LCMS E-S (M+H)=286.3 1H NMR (400 MHz, DMSO-d6) δ ppm 0.15-0.33 (m, 2H), 0.38 (dq, J=9.57, 4.89 Hz, 1H), 0.50-0.65 (m, 1H), 0.90-1.10 (m, 4H), 1.27-1.42 (m, 1H), 1.57 (d, J=6.82 Hz, 3H), 2.23-2.36 (m, 1H), 2.57 (s, 3H), 4.18 (dq, J=9.32, 6.83 Hz, 1H), 7.44 (s, 1H), 12.79 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][OH:10].[H-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=[C:21]2I)=[CH:16][CH:15]=1.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][C:21]1[N:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=1
Reactant: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1
Reactant: OCc1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(OCc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of (2-chloro-6-fluorophenyl)methanol (160.5 mg, 0.99 mmol) in THF (8 mL) was added sodium hydride (40 mg, 0.99 mmol) and the reaction was stirred at room temperature. After 25 minutes ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (300 mg, 0.83 mmol) was added and the reaction was refluxed overnight. Water was added slowly and the solution was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl 2-((2-chloro-6-fluorobenzyl)oxy)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (39).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15]#[CH:16].[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.[Cl-].[Na+]>CCCCCC.C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15]#[C:16][C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:21]
Reactant: O=C(Cl)C1CC1
Reactant: C#Cc1ccc(SC)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C#CC(=O)C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexane (4.4 ml) was added to a stirred solution of [2-chloro-4-(methylsulphenyl)phenyl]acetylene (2.0 g) in THF while maintaining the temperature below -70° C. The mixture was stirred for 5 minutes and cyclopropanecarbonyl chloride (2.4 g) was added. The mixture was warmed to room temperature and poured onto aqueous sodium chloride solution. The aqueous layer was extracted with ether and combined organic layers dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was dissolved in methanol and heated at reflux for 5 minutes. Toluene was added and the mixture was evaporated to dryness. The residue was purified by chromatography eluted with a mixture of hexane and ether to give 1-[2-chloro4(methylsulphenyl)phenyl]-3-cyclopropylprop-1-yn-3-one as yellow oil which crystallized on standing, m.p. 46°-50° C. [2-Chloro-4-(methylsulphenyl)phenyl]acetylene was prepared by the reaction of 1-bromo-2-[2-chloro-4-(methylsulphenyl)phenyl]acetylene with n-butyllithium and wet zinc chloride in THF at -70° C.