Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][CH2:8][CH2:9][S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.CC(O)=O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]([NH:7][CH2:8][CH2:9][S:10][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCBr
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromopropionylchloride (62.5 μl, 0.62 mmol) was dissolved in 0.5 ml CH2Cl2 and added to a solution of H2N—CH2—CH2-STrt (200 mg, 0.56 mmol), DIEA (196 μl, 1.1 mmol) in CH2Cl2 (1 ml). The mixture was stirred for 1 h at RT. The reaction mixture was acidified with AcOH (100 μl) and the solvent was removed in vacuo. The residue was purified over silica gel (heptane/EtOAc=1:1) to obtain Br—(CH2)2CONH—(CH2)2-STrt.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[CH2:19]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=CCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
p-hydroxybenzoic acid (33.2 g), 8-bromo-1-octene (57.3 g), potassium carbonate (41.5 g) and N,N-dimethylacetamide (200 mL) were put into a 500-mL three-neck flask, and stirred at 120° C. for 5 hours. After cooled, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (500 mL), and washed two times with water (100 mL). This was dried with anhydrous magnesium sulfate and then filtered. The solvent was removed through concentration under reduced pressure, the residue was dissolved in methanol (100 mL), and a methanol solution (20 mL) of potassium hydroxide (16.8 g) was dropwise and gradually added thereto, and heated under reflux for 2 hours. After cooled, the formed crystal was collected through filtration and washed with water. This was dried to give TP-5C (63.3 g, 85%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][CH2:8][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][NH:14][C:13](=O)[CH2:12][CH2:11][CH2:10]1.B.C1COCC1.CO.Cl>C1COCC1>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][CH2:8][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: O=C1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CCN1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCCNCC2)cc(C(F)(F)F)c1
Temperature: 65 °C

Procedure:
To a solution of 6-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-6-phenylazocan-2-one (18 mg, step H) in THF (0.10 mL) at room temperature was added borane-THF complex (1.50 M solution in THF, 0.10 mL) and the resulting solution was heated at 65° C. in a sealed vial for 3 h. The solution was cooled to room temperature, and methanol (0.10 mL) was added slowly followed by 1N hydrochloric acid (0.10 mL), and the reaction mixture was heated at 65° C. for 2 h. The solvents were removed in vacuo, dichloromethane and 1N sodium hydroxide were added, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound as an oil. 1H NMR (400 MHz, CDCl3) δ 1.58 (5H, m), 2.09 (3H, m), 2.30 (1H, m), 2.94 (4H, m), 3.44 (1H, d, J=8.8 Hz), 3.47 (1H, d, J=8.8 Hz), 4.42 (2H, s), 7.21 (1H, m), 7.37 (4H, m), 7.55 (2H, s), and 7.73 (1H, s). HPLC retention time (1.88 min, column: 4.6×50 mm XTERRA C18 S5, flow rate: 5 mL/min, gradient: 0-100% MeOH/H2O 0.1% TFA over 2 min). MS: 446 (MH+).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.[CH3:18][O:19][C:20](=O)[O:21]C>O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][C:20]([O:19][CH3:18])=[O:21])=[CH:11][CH:10]=1
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)c1ccc(O)cc1
Yield: 48.6 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with sodium hydride (3.5 g, 147 mmol). At 0 deg C., 100 mL of DMF was added slowly with stirring. To the stirred solvent were added 1-(4-hydroxyphenyl)ethanone (5 g, 36 mmol) and dimethylcarbonate (15.5 g, 170 mmol), stirred at room temperature overnight. The RM was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as elutants. The product was obtained as pale yellow oil (3.4 g, yield: 47.66%). MS (ESI, 120 eV): m/z=195 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.79-7.82 (d, 2H), 6.81-6.84 (d, 2H), 6.21 (br s, 1H), 3.90 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: O=O.C1C=C(C=O)OC=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16]C(O)=O.C(O)(=O)CC(O)=O.N1CCCCC1.O1C=CC=C1C=C[C:40]([N:42]=[N+]=[N-])=[O:41].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C(N(CC)CC)C>[O:10]1[C:11]2[CH:15]=[CH:16][NH:42][C:40](=[O:41])[C:12]=2[CH:13]=[CH:14]1
Reactant: [N-]=[N+]=NC(=O)C=Cc1ccco1
Reactant: O=C(O)C=Cc1ccco1
Agent: O=C(O)CC(=O)O
Agent: O=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: O=Cc1ccco1
Product: O=c1[nH]ccc2occc12

Procedure:
For example, in making a compound of formula I in which Y is oxygen, Scheme A can be followed. Briefly, 2-furfural (1) is converted under heating into 3-furan-2-yl-acrylic acid (2) using malonic acid and a suitable base such as piperidine. 3-(Furan-2-yl)-acrylic acid (2) is converted into 3-(furan-2-yl)-acryloyl azide (3) using DPPA and a suitable base such as triethylamine. The azide (3) was cyclized to afford 5H-furo[3,2-c]pyridin-4-one (4) upon heating and a catalytic amount of iodine. 5H-furo[3,2-c]pyridin-4-one is chlorinated on the 4th position with POCl3 to afford 4-chloro-furo[3,2-c]pyridine (5). 4-Chloro-furo[3,2-c]pyridine is treated with bromine, and subsequently with DBU to afford compound (6). The chlorine atom of compound (6) is replaced with an amino group by the action of aqueous ammonia to afford compound (7). Compound (7) is subsequently subjected to Pd(PPh3)4, sodium carbonate, R—B(OH)2 or a compound of formula R—B(OR′)2, in which the radical —B(OR′)2 can be represented as
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[Cl:12][C:13]1[C:18]([NH2:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Br:1][C:15]1[C:16]([O:20][CH3:21])=[CH:17][C:18]([NH2:19])=[C:13]([Cl:12])[CH:14]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(N)c(Cl)cc1Br
Temperature: -5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
1,3-Dibromo-5,5-dimethylhydantoin (commercially available, for example, from Aldrich) (9.1 g, 32 mmol) was added over 20 minutes to a stirred solution of 6-chloro-3-methoxyaniline (commercially available, for example, from Apollo Scientific) (10.0 g, 63 mmol) in ethyl acetate (150 ml) at −5° C. The resulting solution was stirred at −5° C. for 1 hour then washed with a solution of potassium carbonate (6 g, 43 mmol) in water (40 ml and then with water (20 ml). The resulting solution was concentrated under reduced pressure to give 4-bromo-2-chloro-5-methoxyaniline as a pale brown solid (14.3 g, 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.[CH3:19][PH:20](=[O:26])[O:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH2:22]([O:21][P:20]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9])([CH3:19])=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: NS(=O)(=O)c1ccccc1Br
Reactant: CC(C)CO[PH](C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)COP(C)(=O)c1ccccc1S(N)(=O)=O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A solution of 11.8 g (0.05 mole) of 2-bromophenylsulfonamide in 14 ml (0.1 mole) of triethylamine and 3 ml of dimethylformamide is treated with 6.8 g (0.05 mole) of isobutyl methylphosphinate and 1.1 g (0.001 mole) of tetrakistriphenylphosphine-palladium complex. The yellow suspension is stirred for 15 hours at 100° C., cooled and filtered. After the filtrate has been evaporated, the residue is crystallised from toluene. This gives 4.12 g of 2-(i-butoxy-P-methylphosphinyl)-phenylsulfonamide, melting point 50°-52° C.
Reaction SMILES: [C:1]([O:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[NH:21][C:20]2[C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[C:1]([O:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[N:21]([CH3:29])[C:20]2[C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(OC/C=C/c1cc2ncnc(Oc3ccccc3)c2[nH]1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1c(/C=C/COC(=O)c2ccccc2)cc2ncnc(Oc3ccccc3)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
(2E)-3-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl benzoate (500 mg) was dissolved in N,N-dimethylformamide (4 mL), and potassium carbonate (279 mg) and iodomethane (0.1 mL) were sequentially added. After stirring at room temperature for 4 hrs, water (30 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound (301 mg) as crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([C:24]2[NH:28][C:27]([C:29]3[O:30][CH2:31][C@@H:32]([C@@H:34]([OH:36])[CH3:35])[N:33]=3)=[CH:26][CH:25]=2)[CH:10]=[C:11]([O:13][Si](C(C)C)(C(C)C)C(C)C)[CH:12]=1)[CH3:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[OH:36][C@H:34]([C@@H:32]1[CH2:31][O:30][C:29]([C:27]2[NH:28][C:24]([C:9]3[CH:10]=[C:11]([OH:13])[CH:12]=[C:7]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH:8]=3)=[CH:25][CH:26]=2)=[N:33]1)[CH3:35]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (1.48 g, 2.88 mmol) synthesized in Example (112b) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 3.50 mL, 3.50 mmol) was added at room temperature, followed by stirring at room temperature for 1.5 hours under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-6%) to afford the desired compound (880 mg, yield 85%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[OH:40][N:39]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(C(=O)NCC(=O)O)cc3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(-c3ccc(C(=O)NCC(=O)O)cc3)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from ({4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carbonyl}-amino)-acetic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3.8:1) as a white solid, MS (ESI+): m/z=508.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:37])[C:9]([N:12]2[C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30]5[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=5)[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[CH:14]=[N:13]2)([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>O1CCOCC1.CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:37])[C:9]([N:12]2[C:16](=[O:17])[N:15]([C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:25][CH2:26][N:27]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)[CH2:28][CH2:29]4)=[CH:22][CH:23]=3)[CH:14]=[N:13]2)([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)c1ccc(Br)cc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C(O)c1ccc(Br)cc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of 2-[2-(4-bromophenyl)-1,1-dimethyl-2-oxoethyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.009 mol) and sodium tetrahydroborate (0.025 mol) in 1,4-dioxane (100 ml), methanol (30 ml) and water (50 ml) was stirred overnight. Acetic acid (5 ml) was added, followed by addition of water (500 ml). Crystallization resulted. The reaction mixture was stirred for 4 hours at room temperature. The precipitate was filtered off by suction (Buchner) and the solid was crystallized from 1-butanol. The precipitate was filtered off and dried, yielding 4.4 g (87%) of (±)-2-[2-(4-bromophenyl)-2-hydroxy-1,1-dimethylethyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one; mp. 224.5° C. (comp. 21).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]Cl)=[C:6]2[CH2:5][CH2:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH:25]([N:28](C(C)C)[CH2:29]C)(C)C.Cl.CNC.O>CN(C=O)C>[CH3:25][N:28]([CH3:29])[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([NH:17][CH2:16][CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=12)=[O:24]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(CCCCCl)NCCc1c2n(c3ccccc13)C(=O)CCC2
Agent: CNC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCCC(=O)NCCc1c2n(c3ccccc13)C(=O)CCC2
Reaction time: 48 h

Procedure:
15 g 6-Oxo-10-[2-(5-chlorovaleryl)aminoethyl]-6,7,8,9tetrahydropyrido[1,2-a]indole (D 3 of EP-0213696), 14.6 ml diisopropylethylamine, 1 g KI and 3.5 g dimethylamine hydrochloride were dissolved in 100 ml DMF and stirred for 48 hours at room-temperature. After further stirring for 7 hours at 40° C. the reaction mixture was dissolved with water and extracted with ethyl acetate. After acid-base separation the product was crystallised from diisopropylether.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:16](Cl)(Cl)=[O:17]>C(Cl)(Cl)Cl.O1CCCC1>[CH3:15][O:14][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]2[NH:1][C:16](=[O:17])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: COc1cc(C(=O)O)c(N)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)oc(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
2.0 g (9.4 mmol) of 2-amino-5-methoxy-4-nitrobenzoic acid were dissolved in 20 ml of chloroform and 10 ml of tetrahydrofuran, and 20 ml of 20% strength phosgene solution (1.8 M in toluene) were added. After 3 hours under reflux, a further 10 ml of phosgene solution were added at 60° C., and the mixture was stirred at 60° C. for a further 12 hours. The phosgene was distilled off and the residue was concentrated in vacuo after addition of toluene several times. 2.2 g (100%) of the desired product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[CH:5][C:6]([CH2:12][C:13]2[C:14]([CH3:22])=[N:15][N:16]([CH2:19][C:20]#[N:21])[C:17]=2[CH3:18])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:26][NH:25][C:20](=[NH:21])[CH2:19][N:16]1[C:17]([CH3:18])=[C:13]([CH2:12][C:6]2[CH:5]=[C:4]([CH3:23])[C:3]([O:2][CH3:1])=[C:11]3[C:7]=2[CH2:8][CH2:9][CH2:10]3)[C:14]([CH3:22])=[N:15]1
Reactant: NO
Reactant: COc1c(C)cc(Cc2c(C)nn(CC#N)c2C)c2c1CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1c(C)cc(Cc2c(C)nn(CC(=N)NO)c2C)c2c1CCC2
Temperature: 70 °C
Reaction time: 33 h
Yield: 81.2 %

Procedure:
To a stirred solution of [4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-acetonitrile (2.0 gm 0.00647 mole) in methanol (50 ml), A suspension of Hydroxylamine hydrochloride (2.29 gm, 0.033 mole) and Potassium carbonate (4.37 gm, 0.0317 mole) in water (20 ml) was added. The reaction mixture was stirred for 30-36 hours at 70° C., cooled and then was filtered. The obtained solid was washed with water (10 ml) and finally with Hexane and dried under vacuum to give 1.8 gm of desired product
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:29]=[CH:28][C:27]([CH:30]=C)=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:9])[CH2:3]1.S([O-])([O-])=[O:35].[Na+].[Na+]>O1CCCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[F:1][C:2]1([F:33])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][OH:35])=[CH:28][CH:29]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: O=S([O-])[O-]
Reactant: C=Cc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)[C@](O)(c2ccc(CO)cc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 69 mg of the t-butyl 4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoyloxy)-tetrahydropyridine-1(2H)-carboxylate as obtained in Referential Example 56 in 2 ml of tetrahydrofuran-water (1:1), 85 mg of sodium periodide and 0.1 ml of 2% osmium tetraoxide were added at 0° C., followed by an hour's stirring at the same temperature. Adding sodium sulfite to the reaction liquid, stirring was continued for further 30 minutes. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was dissolved in 1 ml of methanol. To the solution 10 mg of sodium borohydride was added, stirred for 10 minutes and acetone was added. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on preparative thin layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), hexane/ethyl acetate=1/1) to provide 42 mg of the title compound as a colorless oily substance.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[C:12]1=[O:25].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45](/[CH:55]=[CH:56]/[C:57](O)=[O:58])[CH:46]=[CH:47][C:48]=1[N:49]1[CH:53]=[C:52]([CH3:54])[N:51]=[CH:50]1>C(Cl)Cl.O>[F:24][C:19]1[CH:18]=[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][N:11]([NH:10][C:57](=[O:58])/[CH:56]=[CH:55]/[C:45]3[CH:46]=[CH:47][C:48]([N:49]4[CH:53]=[C:52]([CH3:54])[N:51]=[CH:50]4)=[C:43]([O:42][CH3:41])[CH:44]=3)[C:12]2=[O:25])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: NN1CCCC(c2ccc(F)c(F)c2)C1=O
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1cc(/C=C/C(=O)NN2CCCC(c3ccc(F)c(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
IPEA (1.5 mL), 1-amino-3-(3,4-difluorophenyl)piperidin-2-one (420 mg) and BOPCl (0.53 g) were added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (450 mg) in methylene chloride (15 mL) at room temperature, and the reaction solution was stirred at room temperature for three hours. Water was added to the reaction solution, followed by extraction with chloroform. The resulting extract was washed with a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 572 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: BrC1C=CC([C:8]2C3C=CC(O)=CC=3O[N:9]=2)=CC=1.BrC/C=C/CBr.Br[CH2:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]1[CH:45]=[CH:44][C:33]2[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=3)=[N:35][O:36][C:32]=2[CH:31]=1.C(NC)C=C>>[Br:43][C:40]1[CH:41]=[CH:42][C:37]([C:34]2[C:33]3[CH:44]=[CH:45][C:30]([O:29][CH2:28][CH:27]=[CH:26][CH2:25][NH:9][CH3:8])=[CH:31][C:32]=3[O:36][N:35]=2)=[CH:38][CH:39]=1
Reactant: BrC/C=C/COc1ccc2c(-c3ccc(Br)cc3)noc2c1
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)noc2c1
Agent: BrC/C=C/CBr
Agent: C=CCNC
Product: CNCC=CCOc1ccc2c(-c3ccc(Br)cc3)noc2c1

Procedure:
Analogously to Example 1, from 3-(4-bromo-phenyl)-benzo[d]isoxazol-6-ol and (E)-1,4-dibromo-2-butene via (E)-6-(4-bromo-but-2-enyloxy)-3-(4-bromo-phenyl)-benzo[d]isoxazole and by reaction with N-allyl-methyl-amine there is obtained (E)-allyl-[4-[3-(4-bromo-phenyl)-benzo[d]isoxazol-6-yloxy]-but-2-enyl-methyl-amine which is converted into the fumarate, MS: m/e 412 (M30 , 1 Br).
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.[CH2:22]([N:24](CC)CC)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.C(Cl)CCl>[NH:1]([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([NH:24][CH3:22])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)O)c(Nc2ccccc2)c1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(OC)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-anilino-4-methoxybenzoic acid (220 mg), methylamine hydrochloride (100 mg), triethylamine (0.31 mL), EDC (260 mg), and HOBt (210 mg) were combined in 4 mL DMF and stirred overnight at room temp. The reaction was diluted with EtOAc and washed with 10% citric acid (1×), water, and 10% sodium bicarbonate, then dried (Na2SO4) concentrated to give 0.23 g of 2-anilino-4-methoxy-N-methylbenzamide.