Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][C:25]([C:23]([O:22][CH2:20][CH3:21])=[O:24])=[CH:26][CH:27]=4)=[CH:3][CH:4]=3)[O:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(-c2coc(-c3ccc(Br)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(C)cc4)co3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of Example 186B (140 mg, 0.45 mmol) in ethylene glycol dimethyl ether (7.0 mL) at room temperature was treated with tetrakis(triphenylphosphine)palladium (26 mg, 0.02 mmol), stirred for 5 minutes, treated with a solution of Example 186A (104 mg, 0.54 mmol) in ethanol (1.5 mL), stirred for 5 minutes, treated with 2M sodium carbonate (1.1 mL, 2.23 mmol), heated to reflux, and stirred for 4 hours. The reaction mixture was cooled to room temperature and concentrated. The concentrate was dissolved in water (20 mL) and extracted with diethyl ether (4×20 mL). The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product. MS (DCI) m/e 384 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.18-8.16 (m, 2H), 8.09-8.06 (m, 4H), 7.97-7.89 (m, 4H), 7.30-7.28 (m, 2H), 4.35 (q, 2H), 2.34 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[S:57]1[CH:61]=[CH:60][N:59]=[C:58]1[NH2:62]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([NH:62][C:58]2[S:57][CH:61]=[CH:60][N:59]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)nc1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Cl)nc1

Procedure:
A solution of 2-(6-chloropyridin-3-yl)-3-cyclopentylpropionic acid (Preparation 1, 0.56 g, 2.2 mmol), TBTU (1.41 g, 4.4 mmol), HOBt (0.45 g, 3.3 mmol), NEt3 (0.31 mL, 2.2 mmol), and thiazol-2-ylamine (0.44 g, 4.4 mmol) in anhydrous DMF (23 mL) was stirred at 20° C. for 16 h. The reaction mixture was diluted with EtOAc, before being washed with 2 M Na2CO3, H2O, and brine. After drying (Na2SO4), the organic phase was filtered and concentrated to give the title compound: RTA=3.82 min; m/z (ES+)=336.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.[C:15](Cl)(=[O:17])[CH3:16]>C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[C:15]([N:11]1[CH2:12][CH:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)([CH2:14]2)[CH2:10]1)(=[O:17])[CH3:16]
Reactant: COc1ccc(C23CNCC2C3)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(C23CC2CN(C(C)=O)C3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 1-(p-methoxyphenyl)-3-azabicyclo[3.1.0]hexane in benzene and aqueous sodium carbonate is added acetyl chloride and the mixture is stirred at ambient temperature for 18 hours. Benzene is removed by evaporation under reduced pressure, and filtration of the residual mixture gives 3-acetyl-1-(p-methoxyphenyl)-3-azabicyclo[3.1.0]hexane.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:2]1.C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[CH3:29]I>C(O)C>[CH3:29][S:27][C:26]([N:2]1[C@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:28]
Reactant: S=C=S
Reactant: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: CI
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SC
Yield: 68 %

Procedure:
In the same manner as described in Example 53, ethyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (2.50 g), triethylamine (1.34 g), carbon disulfide (0.82 ml), ethanol (60 ml) and methyl iodide (0.84 ml) are reacted and treated. The product is recrystallized from ethyl acetate-n-hexane to give the title compound (2.55 g, 68%) as colorless prisms, m.p. 138°-140° C.
Reaction SMILES: [CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1.Cl[Si](C)(C)C.C(N(CC)CC)C.[N-]1C=CN=C1>CN(C)C=O>[CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([NH:32][C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[O:17])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Reactant: Nc1nnn[nH]1
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1
Reaction time: 2 h
Yield: 29.5 %

Procedure:
1.86 g (0.00715 mol) of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 1) and 1.62 g (0.01 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 210 ml of dimethylformamide are stirred at 50° C. for sixteen hours. To 0.83 g (0.008 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) in 50 ml of dimethylformamide cooled to 0°-5° C. is added 3.0 ml (0.024 mol) of chlorotrimethylsilane (Aldrich Chemical Company) and 6.0 ml (0.043 mol) of triethylamine. After thirty minutes the mixture is allowed to reach room temperature and is stirred for an additional two hours. This mixture is combined with the previous cooled imidazolide mixture and stirred for three days at room temperature. The resulting precipitate is collected, slurried in boiling glacial acetic acid, the mixture is cooled and filtered to give 0.69 g of 2-methyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2 -a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 306°-310° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C@H:8]2[OH:11])=[CH:4][CH:3]=1>C(O)C.CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C@@H:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: O[C@@H]1C[C@H](c2ccccc2)c2ccc(Cl)cc21
Solvent: CCO
Solvent: CO
Product: O[C@H]1C[C@@H](c2ccccc2)c2ccc(Cl)cc21

Procedure:
Racemic cis-6-chloro-3-phenylindan-1-ol (V) (prepared as described in PCT/DK04/000546, i.e. adapting the method described in Bøgesø et al. J. Med. Chem. 1995, 38, 4380-4392 using ethanol as solvent, and performing the reaction at approximately 0° C.) (492 grams) is resolved by preparative chromatography, using a CHIRALPAK® AD column, 10 cm ID×50 cm L, 10 μm at 40° C. Methanol is used as mobile phase at a flow rate of 190 ml/min, detection is performed using a UV detector at 287 nm. The racemic alcohol (V) is injected as a 50,000 ppm solution in methanol; 90 ml is injected with intervals of 28 min. All the fractions, which contain the title compound with more than 98% enantiomeric excess, are combined and evaporated to dryness using a rotary evaporator, followed by drying in vacuo at 40° C. Yield 220 grams as a solid. Elemental analysis and NMR conform to the structure, the enantiomeric excess is higher than 98% according to chiral HPLC, [α]D20 +44.5° (c=1.0, methanol).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[CH:10]([N:21]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:22]#[N:23])[CH2:9][CH:8]1[CH2:39][CH3:40])=[O:6])([CH3:3])[CH3:2].Cl.N[OH:43].[CH2:44]([N:46](CC)CC)[CH3:45]>CCO>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:24][C:25]2[CH:26]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=2)[C:22]2[N:46]=[C:44]([CH3:45])[O:43][N:23]=2)[CH2:9][C@@H:8]1[CH2:39][CH3:40])=[O:6])([CH3:3])[CH3:2]
Reactant: CCC1CC(N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Reactant: CCN(CC)CC
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2noc(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of 4-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (from Example 9) (250 mg, 0.429 mmol) in EtOH (2.6 mL), add hydroxylamine hydrochloride (75 mg, 1.07 mmol) and triethylamine (0.150 mL, 1.07 mmol) at room temperature. Stir the reaction mixture at 80° C. overnight. Cool the mixture and remove the solvents under reduced pressure. Dilute the residue with ethyl acetate and add brine. Separate the layers, dry the organic phase over magnesium sulfate, filter, and concentrate in vacuo. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (84 mg, 32%). MS (ES+): 616 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)[CH:19]=[C:18]([CH3:29])[C:17]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]O)[CH:31]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:29][C:18]1[CH:19]=[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)[CH:21]=[C:16]([CH3:15])[C:17]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:10][CH:9]3[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)[CH:31]=1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Reactant: Cc1cc(OCC2(C)COC2)cc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CC1c1ccc(OCc2cccc(-c3c(C)cc(OCC4(C)COC4)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.157 g, 0.816 mmol), (2′,6′-dimethyl-4′-[(3-methyloxetan-3-yl)methoxy]biphenyl-3-yl}methanol (0.231 g, 0.741 mmol) and tributylphosphine (0.298 g, 1.47 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.372 g, 1.47 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Hexane (15 mL) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-40:60) to give the title compound (0.326 g, yield 82%) as a colorless oil.
Reaction SMILES: CO.[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C@@H:5]([CH2:7][CH3:8])[CH3:6].[O:12]=[CH:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22]O)[OH:21])[OH:19])[OH:17])[OH:15]>N1C=CC=CC=1>[CH2:22]([NH:3][C@@H:4]([C:9]([OH:11])=[O:10])[C@@H:5]([CH2:7][CH3:8])[CH3:6])[C:20]1([O:12][CH2:13][C@@H:14]([OH:15])[C@@H:16]([OH:17])[C@@H:18]1[OH:19])[OH:21]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC[C@@H](C)[C@@H](N)C(=O)O
Solvent: c1ccncc1
Solvent: CO
Product: CC[C@@H](C)[C@@H](NCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O)C(=O)O
Yield: 49.2 %

Procedure:
A dry mixture of 40 ml of methanol and 10 ml of pyridine was added to 100 mg of dry D-isoleucine together with 300 mg of anhydrous glucose, and reaction and purification were carried out as described in Example 9, but making use of smaller-volume chromatography columns. Crystallization of the final product yielded 110 mg of N-(1-deoxyfructopyranos-1-yl)-D-isoleucine. Melting point 142°-144° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[N:6]1.[OH-].[K+]>S(=O)(=O)(O)O>[N+:1]([C:8]1[C:7]([C:13]([OH:15])=[O:14])=[N:6][NH:5][C:9]=1[C:10]([OH:12])=[O:11])([O-:4])=[O:2]
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
Fuming sulphuric acid (105 ml) was added dropwise over 45 minutes to ice-cooled finning nitric acid (88 ml), so as to maintain the internal temperature below 20° C. Once addition was complete the mixture was warmed to 40° C., pyrazole-3,5-dicarboxylic acid (125 g, 0.80 mol) added portionwise over 75 minutes, so as to maintain the reaction temperature below 50° C., and the reaction then stirred at 60° C. for 18 hours. The cooled mixture was poured onto ice (1 kg), and flaked potassium hydroxide carefully added with stirring, until the solution pH was 2. The resulting precipitate was filtered, and triturated with boiling water (500 ml), to afford the title compound (123 g, 76%) as a white solid. m.p. 325-327° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:11])[NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O>>[CH3:11][C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]2[N:1]=[CH:14][CH:15]=[C:16]([C:18]3[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][CH:23]=3)[N:3]2[N:4]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1c(N)n[nH]c1C
Product: COC(=O)c1c(C)nn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
As for Example 1, methyl 3-amino-5-methylpyrazole-4-carboxylate is reacted with 3-dimethylamino-3'-(trifluoromethyl)-acrylophenone to give the product as crystals, m.p. 177°-179° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[S:5]1(=[O:20])=[O:19].ClC([O:24][C:25](Cl)(Cl)Cl)=O.[NH3:29]>O1CCOCC1>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:25](=[O:24])[NH2:29])[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[S:5]1(=[O:20])=[O:19]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CN1c2ccccc2Nc2ccccc2S1(=O)=O
Reactant: N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1c2ccccc2N(C(N)=O)c2ccccc2S1(=O)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
0.9 g (0.027 mol) of 80% sodium hydride are added to 7 g (0.027 mol) of 6-methyl-6,11-dihydro-dibenzo[c,f][1,2,5]thiadiazepine 5,5-dioxide in 200 ml of dioxane, and the mixture is heated for 30 minutes at 80° C. After cooling, 5.4 g of trichloromethyl chloroformate are added dropwise, with cooling in an ice bath, and the mixture is left to stand overnight. Gaseous NH3 is then introduced up to saturation, the mixture is filtered, and the filtrate is concentrated and diluted with water. This gives a solid which is filtered, washed and dried.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:24][C:25]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:22][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)[OH:23])=[O:28]
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 2,3-dichlorobenzoyl chloride (135 mg, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) and recrystallized from ethyl acetate-hexane to give the title compound (161 mg, 77%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:26]2)[CH2:22][CH2:23]1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1N1CCN(CC2CCCNC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CC2CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
Benzoyl chloride (0.49 g, 3.5 mmol) was added to a solution of 1-(2-methoxyphenyl)-4-piperidin-3-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 6 and triethylamine (2 equivalents, 1 mL) in CH2Cl2 (30 mL) and the solution stirred under N2 at 0° C. for 16 hours. The mixture was concentrated under vacuum, water (50(mL) added and the product extracted into ethyl acetate (3×25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (1.08 g, 79% yield). An ethanolic solution of the product was treated
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]2=O.O.[NH2:23][NH2:24]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])=[CH:7][NH:24][N:23]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: COc1ccccc1-c1coc2cc(O)c(Cl)cc2c1=O
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1c[nH]nc1-c1cc(Cl)c(O)cc1O

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-7-hydroxy-3-(2-methoxy-phenyl)-chromen-4-one (2.0 g, 6.6 mmol), hydrazine hydrate (5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give 4-chloro-6-[4-(2-methoxy-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid. Rf 0.8 ethyl acetate/hexane (70/30).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][O:28][CH2:29][CH2:30][O:31][C:32]1[CH:41]=[C:40]2[C:35]([CH:36]=[CH:37][C:38]([CH:42]=O)=[N:39]2)=[CH:34][CH:33]=1.C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:42]([C:38]3[CH:37]=[CH:36][C:35]4[C:40](=[CH:41][C:32]([O:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:33][CH:34]=4)[N:39]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COCCOc1ccc2ccc(C=O)nc2c1
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCOc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.3 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.20 g, 0.53 mmol) and 7-(2-methoxyethoxy)quinoline-2-carbaldehyde (0.12 g, 0.53 mmol) in ethanol (2.7 mL, 0.53 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2.7 mL) and iodosobenzene diacetate (0.19 g, 0.59 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.20 g, 63%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:19]([OH:24])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[CH:17][CH:18]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:32]([O:24][CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)[CH:14]=1)[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCC(O)c1cccc(COc2cccc3cccnc23)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(OC(=O)c1ccccc1)c1cccc(COc2cccc3cccnc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 g (10 mmol) of 1-[3-(quinolin-8-yloxymethyl)phenyl]-pentanol are dissolved in 50 ml of dichloromethane. After the addition of 2.8 ml of triethylamine and 1.16 ml of benzoyl chloride, the mixture is stirred for 2 hours at 25° C. and then heated under reflux for 5 hours. The reaction mixture is washed three times with water, dried over sodium sulphate and evaporated down. The residue is chromatographed over silica gel 60 (mobile phase: 100:2 dichloromethane/methanol). An oil is obtained.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[C:5]([F:27])=[C:6]([C:19]([N+:24]([O-:26])=[O:25])=[C:20]([F:23])[C:21]=1[F:22])[C:7]([C:9](=[CH:15]OCC)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[CH:29]1([NH2:32])[CH2:31][CH2:30]1>C(Cl)Cl>[CH:29]1([NH:32][CH:15]=[C:9]([C:7](=[O:8])[C:6]2[C:19]([N+:24]([O-:26])=[O:25])=[C:20]([F:23])[C:21]([F:22])=[C:4]([O:3][CH:2]([F:28])[F:1])[C:5]=2[F:27])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
The whole of the ethyl 2-(3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)-3-ethoxyacrylate [(XVI), R1 =--OCHF2, R3' =NO2, R17 =C2H5, X=X'=F]obtained as described in step (c) above was dissolved in 500 ml of methylene chloride, and 3.5 g (0.06 moles) of cyclopropylamine were added dropwise to the resulting solution, whilst stirring and ice-cooling. The mixture was then stirred for 1 hour, whilst ice-cooling, and then for an additional 1 hour at room temperature, after which the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a 9:1 by volume mixture of toluene and ethyl acetate as the eluent, to give 19.8 g of ethyl 3-cyclopropylamino-2-(3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)acrylate as an yellow powder, melting at 105°-106° C.