Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[F:16][C:17]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH2:1]([C:5]1[N:10]([CH2:19][C:18]2[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:17]=2[F:16])[C:9](=[O:11])[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)OC)cc(=O)[nH]1
Reactant: Fc1cc(I)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCCCc1cc(C(=O)OC)cc(=O)n1Cc1ccc(I)cc1F

Procedure:
A solution of 2.09 g (10 mmol) of the compound from Example VIII, 3.14 g (10 mmol) of 2-fluoro-4-iodobenzyl bromide and 2.11 g (11 mmol) of caesium carbonate in 40 ml of DME is stirred at 20° C. under argon for 16 hours. The solvent is then removed in vacuo, the residue is taken up in methylene chloride/water, the aqueous phase is extracted once with methylene chloride and the combined organic phases are dried over sodium sulphate and concentrated. The residue is purified on silica gel using petroleum ether/ethyl acetate (5:1 and 3:1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]([OH:18])[C:13](OCC)=[O:14])[CH2:3][CH2:2]1.[CH3:25][NH2:26]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]([OH:18])[C:13]([NH:26][CH3:25])=[O:14])[CH2:3][CH2:2]1
Reactant: CN
Reactant: CCOC(=O)C(O)C(c1ccccc1)N1CCOc2ccccc21
Product: CNC(=O)C(O)C(c1ccccc1)N1CCOc2ccccc21
Temperature: 70 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
A mixture of ethyl (2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpropanoate (283 mg, 0.864 mmol) and ethanolic methylamine solution (5 mL, 33% in ethanol) was stirred at 70° C. in a sealed tube for 5 hours. After cooling, all volatiles were removed under reduced pressure. The resulting yellow solid was purified via Biotage Horizon (FLASH 12 S, silica, 20%, 35%, 50% EtOAc/hexane) to yield 235 mg (87%) (2RS,3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-N-methyl-3 phenylpropanamide as a white solid. MS (ESI) m/z 311.0 ([M−H]−).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=4)=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][C:40]([NH2:42])=[O:41]>CC(C)=O>[C:40]([CH2:39][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:23]4[CH:24]=[CH:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=4)=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5]1)(=[O:41])[NH2:42]
Reactant: Cc1cccc(C(=O)Nc2ccc(N3CCNCC3)cc2)c1-c1ccc(C(C)C)cc1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(C(=O)Nc2ccc(N3CCN(CC(N)=O)CC3)cc2)c1-c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
To a solution of 4′-isopropyl-6-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (206 mg) in acetone (20 mL) containing K2CO3 (206 mg) was added 2-bromo-acetamide (100 mg) and the mixture was heated at reflux for 16 hours. After cooling at room temperature the salts were removed by filtration, washed with acetone and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH (93/7) and the solid obtained was recrystallized from CH2Cl2/diisopropyl ether to give the title compound (190 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6](=[O:23])[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH2:22])=[N:19][O:20][N:21]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:23])[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH:22][C:32](=[O:34])[CH3:33])=[N:19][O:20][N:21]=2)=[CH:24][CH:25]=1
Reactant: CC(=O)Cl
Reactant: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1

Procedure:
A solution of 4-[1-(4-chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.05 g, 0.143 mmol), pyridine (0.022 g, 0.282 mmol), acetyl chloride (0.013 g, 0.169 mmol) and a catalytic amount of DMAP in DMF (5 ml) is stirred at 80° C. for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yellowish solid, m.p. 202-205° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O[N:18]1C2C=CC=CC=2N=N1.O.N>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([NH2:18])=[O:15])[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Agent: N
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CSC[C@H]1C(N)=O
Yield: 71 %

Procedure:
(4R)-3-(tert-Butyloxycarbonyl)thiazolidine-4-carboxylic acid (12.5 g, 54.1 mmol) was dissolved in CH2Cl2/DMF (9:1, 150 ml). To this solution at 0° C. was added 1-hydroxybenzotriazole hydrate (14.6 g, 108 mmol) and water-soluble carbodiimide (13.0 g, 65 mmol). After 1 h at 0° C. ammonia (35%, 50 ml) was added. After 18 h at 0° C. to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (500 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 2% methanol, 98% chloroform) to give a colourless oil identified as the title compound (8.9 g, 38.4 mmol, 71%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13].CS(Cl)(=O)=O.Cl.[OH-].[Na+]>CN(C=O)C.O>[CH2:8]([O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[NH2:3])[CH2:9][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1cc([N+](=O)[O-])ccc1N
Reaction time: 0.5 h

Procedure:
General Procedure for the Preparation of the base compound and Compounds 9-16. NaH (95% powder, 0.265 g, 10.5 mmol, 3.5 equiv) was added to a solution of alkyl instituted 2-amino-5-nitrophenol (3.0 mmol) in anhydrous DMF (8 mL) at room temperature. After being stirred at the same temperature for 30 min, MsCl (1.031 g, 9.0 mmol, 3 equiv) was added to the mixture, and the stirring was continued overnight at room temperature. H2O was added to the mixture, and then it was neutralized with 5 N HCl until pH=1-2. The intermediate precipitated as a yellow solid. It was collected by filtration and washed with H2O, which was used to the next reaction without further purification. The intermediate was added to a 3 N NaOH aq solution and was stirred at 80-90° C. overnight. After being cooled, it was neutralized with 5 N HCl until pH=1-2. The precipitated solid was collected and washed with H2O and cold ether to provide the desired product, and then it was recrystallized from ethyl acetate/hexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: ClCCCBr
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CCCCl)c2ccc(F)cc2)cc1
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
To a stirred solution of 10.6 parts of N-(4-fluorophenyl)-4-methylbenzenesulfonamide in 68 parts of N,N-dimethylformamide were added portionwise 2.1 parts of a sodium hydride dispersion 50%: temp. roses to 35° C. After stirring for 20 minutes, the whole was cooled in an ice-bath (about 15° C.) and 12.6 parts of 1-bromo-3-chloropropane were added quickly. Stirring was continued first for 20 minutes at room temperature, then for 3 hours at 75° C. and further overnight at room temperature. The reaction mixture was poured onto ice-water and the product was extracted with methylbenzene. The extract was washed three times with water, dried, filtered and evaporated. The residue was crystallized from petroleumether. The product was filtered off and recrystallized from 2,2'-oxybispropane, yielding 11.37 parts (83.2%) of N-(3-chloropropyl)-N-(4-fluorophenyl)-4-methylbenzenesulfonamide (intermediate 83).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](/[CH:10]=[CH:11]/[C:12]2[N:13]([CH3:23])[N:14]=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[S:5][C:6]=1[C:7]([OH:9])=O.CN(C(O[N:32]1N=N[C:34]2C=CC=[CH:38][C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[CH:33]([NH:32][C:7]([C:6]1[S:5][C:4](/[CH:10]=[CH:11]/[C:12]2[N:13]([CH3:23])[N:14]=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:3][C:2]=1[CH3:1])=[O:9])([CH3:38])[CH3:34]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1nc(/C=C/c2c(-c3ccccn3)nnn2C)sc1C(=O)O
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2c(-c3ccccn3)nnn2C)sc1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 4-methyl-2-[(E)-2-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-yl)-vinyl]-thiazole-5-carboxylic acid (56 mg, 0.17 mmol) and TBTU (60 mg, 0.19 mmol) in DMF (0.9 mL) was added DIPEA (146 μL, 0.86 mmol). Then isopropylamine (16 μL, 0.24 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 1 to 10% methanol in dichloromethane) afforded the title compound (36 mg, 57%) as a light yellow solid after recrystallisation from methanol-water. MS: m/e=369.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.COC1C=C(B(O)O)C=CC=1.[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:41]=1>>[CH2:46]([O:45][C:43](=[O:44])[CH2:42][C:40]1[N:41]=[C:37]([NH:36][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([O:5][C@@H:4]([CH3:24])[CH2:3][O:2][CH3:1])[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH:12]=2)[S:38][CH:39]=1)[CH3:47]
Reactant: COC[C@H](C)Oc1cc(Oc2cccc(OC)c2)cc(C(=O)O)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: COc1cccc(B(O)O)c1
Product: CCOC(=O)Cc1csc(NC(=O)c2cc(Oc3cccc(OC)c3)cc(O[C@@H](C)COC)c2)n1

Procedure:
{2-[3-(3-Methoxy-phenoxy)-5-(S)-2-methoxy-1-methyl-ethoxy)-benzoylamino]-thiazol-4-yl}acetic acid ethyl ester was prepared from 3-{(1S)-2-methoxy-(methylethyl)oxy}-5-{[3-methoxy-phenyl]oxy}benzoic acid (prepared in analogy to the method described in general synthetic descriptions F, using 3-methoxyphenylboronic acid in step D)) and ethyl 2-aminothiazol-4-ylacetate following synthetic description A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][CH:4]=1.C([O:33][C:34](=[O:37])[CH2:35]Br)(C)(C)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:35][C:34]([OH:37])=[O:33])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCO)c23)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCOCC(=O)O)c23)cc1
Temperature: 0 °C

Procedure:
Put 200 mg (0.53 mmol) 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}propan-1-ol with 518 mg (2.66 mmol) bromoacetic acid tert.-butyl ester and 36 mg (0.106 mmol) tetra-n-butylammonium hydrogensulphate in 5 ml dichloromethane and cool to 0° C. Add 1.0 ml 50% sodium hydroxide solution and stir vigorously at 0° C. Then leave to return to RT and continue stirring vigorously overnight. Then dilute with dichloromethane and water, acidify with 10% citric acid solution and separate the phases. Re-extract the aqueous phase once with dichloromethane. Combine the organic phases, wash once with satd. sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. Dissolve the residue in 5 ml dichloromethane. Add 1.25 ml TFA and stir for 2 h at RT. Then concentrate by evaporation and dry at high vacuum. Purify the residue chromatographically on a silica-gel thick-layer plate (solvent: dichloromethane/methanol 95:5). Extract the product zone with dichloromethane/methanol 9:1. 50 mg (23.0% of theor.) of the target compound is obtained.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1I)[C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])[CH:2]=[CH2:3].CC([O-])=O.[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C)C=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2]>[F:7][C:6]([F:9])([F:8])[C:5]([N:4]1[CH2:1][C:2](=[CH2:3])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11]1)=[O:10]
Reactant: C=CCN(CCc1ccc(Cl)cc1I)C(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=C1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A solution of N-allyl,N-trifluoroacetyl-2-iodo-4-chlorophenethylamine (0.76 g, 1.8 mmol) in dimethylformamide (20 mL) was treated with KOAc (0.53 g, 5.4 mmol), n-Bu4NBr (0.58 g, 1.8 mmol), PPh3 (0.047 g, 0.18 mmol), Pd(OAc)2 (0.041 g, 0.18 mmol) and stirred overnight at 105 C. The product mixture was cooled to 20 C, filtered, diluted with water (100 mL), extracted with ether (3×100 mL), the combined organic phases washed with water (100 mL), brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexane, silica) resulted in 0.228 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.29 (s, 1H), 7.18 (m, 1H), 7.04 (m, 1H), 5.38 (m, 2H), 5.40 (d, J=16 Hz, 2H), 3.80 (m, 2H), 3.00 (m, 2H). MS calculated for C13H11ClF3NO+H: 290, observed: 290.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N+:16]([O-:9])=[CH:15][CH:14]=1
Reactant: COc1ccc2c(Cl)ccnc2c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(Cl)cc[n+]([O-])c2c1C
Yield: 18.3 %

Procedure:
Metachloroperbenzoic acid (90.2 g, 366.0 mmol) was added portion wise over 3 h to a solution of 4-chloro-7-methoxy-8-methylquinoline (60, 15.2 g, 73.2 mmol) in CHCl3 (1 L). Then, the solution was partitioned between ice-cooled NaOH 1N and CH2Cl2 (8 successive extractions). The organic layers were combined, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (gradient of AcOEt/CH2Cl2, 1:2 to 1:0) to give 3.0 g (18.3%) of the title product 61 as a pale yellow powder: m/z=224 (M+H)+.
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40].[NH2:59][N:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>C1COCC1>[F:33][C:34]1[CH:35]=[C:36]([C:41]2[C:45]([CH2:46][O:47][C:48]3[CH:56]=[CH:55][C:51]([C:52]([NH:59][N:60]4[CH2:65][CH2:64][O:63][CH2:62][CH2:61]4)=[O:53])=[CH:50][N:49]=3)=[C:44]([CH2:57][OH:58])[O:43][N:42]=2)[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: NN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN1CCOCC1)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reaction time: 8 h
Yield: 71 %

Procedure:
Hydroxybenzotriazole hydrate (64.7 mg, 0.41 mmol), N-ethyldiisopropylamine (181 ul, 1.04 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (81 mg, 0.41 mmol) were added to a mixture of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (150 mg, 0.41 mmol) and 4-aminomorpholine (41.5 μL, 0.41 mmol) in THF (15 mL) at room temperature. After stirring overnight the solvent was removed by distillation and the residue was purified by chromatography (silica, dichloromethane:methanol=98:2 to 95:5) afforded the title compound (130 mg, 70%) as a white solid. MS: m/e=445.2 [M−H]−.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](O)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:25]([NH:27][NH2:28])=[O:26].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:25]([NH:27][NH:28][C:22]([C:16]1([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:15][CH:14]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:23])=[O:26]
Reactant: NNC=O
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=CNNC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 171.6 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid (0.75 g, 0.225 mmol), formic hydrazide (0.162 g, 0.27 mmol), 1-hydroxybenzotriazole (0.304 g, 0.225 mmol), diisopropylethylamine (1.18 mL, 0.68 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.431 g, 0.225 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (2×20 mL) The organics were dried over sodium sulphate, filtered and concentrated in vacuo to provide a cream solid. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1) to provide the title compound (0.145 g, 17%) as a clear oil. LRMS ESI+ m/z 376 [MH]+, ESI− m/z 374 [M−H+]−.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[C:6]([Cl:19])[C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[Cl:19][C:6]1[C:5]2[O:20][CH:2]([C:36]([OH:37])=[O:39])[CH2:1][C:4]=2[C:17]2[O:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[C:8]=2[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(Cl)cc2c(=O)c3ccccc3oc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1Cc2c(c(Cl)cc3c(=O)c4ccccc4oc23)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.1 %

Procedure:
A mixture of 4-allyl-2-chloro-3-hydroxy-9-oxo-9H-xanthene (2.9 g), m-chloroperbenzoic acid (3.5 g) and chloroform (300 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (10 g) and water (200 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The obtained 4-chloro-1,2-dihydro-2-hydroxymethyl-6-oxo-6H-furo[2,3-c]xanthene was dissolved in acetone (300 ml) and, to the stirred solution, a mixture of chromium trioxide (3.3 g), water (17 ml) and concentrated sulfuric acid (5 g) was added dropwise at room temperature. After standing overnight, to the mixture was added isopropanol (10 ml) and the resulting mixture was filtered and the filtrate was evaporated to dryness under vacuum. After adding water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.7 g of 4-chloro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 292°-295° C. This compound showed a mass spectrum having a molecular ion peak at m/e 316.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[OH:8].CO[C:14](OC)([CH3:16])[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:9][C:10]#[N:11])=[CH:3][C:2]=2[O:1]1
Reactant: N#CCc1ccc(O)c(O)c1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(CC#N)cc2O1
Yield: 16.3 %

Procedure:
To a solution of (3,4-dihydroxy-phenyl)-acetonitrile (0.20 g, 1.3 mmol) in toluene (4 mL) was added 2,2-dimethoxy-propane (0.28 g, 2.6 mmol) and TsOH (0.010 g, 0.065 mmol). The mixture was heated at reflux overnight. The reaction mixture was evaporated to remove the solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCO3 solution, H2O, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give 2-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acetonitrile (40 mg, 20%). 1H NMR (CDCl3, 400 MHz) δ 6.68-6.71 (m, 3H), 3.64 (s, 2H), 1.67 (s, 6H).
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:6]1[C:7]2[CH:7]=[CH:2][CH2:3][CH2:4][CH2:12][C:2]=2[CH:3]=[CH:4][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C1=Cc2ccccc2CCC1
Yield: 1773.9 %

Procedure:
A suspension of this compound (7.00 g, 43.2 mmol) and para-toluenesulfonic acid monohydrate (0.82 g, 4.3 mmol) in toluene (100 ml) was refluxed for 1 hour with the azeotropic removal of water. The resulting solution was diluted with ethyl acetate, then washed with saturated sodium hydrogen carbonate solution, dried over MgSO4, filtered and evaporated to give 6,7-dihydro-5H-benzocycloheptene as a brown liquid (5.5 g, 88% yield).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)OCC1.[H-].[Na+].[CH2:15](I)[CH3:16].Cl>CN(C=O)C.CC(C)=O>[CH2:15]([O:12][CH2:11][CH:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1)[CH3:16]
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOCC1CCC(=O)CC1
Temperature: 25 °C

Procedure:
(1,4-Dioxa-spiro[4.5]dec-8-yl)-methanol (from Example 33, 765 mg, 4.44 mmol) in DMF (3 mL) at 0° C. was treated with NaH (Aldrich, 60% in mineral oil, 355 mg, 8.88 mmol) followed by EtI (Aldrich, 0.7 mL, 8.88 mmol). The resulting solution was slowly warmed to room temperature for 2 hours and heated at 60° C. for additional 30 min. The solution was then partitioned between ethyl acetate and saturated NH4Cl. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, which was treated with 1N HCl (2 mL) and acetone (6 mL) at room temperature for 2 hours. The solvent was removed and the solution was then partitioned between ethyl acetate and saturated NaHCO3. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, purified by silica gel column (hexanes:ethyl acetate 5:1) to afford the title compound as colorless solid.