Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][C:4]([CH3:27])([O:6][C:7]1[N:12]=[N:11][C:10]([N:13]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:5].Cl.NO.C([O-])(=O)C.[Na+]>CO>[CH3:1][N:2]([CH3:28])[CH2:3][C:4]([CH3:5])([CH3:27])[O:6][C:7]1[N:12]=[N:11][C:10]([NH2:13])=[CH:9][CH:8]=1
Reactant: CN(C)CC(C)(C)Oc1ccc(N=C(c2ccccc2)c2ccccc2)nn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CN(C)CC(C)(C)Oc1ccc(N)nn1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 98 %

Procedure:
In a 10 mL pear shape flask was added 6-(1-(dimethylamino)-2-methylpropan-2-yloxy)-N-(diphenylmethylene)pyridazin-3-amine (200 mg, 534 μmol, Eq: 1.00) and MeOH (5.34 ml). To the mixture was added hydroxylamine hydrochloride (66.8 mg, 961 μmol, Eq: 1.8) and sodium acetate (105 mg, 1.28 mmol, Eq: 2.4). The mixture was stirred at room temperature for 25 min. The reaction mixture was absorbed on to silica and purified by LC chromatography eluting with 0-5% (10% NH4OH in MeOH) in 1/1 EtOAc/Hexane to afford 110 mg (98%) of the title compound.
Reaction SMILES: [NH3:1].[OH:2][CH:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][CH:29]([CH3:31])[CH3:30])[N:22]=3)[O:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:4]OS(C)(=O)=O>CO>[NH2:1][CH2:4][CH:3]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:20]=[C:19]([C:21]3[CH:31]=[C:29]([CH3:30])[N:28]=[C:23]([NH:24][CH:25]([CH3:26])[CH3:27])[N:22]=3)[O:18][N:17]=2)=[CH:14][CH:15]=1)[OH:2]
Reactant: Cc1cc(-c2nc(-c3ccc(C(O)COS(C)(=O)=O)cc3)no2)nc(NC(C)C)n1
Reactant: N
Solvent: CO
Product: Cc1cc(-c2nc(-c3ccc(C(O)CN)cc3)no2)nc(NC(C)C)n1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A solution of 7M NH3 in methanol (35 mL) is added to methanesulfonic acid 2-hydroxy-2-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl ester (606 mg, 1.40 mmol, synthesis described for Example 143). The reaction mixture is stirred at 65° C. for 18 h and is then evaporated to give 293 mg of rac-2-amino-1-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethanol as a yellow oil; LC-MS: tR=0.73 min; [M+H]+=355.06.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH2:19][CH:20]([C:22](O)=[O:23])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[CH:28]=[CH:27][C:26]1=[O:35]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH2:19][CH:20]([C:22]([N:31]3[CH2:32][CH2:33][C:34]4[NH:25][C:26](=[O:35])[CH:27]=[CH:28][C:29]=4[CH2:30]3)=[O:23])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)n1ncc(C2=NC(C(=O)O)CS2)c1-c1ccc(F)cc1
Reactant: O=c1ccc2c([nH]1)CCNC2
Product: CC(C)(C)n1ncc(C2=NC(C(=O)N3CCc4[nH]c(=O)ccc4C3)CS2)c1-c1ccc(F)cc1

Procedure:
Using 2-(1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)-4,5-dihydrothiazole-4-carboxylic acid and 5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: N/[C:2](=[CH:5]\[CH3:6])/[C:3]#[N:4].[NH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[NH2:8].C(O)(=O)C>C(O)C>[CH3:6][C:5]1[CH:2]=[C:3]([NH2:4])[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:8]=1
Reactant: NNc1ccccn1
Reactant: C/C=C(\N)C#N
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(N)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To an ice-cold solution of aminocrotononitrile (82 g, 1.0 mol) and 2-hydrazinopyridine (120 g, 1.1 mol) in ethanol (300 mL) was added acetic acid (132 g, 2.2 mol), and the mixture was heated under reflux for 3.5 hours. After the mixture was allowed to cool to room temperature, the reaction solvent was evaporated under reduced pressure and water was added to the residue. After the solution was made basic by the addition of an aqueous sodium hydroxide solution, organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by silica gel column chromatography (ethyl acetate) gave the title compound (156.3 g, 90% yield).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].[Cl:15][C:16]1[S:17][CH:18]=[C:19]([CH3:24])[C:20]=1[N:21]=[C:22]=[O:23]>C1COCC1>[ClH:15].[C:3]([NH:5][C:22]([NH:21][C:20]1[C:19]([CH3:24])=[CH:18][S:17][C:16]=1[Cl:15])=[O:23])(=[NH:2])[NH2:4]
Reactant: Cc1csc(Cl)c1N=C=O
Reactant: N=C(N)N
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1csc(Cl)c1NC(=O)NC(=N)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.5 %

Procedure:
A mixture of guanidine hydrochloride (14.33 g), and 50% aqueous NaOH (10.00 g) in THF (250 ml) is stirred at room temperature overnight. THF (250 ml), and anhydrous Na2SO4 (7.5 g) are added to the mixture and stirring continued for 1 hour. A solution of 2-chloro-3-isocyanato-4-methylthiophene (8.68 g) in THF (500 ml) is added dropwise to the stirred mixture. After the addition is complete, stirring is continued for 30 minutes. The solvent is decanted, leaving a THF insoluble material. The solvent is evaporated under reduced pressure. The evaporated residue is suspended in 500 ml of 2% aqueous HCl and added to the THF insoluble material. This mixture is stirred vigorously with 250 ml of Et2O for 30 minutes. Insoluble material is separated by decantation. The aqueous layer is separated, washed with Et2O and alkalinized with NaHCO3, forming a precipitate. The precipitate is washed with H2O and air dried to afford 8.85 g of a tan crystalline solid. The tan solid is dissolved in 5% aqueous HCl (175 ml), filtered through Celite, and the filtrate cooled rapidly to room temperature. After standing overnight in the cold, the precipitate is collected, washed with a portion of the mother liquor, dried in vacuo, and stirred in 100 ml of CH2Cl2, and air dried in vacuo (50° C.) overnight to yield 7.20 g of the amidinourea hydrochloride as a tan powder, m.p. 173°-174.5° C. w/dec.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][C:19]([CH3:27])=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]=2[CH3:22])=[O:16])=[CH:8][C:7]=1[CH3:28].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[OH:29][CH:3]([CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][C:19]([CH3:27])=[C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]=2[CH3:22])=[O:16])=[CH:8][C:7]=1[CH3:28])[CH2:2][NH:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCC(=O)c2sc(C)c(CC(C)C)c2C)cc(C)c1OCC(O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(CCC(=O)c2sc(C)c(CC(C)C)c2C)cc(C)c1OCC(O)CNS(C)(=O)=O
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of rac-3-[4-(3-amino-2-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(4-isobutyl-3,5-dimethyl-thiophen-2-yl)-propan-1-one (545 mg, 1.31 mmol) in DCM (27 mL), DIPEA (270 mg, 2.09 mmol) is added. The mixture is cooled to 0° C. before methanesulfonylchloride (180 mg, 1.51 mmol) is added. Stirring is continued at 0° C. for 1 h. The mixute is diluted with DCM, washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 4% of MeOH to give N-(2-hydroxy-3-{4-[3-(4-isobutyl-3,5-dimethyl-thiophen-2-yl)-3-oxo-propyl]-2,6-dimethyl-phenoxy}-propyl)-methanesulfonamide (545 mg) as a yellow oil; LC-MS: tR=1.06 min, [M+1]=496.24.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:9](=[O:25])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[NH:24][CH:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)(C)(C)C.[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:33].[ClH:35].[NH2:7][CH:8]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[NH:24][CH:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)=[O:25]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc[nH]c23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc[nH]c23)CC1
Reaction time: 4 h

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-oxo-2-[4-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL) and stirred for 4 hours. The solvent was removed to afford 2-Amino-3-(4-chlorophenyl)-1-[4-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H]+ 385.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C(O[C:17](=[S:19])[S-:18])C.[K+]>>[SH:19][C:17]1[S:18][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N:11]=1
Reactant: CCOC(=S)[S-]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Product: O=C(O)c1ccc2sc(S)nc2c1
Yield: 66 %

Procedure:
2-Mercapto-benzothiazol-5-carboxylic acid (240) (3.5 g, 66%) was synthesized from 4-chloro-3-nitro-benzoic acid, obtained from Fluka, and potassium dithiocarbonate O-ethyl ester, obtained from Lancaster, according to the procedure of Chaudhuri, N. Synth. Commun. 1996, 26, 20, 3783.
Reaction SMILES: [NH2:1][C:2]([CH2:9][CH3:10])=[C:3]([Cl:8])[C:4](OC)=[O:5].[CH:11]([NH2:13])=O.C[O-].[Na+].Cl>CO>[Cl:8][C:3]1[C:4]([OH:5])=[N:13][CH:11]=[N:1][C:2]=1[CH2:9][CH3:10]
Reactant: CCC(N)=C(Cl)C(=O)OC
Reactant: NC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1ncnc(O)c1Cl
Reaction time: 10 h
Yield: 87 %

Procedure:
Two dropping funnels are used for simultaneous dropwise addition of a solution of 35.5 g (0.2 mol) of methyl 3-amino-2-chloro-2-pentenoate and 31.5 g (0.7 mol) of formamide in 150 ml of methanol with stirring to 90.3 ml of a 30% strength sodium methylate solution in methanol at room temperature. The mixture is heated slowly to the reflux temperature and left at this for 10 h. After the mixture has cooled, dry HCl gas is passed through the solution until the pH is 3. Evaporation of the solvent is followed by extraction with butanone, drying and evaporation in a rotary evaporator. Yield: 87% [HPLC]
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.[CH3:21][O-:22].[Na+]>CO.C(OCC)(=O)C>[CH3:21][O:22][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1
Reactant: C[O-]
Reactant: Fc1ccc(-c2cc(Cl)nc(-c3ccccn3)n2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(-c2ccc(F)cc2)nc(-c2ccccn2)n1
Yield: 77 %

Procedure:
5.5 g (0.02 mol) of 4-chloro-2-(2-pyridyl)-6-(4-fluorophenyl)-pyrimidine are dissolved in 50 ml of dry methanol, 8.6 g of a 22% strength solution of sodium methylate in methanol (corresponds to 0.04 mol) are added, and the mixture is refluxed for 40 hours. After the solvent has been removed, the residue obtained is taken up in ethyl acetate and the mixture is washed twice with water and dried over sodium sulphate. After the solvent has been removed, 4.3 g (77% of theory) of 4-methoxy-2-(2-pyridyl)-6-(4-fluorophenyl)-pyrimidine of melting point 97°-98° C. are obtained.
Reaction SMILES: [CH:1](OCC)=[O:2].Cl.[CH3:7][O:8][C:9](=[O:13])[CH2:10][NH:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CCO>[CH3:7][O:8][C:9](=[O:13])[CH2:10][N:11]([CH:1]=[O:2])[CH3:12]
Reactant: CCOC=O
Reactant: CNCC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)CN(C)C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Ethyl formate (850 mL) was added to sarcosine methyl ester HCl salt (205 g, 1.46 mol, grounded into powder prior to use), potassium carbonate (205 g, 1.48 mol), and EtOH (800 mL), stirred overnight at rt, and filtered. The filtrate was concentrated in a rotary evaporator during which the residue separated into two layers. The upper layer was separated and the lower layer was extracted with EA. Combined EA extracts and the upper layer were dried over MgSO4, filtered, and concentrated to yield 185 g (81%) of N-formyl sarcosine methyl ester which was used for the following reaction. NaH (60% oil suspension, 16.0 g, 0.4 mol) was carefully added in several portions in 1 h to a mixture of N-formyl sarcosine methyl ester (50 g, 0.34 mol) and ethyl formate (160 mL) cooled in an ice-water bath. The reaction mixture was stirred, the temperature raised to rt, and the stirring continued overnight. The reaction mixture was triturated twice with hexane (100 mL each time), the residue dissolved in EtOH (100 mL) and concentrated HCl (60 mL), and the reaction mixture stirred at 110° C. After 1 h, the reaction mixture was cooled, filtered, the residue washed with EtOH and the filtrate concentrated to yield a thick brown oil. The oil was added to 10% HOAc in water (200 mL), NH2CN (35 g) and sodium acetate (90 g), stirred at 95° C. After 1 h the reaction mixture was concentrated to ⅓ its original volume in a rotary evaporator and its pH adjusted to about 9 by addition of sodium carbonate. The reaction mixture was then extracted with EA (8×100 mL), the combined EA layers dried, filtered, and concentrated to yield a residue which was purified by recrystallization to yield 1-N-methyl-2-amino imidazole-5-carboxylic acid ethyl ester (“amino ester”).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[C:16]1([C@H:22]([CH3:26])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:23](=[O:24])[C@H:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:26])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1Cn1cc(NC(=O)[C@@H](C)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (200 mg, 1 mmol), (S)-2-phenyl propionic acid (156 mg, 1 mmol), and PyBop (650 mg, 1.3 mmol) were added to DMF (4 mL) followed by triethylamine (0.3 mL, 2.1 mmol). The reaction stirred for 4 hours at room temperature under a nitrogen atmosphere then diluted with ethyl acetate (20 mL), washed with aqueous saturated NaHCO3 solution (2×15 mL) followed by aqueous saturated NaCl solution (15 mL). The organic phase was dried, filtered and concentrated on the rotovap. The crude product was re-suspended in methanol (3 mL) and purified by reversed phase HPLC (5%-95% ACN in H2O: 25 minute gradient). The fractions containing the pure product were concentrated to afford (S)—N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-phenylpropanamide (200 mg, 60%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.36 (d, J=7.2, Hz, 3H), 2.09 (s, 3H), 2.36 (s, 3H), 3.71-3.66 (m, 1H), 5.05 (s, 2H), 7.33-7.17 (m, 5H), 7.37 (s, 1H), 7.90 (s, 1H), 10.05 (s, 1H). MS 325 (M+H). Melting point 108° C.-110° C.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14](C([O-])=O)[CH2:13][CH2:12]2)=[CH:5][C:4]=1[F:22])#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[F:22][C:4]1[CH:5]=[C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:20]=[CH:21][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(OCCCC2CCN(C(=O)[O-])CC2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(OCCCC2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a methylene chloride (5.5 mL) solution of 0.66 g of tert-butyl=4-[3-(4-cyano-3-fluorophenoxy)propyl]-1-piperidinecarboxylate was dropwise added 1.8 mL of trifluoroacetic acid under cooling with ice over a period of 2 minutes, which was then stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and chloroform and a 1.0 mol/L sodium hydroxide aqueous solution were added to the resultant residue. The organic layer was separated and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:methanol=4:1) to provide 0.28 μg of 2-fluoro-4-[3-(4-piperidinyl)propoxy]benzonitrile as pale yellow oily form.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([NH:22][C:23](=[O:40])[C@@H:24]([NH:30][C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.Cl.[H][H]>CO.O1CCOCC1.[Pd]>[F:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH2:11][C@@H:10]([NH:22][C:23](=[O:40])[C@@H:24]([NH:30][C:31]1[O:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=1)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:9][OH:8])[CH2:13][CH2:14]2
Reactant: CC(C)(C)C[C@H](Nc1nc2ccccc2o1)C(=O)N[C@@H](COCc1ccccc1)CN1CCc2cc(F)ccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)C[C@H](Nc1nc2ccccc2o1)C(=O)N[C@@H](CO)CN1CCc2cc(F)ccc21
Reaction time: 2 h
Yield: 58.5 %

Procedure:
The title compound of example 6 (34 mg, 70 μmol) was dissolved in MeOH (3 mL) and treated with 4 M HCl in dioxane (0.5 mL). The reaction was then treated with 10% Pd/C (7 mg) and the atmosphere was exchanged for hydrogen by sparging the solution with a needle and a balloon. After 2 h under a hydrogen balloon, the atmosphere was exchanged back to nitrogen and the catalyst was removed by filtration through celite. The solvent was removed and the residue was purified by preperative reverse phase HPLC to afford the title compound as a gum (18.6 mg, 47%); 1H NMR (CDCl3, 400 MHz) δ 0.97 (s, 9H), 1.69 (dd, 1H, J1=9.0, J2=14.5), 1.81 (dd, 1H, J1=3.4, J2=14.5), 2.71-2.90 (m, 2H), 3.04-3.16 (m, 1H), 3.19-3.31 (m, 2H), 3.40-3.50 (m, 1H), 3.66 (d, 1H, J=5.2), 4.13-4.21 (m, 1H), 4.38 (dd, 1H, J1=3.4, J2=9.0), 6.44-6.52 (m, 1H), 6.59-6.66 (m, 1H), 6.70-6.74 (m, 1H), 7.14 (dd, 1H, J1=J2=7.7), 7.23 (dd, 1H, J1J2=7.6), 7.30 (d, 1H, J=7.8), 7.33 (d, 1H, J=8.0); HPLC-MS calcd. for C25H31FN4O3 (M+H+) 455.2, found 455.5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CC(=O)CC>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12]
Reactant: Cc1csc2c(Cl)c(Cl)c(O)cc12
Reactant: CCOC(=O)CBr
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2c(C)csc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A mixture of 3.7 g of 6,7-dichloro-5-hydroxy-3-methylbenzo[b]thiophene, 4.3 g of ethyl bromoacetate and 20 ml of 2-butanone containing 5 ml of dimethylformamide is stirred at 60°-70° for 2 hours. The cooled mixture is diluted with ice-water and extracted 3 times with ether. The combined ether extract is dried over anhydrous magnesium sulfate and concentrated under vacuum to a brownish oil. Purification of the crude product is effected by column chromatography (alumina/ether). The purified ester is recrystallized from ether-pentane to give 4.3 g of ethyl [(6,7-dichloro-3-methylbenzo[b]thien-5-yl)oxy]acetate as fluffy needles, mp 115°-117°.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:16]=1.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C([O-])(=O)/C=C/C([O-])=O>CC(OC)(C)C.C(O)C.CO>[CH3:18][O:17][C:3]1[C:2]([O:1][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[CH:16][C:6]2[C:7]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)cc(C(F)(F)F)c2cc1O
Reactant: ClCCCN1CCC(c2ccccc2)CC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CCO
Solvent: CO
Product: COc1cc2oc(=O)cc(C(F)(F)F)c2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 45 %

Procedure:
Method D (3 h at 85° C.); starting materials: 6-hydroxy-7-methoxy-4-(trifluoromethyl)-2H-1-benzopyran-2-one (example 104) and 1-(3-chloropropyl)-4-phenylpiperidine; yield 45%; fusion point 125°-126° C. (from TBME and methanol). Fumarate: method E; yield 59%; fusion point 176°-179° C. (from ethanol and TBME).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]([O:12][CH2:19][C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)=[O:11]
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCOC1CCCCO1
Solvent: ClCCl
Product: O=C(CCOC1CCCCO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of 3-(tetrahydro-2H-pyran-2-yloxy) propanoic acid (1 g, 5.7 mmol) and TEA (0.863 g, 8.55 mmol, Shantou Xilong chemical factory) in 50 mL of CH2Cl2 was added BnBr (0.98 g, 5.7 mmol, Aldrich) via a syringe at 0° C. After stirring at rt overnight, the reaction mixture was quenched with 20 mL of water, and was extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) petroleum ether/EtOAc) to give the title compound as colorless oil (270 mg, 18.6%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.CC1C=CC(S(O[CH2:56][C@@H:57]2[CH2:62][O:61][CH2:60][CH2:59][O:58]2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[O:58]1[CH2:59][CH2:60][O:61][CH2:62][C@@H:57]1[CH2:56][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(C[C@H]2COCCO2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]-benzodioxole-7,3′-indol]-2′(1′H)-one, and (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-[(2S)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (91%) as a colorless solid: mp 137-139° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.33-7.27 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 7.08-7.01 (m, 2H), 6.58 (s, 1H), 6.36, 6.33 (s, 1H), 4.91, 4.90 (d, J=9.0 Hz, 1H), 4.67, 4.66 (d, J=9.0 Hz, 1H), 4.28-4.20 (m, 1H), 4.14-4.02 (m, 2H), 3.99-3.78 (m, 5H), 3.76-3.57 (m, 4H), 3.46-3.38 (m, 1H), 2.22-2.00 (m, 2H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ177.8, 177.7, 156.8, 156.7, 153.08, 153.05, 146.38, 146.35, 142.65, 142.63, 132.3, 132.2, 129.0, 128.9, 124.0, 123.9, 123.6, 123.2, 123.1, 116.1, 116.0, 109.6, 109.4, 103.59, 103.56, 80.5, 80.4, 73.34, 73.31, 70.9, 69.4, 69.2, 66.8, 66.7, 66.52, 66.49, 57.98, 57.96, 41.9, 41.8, 32.3; MS (ES+) m/z 410.0 (M+1).