Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.C([O-])([O-])=O.[K+].[K+].[CH:24]1([N:30]([CH2:37][CH2:38][OH:39])[C:31](=[O:36])/[CH:32]=[CH:33]/[CH2:34]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O>[OH:39][CH2:38][CH2:37][N:30]([CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)[C:31]([CH:32]=[CH:33][CH2:34][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)=[O:36]
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: O=C(/C=C/CBr)N(CCO)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C=CCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Into 200 ml of N,N-dimethylformamide and 50 ml of water was added 16 g of 6-hydroxycarbostyril and 17 g of K2CO3, while the mixture was stirred at a room temperature, 31 g of N-cyclohexyl-N-(2-hydroxyethyl)-γ-bromocrotonamide was added dropwise. After the addition the reaction mixture was stirred for 3 hours and was concentrated. To the residue thus obtained 500 ml of chloroform was added and washed with water, a dilueted NaOH aqueous solution and water. The organic layer was concentrated. The residue thus obtained was recrystallized from methanol-water to obtain 27 g of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]-2-propenyloxy}-carbostyril as in the form of colorless needle-like crystals. The chemical structure of this substance was identified by the NMR spectrum and the data of elementary analysis.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]([C:6]1[NH:10][C:9]([C:11]([O:13]C)=[O:12])=[C:8]([Cl:15])[CH:7]=1)=[O:5]>C1COCC1.CO>[NH2:3][C:4]([C:6]1[NH:10][C:9]([C:11]([OH:13])=[O:12])=[C:8]([Cl:15])[CH:7]=1)=[O:5]
Reactant: COC(=O)c1[nH]c(C(N)=O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
LiOH (1 N in water, 2 mL, 2 mmol) was added to a solution of methyl 5-(aminocarbonyl)-3-chloro-1H-pyrrole-2-carboxylate (0.0602 g, 0.297 mmol) in THF (2 mL) and methanol (2 mL) and the solution was stirred at RT overnight. The reaction mixture was evaporated to a residue and partitioned with EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4 and evaporated to a solid to afford the title compound (0.057 g, 77%) as a tan solid which was used with no further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (br. s., 1H), 7.80 (br. s., 1H), 7.43 (br. s., 1H), 6.57-6.89 (m, 1H).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([S:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[C:10]([CH3:22])[N:11]2[CH2:16][C:17]([O:19]CC)=[O:18])(=[O:5])[CH3:4]>C(O)CC>[C:3]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([S:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)=[C:10]([CH3:22])[N:11]2[CH2:16][C:17]([OH:19])=[O:18])(=[O:5])[CH3:4]
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(C)=O)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: CC(=O)Nc1cccc2c1c(Sc1ccc(Cl)cc1)c(C)n2CC(=O)O
Temperature: 68 °C

Procedure:
Aqueous sodium hydroxide (1 M, 11.7 kg) was added to a solution of [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetic acid, ethyl ester (2.20 kg, 5.28 mol) in 1-propanol (8.2 kg) and the mixture heated to 68° C. After cooling to 40° C., the solution was filtered, the filter rinsed with water (1 kg) then methyl isobutyl ketone (17.8 kg) was added to the filtrate, which was re-heated to 80° C. Aqueous hydrochloric acid (1 M, 12.2 kg) was added over a period of 90 minutes then the mixture cooled to 19° C. The crystalline solid was collected by filtration, washed with water (2×4 kg), ethyl acetate (6 kg) then dried in a vacuum oven at 40° C. to provide [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetic acid as white crystals, 1.87 kg (91%).
Reaction SMILES: Br[C:2]1[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]=1[O:8]C.Cl.[CH3:12][CH:13]([CH3:17])[C:14](=[NH:16])[NH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH3:12][CH:13]([C:14]1[NH:16][C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]=2[N:15]=1)[CH3:17]
Reactant: COC1=C(Br)C(=O)CCC1
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1nc2c([nH]1)CCCC2=O
Temperature: 100 °C
Yield: 53.1 %

Procedure:
To a stirred solution of 2-bromo-3-(methyloxy)-2-cyclohexen-1-one (1.88 g) in anhydrous N,N-dimethylformamide (35 mL) at ambient temperature was added solid 2-methylpropanimidamide hydrochloride (1.349 g) and potassium carbonate (3.17 g). The reaction was then heated to 100° C. under an atmosphere of nitrogen for 3 hr. The reaction was diluted with dichloromethane (100 mL) the resultant solid was removed by filtration. The filtrate was concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-25% methanol-dichloromethane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (867 mg). LC/MS MH+ 179, Rt 0.34 min (2 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:17](=[O:18])[CH2:16][Cl:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Clc1cccc(Nc2ccccc2)c1
Solvent: Cc1ccccc1
Product: O=C(CCl)N(c1ccccc1)c1cccc(Cl)c1

Procedure:
N-(3-Chlorophenyl)aniline (25.1 g, 0.123 mole) and chloroacetyl chloride (19.6 ml, 0.246 mole) were refluxed in toluene (100 ml) for 4 hours, then stripped of toluene and excess acid chloride in vacuo to yield an oil which crystallized on scratching. Recrystallization from ethanol/H2O gave purified title product, 32.6 g, m.p. 94°-96.5°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[N:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[N:15][CH:14]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CCOC(C)=O.[Cu]Cl>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=1[O:19][C:17]1[CH:18]=[N:13][CH:14]=[N:15][CH:16]=1
Reactant: Oc1cncnc1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1cncnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A solution of 1-bromo-2,5-dimethyl-4-nitrobenzene (3.53 g, 15.34 mmol), pyrimidin-5-ol (1.474 g, 15.34 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (0.141 g, 0.767 mmol), cesium carbonate (5.15 g, 15.80 mmol) and copper(I) chloride (0.410 g, 4.14 mmol) in N-methyl-2-pyrrolidinone (15.34 mL) was heated in a sealed pressure tube at 130° C. and stirred overnight. The reaction was cooled to room temperature, diluted with EtOAc and washed with water (2×) and brine, successively, dried over Na2SO4, filtered and concentrated in vacuo. This was triturated with diethyl ether to give the first crop of the desired product (1.682 g) as a light tan solid. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography using an ISCO 80 g column eluting with 0-50% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the second crop of the desired product (0.3973 g) as an off-white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].ClC(Cl)Cl>O>[C:1]1([CH2:7][O:8][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 54 parts of (phenylmethyl)carbonochloridate, 60 parts of ethyl 4-piperidinepropanoate, 31.8 parts of sodium carbonate and 600 parts of trichloromethane was stirred overnight at room temperature. Water was added and the layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 71 parts (74%) of ethyl 1-(phenylmethoxycarbonyl)-4-piperidinepropanoate as a residue (interm. 1).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]([F:21])([F:20])[C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH2:17]2)=[CH:12][CH:11]=1.Br[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:25]([CH3:38])[CH:24]=1>C1(C)C=CC=CC=1>[CH3:29][C:27]1[CH:28]=[C:23]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][C:10]([C:9]([F:8])([F:20])[F:21])=[CH:11][CH:12]=3)[CH2:17]2)[CH:24]=[C:25]([CH3:38])[C:26]=1[NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccc(C(F)(F)F)cc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene (150 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (4.75 g, 42.3 mmol), 7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (4.82 g, 20.3 mmol) and N-(4-Bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 16.8 mmol) were then added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature, filtered through silica gel, and recrystallized from toluene to afford the title compound as a solid. (5.94 g, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[C:15]=1OC)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N[C@@H](CC1C=C(OC)C(OC)=C(OC)C=1)[C:28](O)=[O:29]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[C:16]([O:22][CH3:23])[C:17]([O:20][CH3:21])=[C:18]([O:29][CH3:28])[CH:19]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(C[C@H](N)C(=O)O)cc(OC)c1OC
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Product: COc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc(OC)c1OC

Procedure:
The title compound is synthesised as described for (S)-2-tert-Butoxycarbonylamino-3-(2,3,4-trimethoxy-phenyl)-propionic acid (Example 3) but starting from (S)-2-Amino-3-(3,4,5-trimethoxy-phenyl)-propionic acid.
Reaction SMILES: [N:1]1[NH:2][N:3]=[CH:4][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC.Br[C:23]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:24]=1[C:25]([OH:27])=[O:26]>O1CCOCC1.[Cu]I.O>[F:32][C:31]1[C:23]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[C:24]([C:28]([F:33])=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26]
Reactant: c1cn[nH]n1
Reactant: O=C(O)c1c(F)ccc(F)c1Br
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(F)ccc(F)c1-n1nccn1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To the solution of 2H-1,2,3-triazole (CAS number 288-36-8; 0.23 g, 3.33 mmol) in 1,4-dioxane (4.0 ml) was added cesium carbonate (1.0 g, 3.33 mmol), trans-1-N,2-N-dimethylcyclohexane-1,2-diamine (0.047 g, 0.33 mmol), copper(I) iodide (0.015 g, 0.08 mmol) and 2-bromo-3,6-difluorobenzoic acid (CAS number 124244-65-1; 0.40 g, 1.68 mmol). The reaction was stirred at 120° C. for 30 minutes and was then poured into water (10 ml) and extracted with ethyl acetate (2×30 ml). The organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-5% methanol/DCM) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[O:11][CH2:10][CH2:9][O:8]3)[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[O:11][CH2:10][CH2:9][O:8]3)[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2c1ccc1c2OCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2c1ccc1c2OCCO1

Procedure:
In close analogy to the procedure described above, 8-methyl-2,3,5,6-tetrahydro-1,4-dioxa-7-aza-phenanthrene is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>>[Cl:23][CH2:24][C:25]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C(CCl)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 180 step C) and chloroacetyl chloride. White solid. MS (ESI): 391.1 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([CH3:12])=[C:10]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:9]=[C:8]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[N:7]=1)=[CH2:5])C.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:8]2[N:7]=[C:6]([C:4](=[O:3])[CH3:5])[C:11]([CH3:12])=[C:10]([CH2:13][O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[N:9]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: C=C(OCC)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(COCC(F)(F)F)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)c(C)c(C(C)=O)n2)ccc1-n1cnc(C)c1

Procedure:
A solution of 4-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-2-amine (52 mg, 0.11 mmol) in dioxane (4 mL), water (0.5 mL) and concentrated hydrochloric acid (0.028 mL, 0.33 mmol) was heated at 40° C. for 35 min. Sodium bicarbonate (40 mg) and water (2 mL) were added. The volatiles were removed in vacuum, the residue was coevaporated with dioxane to give the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Si:13]([O:20][CH2:21]/[CH:22]=[N:23]/[S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Si:13]([O:20][CH2:21][C@@H:22]([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[S@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccccn1
Yield: 46.4 %

Procedure:
To a solution of toluene (40 mL) cooled to −78° C. was added butyl lithium (1.6 M in hexanes, 5.57 mL, 13.9 mmol) at a rate such that the internal temperature did not exceed −50° C., and the reaction stirred until the internal temperature returned to −78° C. 2-Bromopyridine (1.20 mL, 12.7 mmol) in toluene (4 mL) was added to the reaction mixture at a rate such that the temperature did not exceed −65° C. The reaction was stirred at −78° C. for 1 hour. To the reaction was added (S,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (3.58 g, 13.9 mmol) in toluene (20 mL) at a rate such that the internal temperature did not exceed −60° C. The reaction was stirred at −78° C. for 2 hours. To the −78° C. solution was added brine (50 mL) and the mixture was partitioned between EtOAc/water (300 mL total). The organic layer was washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed using 40% EtOAc/DCM as eluent to yield (S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (2.1 g, 46.7%).
Reaction SMILES: [CH2:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:2]=[CH2:3].O1[CH2:21][CH2:20][CH2:19][CH2:18]1.C([Li])CCC.C(Cl)/C=C/C>O.CCCCCC>[CH2:1]([C:4]1([CH2:18]/[CH:19]=[CH:20]/[CH3:21])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH2:3]
Reactant: C1CCOC1
Reactant: C=CCC1c2ccccc2-c2ccccc21
Agent: C/C=C/CCl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: C=CCC1(C/C=C/C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
There were put 2.5 g of 9-allylfluorene and 31.3 mL of dry tetrahydrofuran manufactured by Kanto Chemical Co., Inc. in a 100 mL-three necked flask. There were added dropwise thereto at 0° C. over 30 minutes 9 mL of a hexane solution of n-butyllithium (concentration: 1.6 M) manufactured by Kanto Chemical Co., Inc. The resultant mixture was stirred for 2 hours at room temperature, and then 1.4 mL of trans-crotyl chloride manufactured by Aldrich Chemical Company was added dropwise thereto at 0° C. The temperature of the mixture was raised gradually up to room temperature, and then the mixture was stirred for 6 hours at room temperature. Water was added to the reaction mixture, and the obtained mixture was subjected to extraction with ether. The extract was washed with water and with a saline solution in this order. The washed extract was dried over anhydrous magnesium sulfate manufactured by Nacalai Tesque, Inc. The dried extract was subjected to removal of the solvent by distillation, and the resultant liquid was distilled in vacuo, thereby obtaining 2.43 g of 9-allyl-9-((2E)-2-butenyl)-fluorene at 155° C. under 4 mmHg.
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].C1(=O)CCCCC1.[OH:20][C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:27][C:25]1[N:24]=[N:23][C:22]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:21]([OH:20])[CH:26]=1
Reactant: Cc1cccc(C2CC2)c1[O-]
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: O=C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a mixture of 27.4 g (purity: 92.9%; 149 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of cyclohexanone was added 2.5 g (purity: 98.5%; 14.9 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 120 g of pure water and 100 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 2.48 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 60.2%) and 16 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:17])=[C:14](Br)[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CC(O)=O.O.[Zn]>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:17])=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2sc(Br)c(Br)c2CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)N1CCc2scc(Br)c2CC1
Yield: 73.7 %

Procedure:
The product of step (e) (1.3 g, 3.39 mmol) was dissolved in 1:1 HOAc:water (40 mL), treated with Zn dust (0.44 g, 6.79 mmol), and heated to reflux for 1 hour. The reaction was cooled, diluted with water and extracted 2× EtOAc. The organic extracts were dried over MgSO4 and concentrated to give 0.76 g of the sub-title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([Cl:32])=[C:11]([C:28]([Cl:31])=[CH:29][CH:30]=1)[C:12]([NH:14][C:15]1[C:23]2[O:22][C:21]3[CH2:24][CH2:25][CH2:26][CH2:27][C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:13])=[O:7])(=O)C.[OH-].[Na+]>ClCCl.CO>[Cl:32][C:10]1[C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])=[CH:30][CH:29]=[C:28]([Cl:31])[C:11]=1[C:12]([NH:14][C:15]1[C:23]2[O:22][C:21]3[CH2:24][CH2:25][CH2:26][CH2:27][C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:13]
Reactant: CC(=O)OCC(=O)Nc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(CO)Nc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
A mixture of 6-(3-acetoxyacetylamino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (67 mg) and aqueous 1N-sodium hydroxide (0.5 ml) in a mixture of dichloromethane (1 ml) and methanol (1 ml) was stirred at ambient temperature for 1 hour. The mixture was partitioned between a mixture of dichloromethane and ethanol (8:2) and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from ethanol to give 6-(2,6-dichloro-3-hydroxyacetylamino-benzoylamino)-1,2,3,4-tetrahydrodibenzofuran (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15][C:16](OCC)=[O:17])[CH2:8]1.[BH4-].[Na+].O1CCCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH2:8]1
Reactant: CCOC(=O)CCCN1CC(COc2cccc(Cl)c2)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1OC(COc2cccc(Cl)c2)CN1CCCCO
Yield: 100.5 %

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 1.43 g of ethyl 4-[5-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]butyrate (prepared as described in Preparation 116), 183 mg of sodium borohydride, 20 ml of anhydrous tetrahydrofuran and 135 mg of anhydrous methanol were used, to give 1.26 g of the title compound having an Rf value of 0.31 (on silica gel thin layer chromatography, using ethyl acetate as the developing solvent).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH:24]([CH:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][O:27]2)[OH:25])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]([CH:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][O:27]2)=[O:25])[CH2:22][CH2:23]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC(C1CCN(Cc2ccccc2)CC1)C1OCc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(C1CCN(Cc2ccccc2)CC1)C1OCc2ccccc21
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
After adding 0.511 ml of dimethylsulfoxide dropwise to a dichloromethane solution (15 ml) containing 0.315 ml of oxalyl chloride at −70° C., the mixture was stirred for 10 minutes, a solution of 597 mg of (1-benzylpiperidin-4-yl)-(1,3-dihydroisobenzofuran-1-yl)methanol in dichloromethane (5 ml) was added dropwise, and stirring was continued for 1 hour. Next, 2.5 ml of triethylamine was added dropwise to the reaction solution, the cooling bath was removed, and the mixture was stirred at room temperature. Water was added to the reaction solution, and extraction was performed with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (517 mg, 33% yield).