Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH:7]=[CH:8][CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(OCC)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][Br:36]
Reactant: OCC=CCOCc1cc(Br)ccc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(Br)cc1COC/C=C\CBr
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 100 ml round bottom flask 4-(2-fluoro-5-bromobenzyloxy)but-2-en-1-ol (2.145 g, 7.80 mmol) was dissolved in diethyl ether under a nitrogen atmosphere. Triphenylphosphine (2.66 g, 10.1 mmol) and then carbon tetrabromide (3.36 g, 10.1 mmol) were added to the reaction mixture. The resulting mixture was stirred for six hours at ambient temperature. A white precipitate formed during the stirring. The progress of the reaction was monitored by thin layer chromatography. The solution was filtered and the filtrate was evaporated to give a thick oil. The desired title intermediate was further purified by liquid chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:13]([NH:15][O:16]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=1)(=[O:23])=[O:24])[C:13]([NH:15][OH:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)ONC(=O)[C@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO)OCc1ccccc1
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A solution of (R)-2-(benzyloxycarbonylamino)-N-tert-butoxy-3-(4-phenoxyphenylsulfonyl)-propionamide (1.2 g) obtained from Example 16 in methylene chloride (5 ml) was diluted with trifluoroacetic acid (30 ml). The solution was allowed to stand overnight, and solvent was removed under reduced pressure. This residue was chromatographed on silica gel, eluting with 10% methanol/methylene chloride to give (R)-2-(benzyloxycarbonylamino)-N-hydroxy-3-(4-phenoxyphenylsulfonyl)-propionamide (400 mg), m.p. 195-202° C.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:40]1[CH2:45][CH2:44][S:43][CH2:42][CH2:41]1.O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([S:8][CH:9]([CH2:38][N:40]1[CH2:45][CH2:44][S:43][CH2:42][CH2:41]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C=O)SCc3ccccc3)cc2c1
Reactant: C1CSCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A mixture of N-[2-(benzylthio)-3-oxopropyl]-5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (800 mg), thiomorpholine (290 mg) and tetrahydrofuran (30 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (450 mg) was added at room temperature, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (3:2-1:4, volume ratio) to give the title compound (590 mg, yield 64%) as colorless crystals. The crystals were recrystallized from acetone-hexane to give colorless prism crystals. melting point 160-161° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[CH2:18]3)=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].Cl.[H][H]>C(O)(C)C.C(O)(=O)C.[Pt]=O>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[CH2:18]3)=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1C#N
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1CN

Procedure:
A mixture of 1-(3-cyano-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.54 g, 1.0 mmol), platinum oxide (0.1 g), and 5-6M HCl in isopropanol (2 mL) in acetic acid (15 mL) is hydrogenated under 50 psi hydrogen for 48 hrs. The mixture is filtered through Celite, the filtrate is evaporated under vacuum, and the residue is purified by preparative HPLC to provide the product.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1)[CH3:28]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:34]3[CH:35]=[CH:36][C:31]([C:30]([O:29][CH2:27][CH3:28])=[O:38])=[CH:32][CH:33]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1ccc(C2(N(Cc3ccccc3)Cc3ccccc3)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(Cc4ccccc4)Cc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; dibenzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 129, 40.0 mg, 0.12 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 5 minutes. Dichlorobis (triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][C:13]=2Br)=[CH:8][CH:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][C:13]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(C2=C(Br)CCCc3ccccc32)cc1
Reactant: OB(O)c1ccccc1
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: COCCOC
Product: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Yield: 62.3 %

Procedure:
To a solution of the bromide (2c) (6.85 g, 17.9 mmol) in DME (125 mL) was added benzene boronic acid (3.25 g, 26.8 mmol), tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol), and 2N aqueous sodium carbonate(13.5 mL). After refluxing overnight the solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 7.5 EtOAc/hexanes to 100% EtOAc) followed by recrystalization from EtOAc to give (2d) as a white solid (4.24 g, 62%): 1H NMR (CDCl3) δ 7.58 (d, J=16.1 Hz, 1H), 7.20 (m, 10H), 6.92 (d, J=8.1 Hz, 2H), 6.85 (dd, J=7.3, 1.1 Hz, 1H), 6.32 (d, J=16.1 Hz, 1H), 3.78 (s, 3H), 2.82 (t, J=7.0 Hz, 2H), 2.40 (t, J=7.0 Hz, 2H), 2.20 (m, 2H); APcI m/z: 422 (M+H+CH3CN+, 100%).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].CSC.B.CO.O>C1COCC1>[CH3:6][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:1])[CH2:3][OH:4]
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: B
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccccc1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 2-methyl-2-phenyl- propionic acid (82 g, 0.5 mol) in THF (200 mL) was added dropwise borane-dimethyl sulfide (2M, 100 mL) at 0-5° C. The mixture was stirred at this temperature for 30 min and then heated at reflux for 1 h. After cooling, methanol (150 mL) and water (50 mL) were added. The mixture was extracted with EtOAc (100 mL×3), and the combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to give 2-methyl-2-phenyl-propan-1-ol as an oil (70 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][N:14]=3)=[C:9]([CH2:23][CH2:24][CH3:25])[CH:8]=2)=[CH:4][CH:3]=1.[C:28]([O:33]C)(=[O:32])[C@@H:29]([CH3:31])O>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([O:22][C@@H:29]([CH3:31])[C:28]([OH:33])=[O:32])[CH:20]=[CH:21][C:16]=4[O:15][N:14]=3)=[C:9]([CH2:23][CH2:24][CH3:25])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O)cc12
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O[C@@H](C)C(=O)O)cc12

Procedure:
The phenol from Step 6 (0.38 g, 1.0 mmol) and methyl (R)-lactate (0.16 g, 1.5 mmol) was reacted according the general procedure described in Step 11 of Example 1 to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:36]I)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:36][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1cnc(-c2ccc(Cl)cc2)nc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OCC)C1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccccc2OCC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 2-(4-chloro-phenyl)-pyrimidin-5-ol (Preparation 27) and 1-(2-ethoxy-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 16) to afford the racemate as a white solid (238 mg, 83.9%)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:26][NH:27][O:28][CH3:29].C(N(CC)CC)C>ClCCl.O>[CH3:29][O:28][N:27]([CH3:26])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=1
Reactant: CNOC
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a stirred solution of 3-(trifluoromethoxy)benzoic acid (20.0 g, 96.1 mmol) in dichloromethane (200 mL), cooled to 0° C. with a brine/ice bath, was added N,N-dimethylformamide (0.37 mL, 4.8 mmol) followed by oxalyl chloride (10.1 mL, 115 mmol). The resulting mixture was stirred 5 h at room temperature, until gas evolution stopped and a clear solution was obtained. The mixture was cooled to 0° C. with a brine/ice bath, N,O-Dimethylhydroxylamine (9.37 g, 96 mmol) was added at once, followed by dropwise addition of triethylamine (45.5 mL, 326 mmol) through a dropping funnel, while keeping the internal temperature below 10° C. The resulting suspension was diluted with dichloromethane (200 mL), stirred overnight at room temperature, poured into water (400 mL) and the aqueous layer was extracted with dichloromethane (2×150 mL). The organic layers were combined, washed with water (2×200 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified over silica gel to afford N-methoxy-N-methyl-3-(trifluoromethoxy)benzamide as an oil [22.4 g, yield 80%; HPLC/MS:m/z=250 (M+H); log P(HCOOH)=2.41].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:15]#[CH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 44.7 %

Procedure:
To a solution of 10.0 g (54.8 mmol) of tert-butyl-1-piperazine carboxylate in 60 mL acetonitile was added 5.20 mL (60.4 mmol) propargyl bromide and 37.9 g (274 mmol) anhydrous potassium carbonate. Additional propargyl bromide, 1.5 mL, was added after stirring for 36 hours at room temperature. The residue was evaporated to dryness. Dichloromethane, 50 mL, and water, 50 mL, were added. The reaction mixture was extracted with CH2Cl2, 4×40 mL, dried over magnesium sulfate, and evaporate to provide a brown oil. The oil was dissolved in dichloromethane and purify with a RT Scientific system using hexane/ethyl acetate gradient to yield 5.5 g (46%) of yellow oil, which ultimately crystallized upon standing.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]2)[S:15][CH:16]=1.[OH-].[Na+].O>C(O)C.O1CCCC1>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]2)[S:15][CH:16]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3F)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3F)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85226936 %

Procedure:
To a mixed solution of the compound (320 mg, 0.79 nmol) obtained in Example 52a in ethanol/tetrahydrofuran (v/v=1/1, 8 mL) was added 2N aqueous sodium hydroxide solution (1.6 mL, 3.2 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (250 mg, 84%) as colorless crystals.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([NH:27][S:28]([C:31]1[S:32][C:33]([Cl:36])=[CH:34][CH:35]=1)(=[O:30])=[O:29])=[N:9][N:10]2[CH2:15][C:16]1[CH:17]=[C:18]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[CH:19]=[CH:20][CH:21]=1)(=[O:5])[CH3:4].Cl>CO>[Cl:36][C:33]1[S:32][C:31]([S:28]([NH:27][C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[CH:14][C:6]=3[CH:3]([OH:5])[CH3:4])[N:10]([CH2:15][C:16]3[CH:17]=[C:18]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[CH:19]=[CH:20][CH:21]=3)[N:9]=2)(=[O:29])=[O:30])=[CH:35][CH:34]=1
Reactant: CC(=O)NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(C(C)=O)cccc32)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(C(C)O)cccc32)c1
Reaction time: 2 h
Yield: 48 %

Procedure:
Sodium borohydride (3.09 mg, 0.082 mmol) was added to a stirring solution of N-({3-[(4-acetyl-3-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indazol-1-yl)methyl]phenyl}methyl)acetamide (for a preparation see Intermediate 75) (40 mg, 0.068 mmol) in MeOH (2 mL) at 25° C. under nitrogen. The reaction mixture was stirred at room temp. for 2 hours, and then 1N HCl (5 mL) was slowly added and the methanol was evaporated in vacuo. The product was extracted with EtOAc (2×20 mL) and the combined organic layers were dried by passing through a hydrophobic frit and concentrated. The residue was dissolved in DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was evaporated in vacuo to give the title compound (18 mg, 48%). LCMS (System A) RT=0.97 min, ES+ve m/z 519/521 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:27](O)(=O)[CH3:28].C(=O)([O-])O.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:24][CH2:23][CH2:27][CH3:28])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Cl)cc2)cs1
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-[(4-{2-[(4-Chlorophenyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.03 g) synthesized in Example 286-2 and heptylaldehyde (0.34 g) were dissolved in dichloroethane (15 mL), acetic acid (171 μL) and hydrogenated tri(acetoxy)boric acid (0.79 g) were successively added thereto, and the mixture was stirred at room temperature for 2.5 hr. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1) to give the title compound (1.07 g) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C:23](O)=O)[CH:18]=[CH:19][CH:20]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:23]([CH2:22][CH2:21][C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=4)=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: NNC(=O)c1ccc2c(c1)CCO2
Reactant: O=C(O)CCc1cccc(F)c1
Product: Fc1cccc(CCc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Yield: 59 %

Procedure:
In the same manner as in Example 14 and using 2,3-dihydro-1-benzofuran-5-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 3-(3-fluorophenyl)propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 59%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:22])[NH:11][C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(N(C(C)C)C(C)C)C.Cl[C:33]([O:35][CH3:36])=[O:34]>ClC1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[O:14][C:13]1[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[NH:11][C:10](=[O:22])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: COC(=O)Cl
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(C)ccc1C)=C2O
Solvent: Clc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC12CCN(OC)CC2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 200 mg of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one and 0.14 ml of ethyl diisopropyl amine in 2 ml of chlorobenzene is added a solution of 66 mg of methyl chloroformate in 0.5 ml of chlorobenzene at 50° C. After stirring for 1 hour at 50° C., the reaction mixture is cooled to room temperature, diluted with 5 ml of chlorobenzene and washed with cold 5% aqueous sodium hydroxide and water. The organic phase is separated, dried over sodium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel. Yield: 120 mg of carbonic acid 3-(2,5-dimethyl-phenyl)-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester methyl ester. This material is triturated with ethyl acetate/hexane, filtered and dried to afford a solid, mp: 186-188° C.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([NH:25][C:26]([NH2:28])=[O:27])=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)(=[O:15])=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([NH:28][C:26](=[O:27])[NH:25][C:19]1[CH:18]=[CH:17][C:16]([S:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:15])=[O:14])=[CH:21][C:20]=1[N+:22]([O-:24])=[O:23])(=[O:31])[CH3:30]
Reactant: NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
1 ml of concentrated sulfuric acid is added, with stirring, to 50.5 g of 5-phenoxysulfonyl-2-ureidonitrobenzene in 250 ml of acetic anhydride. A clear solution is produced, followed rapidly by precipitation. The mixture is stirred for a further two hours, and the solid is filtered off with suction and washed consecutively with glacial acetic acid and diisopropyl ether, melting point 198° C., decomposition.
Reaction SMILES: C([O-])=O.[NH4+].[CH:5]([N:18]1[CH2:21][CH:20]([O:22][Si](C(C)(C)C)(C)C)[CH2:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14]C=1)C1C=CC=CC=1.FC1C=CC([N+:37]([O-:39])=[O:38])=CC=1>CO.N1C=CC=CC=1.[Pd]>[N+:37]([C:16]1[CH:17]=[CH:12][C:5]([N:18]2[CH2:19][CH:20]([OH:22])[CH2:21]2)=[CH:14][CH:15]=1)([O-:39])=[O:38]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
Ammonium formate (15.1 g, 246 mmol) was added to a solution of 1-benzhydryl-3-(tert-butyl-dimethyl-silanyloxy)-azetidine (which was obtained in Example 395) (8.7 g, 24.6 mmol) and 10%Pd/C (1 g) in methanol (100 mL). The reaction was stirred for 3 hours at room temperature. The solution was passed through celite and concentrated to afford a crude solid. The crude solid was taken up in pyridine (75 mL) and the salts were removed by filtration. 4-Fluoronitrobenzene (2.9 mL, 27.1 mmol) was added to the above solution and the reaction was stirred at reflux overnight. Pyridine was removed by vacuum distillation and the resultant crude was treated with water (100 mL), followed by extraction with ethyl acetate (3×25 mL). The organic layers were combined, dried (Na2SO4), filtered, and passed through a plug of silica. The solvent was evaporated and triturated with hexanes to give 3.91 g of the desired product as red solid; 1H NMR (300 MHz, CDCl3) δ 1.62 (s, 1H), 3.89(m, 2H), 4.31 (m, 2H), 4.87 (m, 1H), 6.31 (d, 2H, J=7.14), 8.09 (d, 2H, J=7.14 Hz); MS (ES) m/z: 194.8 (MH+); Anal. Calcd. for C9H10N2O3: C, 55.67; H, 5.19; N, 14.43. Found: C, 55.67; H, 5.05; N, 14.59.