Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])[C:3]1[CH:4]=[C:5]([O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)[CH2:15][N:16]=1)=[CH:8]2.O.[OH:39]OS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.C(O)C.C(OCC)(=O)C>[CH3:1][N:2]([S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])[C:3]1[CH:4]=[C:5]([O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:39])[CH2:20][CH2:19]3)[CH2:15][N:16]=1)=[CH:8]2
Reactant: O=S([O-])OO
Reactant: CN(c1cc(OCC(N)=O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cc(OCC(N)=O)cc2cc(C3=NCC(CN4CCS(=O)CC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
To a solution of 2-({7-[methyl(pyridin-2-ylsulfonyl)amino]-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-5-yl}oxy)acetamide (31.7 mg) in tetrahydrofuran (1 mL) and ethanol (1 mL) were added water (1 mL) and OXONE (registered trade mark, 20 mg), and the mixture was stirred at room temperature for 3 hr. Aqueous sodium thiosulfate solution was added, and the mixture diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (15.7 mg, yield 48%) as colorless crystals. melting point 160-161° C.
Reaction SMILES: C([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[Li+].[OH-]>C1COCC1>[C:9]1([CH2:8][CH2:7]/[CH:6]=[CH:5]/[C:4]([OH:15])=[O:3])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C=C/CCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C/CCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of the intermediate 32.1 from above in 1:1 aqueous 1 N LiOH:THF (250 mL) was refluxed for 18 h. It was then cooled to room temperature and washed with ethylacetate (2×200 mL). The aqueous was acidified to pH2 by the addition of conc. HCl, and extracted with ethylacetate (3×200 mL). These last organic extracts were combined, dried r with MgSO4 and concentrated to afford the intermediate trans-5-phenyl-2-pentenoic acid (32.2).
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.O.NN>>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN)CC1
Yield: 63.9 %

Procedure:
4-Amino-5-chloro-N-(1-(3-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)propyl)piperidin-4-ylmethyl)-2-methoxybenzamide (7.7 g) as starting compound and hydrazine monohydrate (0.76 ml) were reacted and treated in the same manner as in Example 117 to give 3.6 g of 4-amino-N-(1-(3-aminopropyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][CH:13]([OH:16])[CH2:12][S:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][C:13](=[O:16])[CH2:12][S:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CSC(COCc2ccccc2)CO1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: O=C1CSC(COCc2ccccc2)CO1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 102.3 %

Procedure:
5-Benzyloxymethyl-1,4-oxathian-2-ol (3.42 g) was dissolved in dried methylene chloride (60 ml), and the solution cooled to -78° C. A solution 1.0M diisobutyl aluminum hydride (21.5 ml) was added dropwise thereto for 20 minutes, and the resultant mixture stirred at the same temperature for 30 minutes to complete the reaction. To the reaction mixture, methanol (0.6 ml), saturated sodium sulfate solution (9 ml) and sodium sulfate (4.4 g) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. The residue obtained by concentrating the reaction mixture was extracted with ethyl ether until the product could not be extracted any more with the same solvent. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, to obtain the desired product (3.47 g) as pale yellow semi-solid.
Reaction SMILES: Cl[C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[CH:22][CH:21]=3)=[O:19])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:33]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[F-].[K+].CB(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[O:31]=[S:27]1(=[O:32])[CH2:28][CH2:29][CH2:30][N:26]1[C:23]1[CH:24]=[CH:25][C:20]([C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:3]3[C:2]([CH3:33])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=3)[CH2:13][CH2:14]2)=[O:19])=[CH:21][CH:22]=1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: O=C(c1ccc(N2CCCS2(=O)=O)cc1)N1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2)CC1
Yield: 173.9 %

Procedure:
Under a nitrogen stream, to a mixture of [4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]methanone (150 mg) described in Preparation Example 194, palladium(II) acetate (6.8 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (25.2 mg), potassium fluoride (141.2 mg) and methylboronic acid (73.6 mg) was added tetrahydrofuran (1.5 mL), and the mixture was stirred with heating under reflux for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (50 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:27][C:28]([OH:32])([C:30]#[CH:31])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C(NC(C)C)(C)C.[Cu](I)I>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:31]#[C:30][C:28]([OH:32])([CH3:29])[CH3:27])[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3cccc(I)c3)n2)s1
Reactant: C#CC(C)(C)O
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1cccc(Nc2nccc(-c3sc(N)nc3-c3ccccc3)n2)c1

Procedure:
A suspension of N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-iodo-phenyl)-amine (300 mg, 0.64 mmol) and 2-methyl-3-butyn-2-ol (110 mg, 1.3 mmol) in dimethylformamide (20 ml) and diisopropylamine (5 ml) are stirred in the presence of bis triphenylphosphine palladiumdichloride (20 mg), triphenylphosphine (20 mg) and copper iodide under a nitrogen atmosphere for 16 hours. After an aqueous work-up the residue is purified by chromatography (eluent: 1:2 mixture of ethyl acetate/hexane) to give the N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-[3-(3-hydroxy-3-methyl-1-butynyl)-phenyl]-amine, m.p. 262–263° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Br[CH2:13][CH2:14][CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])[CH2:14][CH2:15][CH3:16]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with 4-bromo-butane in DMF using K2CO3 as base. MS (ISP): 209.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[NH2:10][C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1.O>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:10][C:11]1[C:16]([O:17][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Nc1ncccc1O
Reactant: Fc1ccccc1CCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1ncccc1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
A mixture of 2-fluorobenzyl chloride (50 g, 0.346 mol) and 2-amino-3-hydroxypyridine (39 g, 0.3 15 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. A further 200 ml of water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to obtain the product (54.9 g, 80%), m.p. 85°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:62]([CH3:64])[CH3:63])[C:7]([N:9]1[CH2:13][C@@H:12]([CH2:14][O:15][CH3:16])[CH2:11][C@H:10]1[C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[NH:38][C:37]([C@@H:39]5[CH2:43][C@H:42]([CH3:44])[CH2:41][N:40]5[C:45](=[O:61])[C@H:46]([NH:53][C:54](=O)[O:55]C(C)(C)C)[C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)=[N:36][CH:35]=4)=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:8])=[O:4].Cl.[CH:66]1(C(O)=O)[CH2:68][CH2:67]1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CCOC(C)=O.CN(C=O)C.CO>[CH:66]1([C:54]([NH:53][C@H:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:45]([N:40]2[CH2:41][C@@H:42]([CH3:44])[CH2:43][C@H:39]2[C:37]2[NH:38][C:34]([C:31]3[CH:32]=[CH:33][C:28]([C:25]4[CH:24]=[CH:23][C:22]([C:19]5[NH:18][C:17]([C@@H:10]6[CH2:11][C@H:12]([CH2:14][O:15][CH3:16])[CH2:13][N:9]6[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:62]([CH3:64])[CH3:63])=[N:21][CH:20]=5)=[CH:27][CH:26]=4)=[CH:29][CH:30]=3)=[CH:35][N:36]=2)=[O:61])=[O:55])[CH2:68][CH2:67]1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6C[C@H](C)CN6C(=O)[C@H](NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reactant: O=C(O)C1CC1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6C[C@H](C)CN6C(=O)[C@H](NC(=O)C6CC6)c6ccccc6)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
Tert-butyl (R)-2-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (296 mg, 0.33 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4 M in dioxane, 1 mL) was added. The reaction mixture was stirred over night and then concentrated under reduced pressure. The crude residue was treated with cyclopropanecarboxylic acid (38 μL, 0.28 mmol), COMU (162 mg, 0.34 mmol) and DMF (4 mL), then DIPEA (0.29 mL, 1.65 mmol) was added dropwise. After 30 min, the mixture was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl (S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (68 mg, 24%). LCMS-ESI+: calculated for C48H56N8O6: 840.43; observed [M+1]+: 842.14.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([O:10][CH:8]2[CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]3[S:13][CH:12]=[CH:11][C:7]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CCN1CCc2sccc2C(O)C1
Product: CCN1CCc2sccc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 6-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 45) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:22][CH2:21][C:5]2([C:9](=[O:10])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].C(=O)(O)[O-].[Na+]>ClCCl.O.Cl[O-].[Na+]>[CH:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:21][CH2:22][C:2](=[O:1])[CH2:3][CH2:4]3)[C:9]2=[O:10])=[CH:12][CH:13]=1)([CH3:20])[CH3:19]
Reactant: CC(C)Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CC(C)Oc1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a solution of 8-hydroxy-2-(4-isopropoxy-phenyl)-2-aza-spiro[4.5]decan-1-one (7 g) and 2,2,6,6-tetramethylpiperidine-1-oxyl (721 mg) in dichloromethane (250 ml) were added sequentially a solution of potassium bromide (549 mg) in water (60 ml), sodium hypochlorite (52.8 ml), sodium bicarbonate (5.81 g) and the reaction mixture was then stirred for 3 hour at RT. The reaction mixture was poured into ice/water and extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated off. The residue was purified by flash chromatography (silica gel, gradient 0% to 50% ethyl acetate in heptane) to give the title compound as a brown solid (5 g). MS (m/e): 302.174 [MH+].
Reaction SMILES: [NH:1]1[C:5]2(CCCCC2)[CH:4]=CS1(=O)=O.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22](=[O:33])(=[O:32])[NH:23][C:24]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:25]=2[CH3:26])=[CH:17][CH:16]=1.C(N)C>C(O)C>[CH2:5]([NH:1][CH2:26][C:25]1[C:24]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[NH:23][S:22](=[O:33])(=[O:32])[C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=1)[CH3:4]
Reactant: CC1=C(c2ccc(CBr)cc2)S(=O)(=O)NC12CCCCC2
Reactant: O=S1(=O)C=CC2(CCCCC2)N1
Agent: CCN
Solvent: CCO
Product: CCNCC1=C(c2ccc(C)cc2)S(=O)(=O)NC12CCCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Ethylaminomethyl-3-(4-methylphenyl)-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide, shown below, was prepared according to the methods described in Examples 1 and 2. Bromination with N-bromosuccinimide afforded a mixture of 4-bromomethyl-3-4-methylphenyl)-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide and 3-(4-bromomethyl-phenyl)-4-methyl-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide. The raw mixture (400 mg) was dissolved in ethanol (10 mL) and ethylamine (70% in water, 5 mL) was added. The solution was stirred overnight at room temperature, concentrated and the residue was dissolved in CH2Cl2, washed with water and extracted with 0.5 M HCl. After addition of NaOH and extraction with CH2Cl2 the organic layer was dried (Na2SO4) and evaporated. The two products were separated by column chromatography (CH2Cl2/acetone 9:1) and the title compound compound [4-Ethylaminomethyl-3-(4-methylphenyl)-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide] was isolated as white crystals. Yield: 80 mg, 24%; MS (IS): 334 [MH]+.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:32]([O:36][C:37]([N:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[C:48]([CH:49]=[O:50])[C:43]=2[O:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C1COCC1>[C:32]([O:36][C:37]([N:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[C:48]([CH:49]([C:2]3[C:7]([N:8]([S:9]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=4)(=[O:11])=[O:10])[CH2:23][O:24][CH3:25])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=3)[OH:50])[C:43]=2[O:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(C=O)cccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1cccc2c1OCCN2C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (2.92 g, 6.18 mmol) in THF (12 mL) under nitrogen atmosphere at −20° C. was added isopropylmagnesium chloride (2 M solution in THF, 6.5 mL, 13.0 mmol) via dropwise addition. The mixture was then stirred for 1 hour at 0° C. followed by the addition of a solution of 8-formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (273.5 mg, 1.54 mmol) in THF (2 mL) at −20° C. The mixture was stirred at room temperature overnight, quenched with saturated aqueous NH4Cl solution (5 mL), and extracted with EtOAc (2×200 mL). The combined organic extracts were washed with saturated aqueous NH4Cl solution (40 mL) and brine (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (10% EtOAc-hexanes to 90% EtOAc-hexanes) to obtain 8-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (590.2 mg) as yellow syrup. MS m/z: 678.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH2:1]([O:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCBr
Reactant: O=C1NCCN1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCN1CCN(OCc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred solution of this imidazolidinone (4.0 g, 20.8 mmol) in DMF (50 ml) under nitrogen at 50° C. was added sodium hydride (1.0 g of a 60% dispersion in oil). A thick slurry formed at once. After 30 minutes, 1-bromopentane (2.84 ml) was added. After 15 minutes, the resulting clear solution was evaporated, and the residue was partitioned between ether and water. The organic extract was washed with water and brine, then dried (MgSO4), filtered, and evaporated. Purification by chromatography on silica provided 3-benzyloxy-1-pentyl-2-imidazolidinone as a colorless oil (4.15 g, 83% yield). Hydrogenolysis as in Example 2 above provided the title compound, after purification by chromatography on silica, as a white solid, mp 60°-61° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]1([CH3:20])[C:16]2([CH2:18][CH2:17]2)[CH2:15][O:14][C:13]([NH2:19])=[N:12]1>C(O)C.CCN(CC)CC.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:11]2([CH3:20])[C:16]3([CH2:17][CH2:18]3)[CH2:15][O:14][C:13]([NH2:19])=[N:12]2)[CH:4]=1
Reactant: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)OCC12CC2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC12CC2
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Intermediate Fa3 (R1,2=cyclopropyl, R3=Me): A suspension of (S)-8-(2-fluoro-5-nitro-phenyl)-8-methyl-5-oxa-7-aza-spiro[2.5]oct-6-en-6-ylamine (279 mg) in ethyl alcohol (25 ml), NEt3 (0.10 ml) and Pd/C (10%, 50 mg) was hydrogenated at normal pressure and 22° C. for 1 h. The mixture was filtered, the filtrate evaporated and the residue triturated with ether to give (S)-8-(5-amino-2-fluoro-phenyl)-8-methyl-5-oxa-7-aza-spiro[2.5]oct-6-en-6-ylamine (213 mg) as a pale yellow solid. MS (ESI): m/z=250.1 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=2[F:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:14][C:8]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: Fc1cccc(-c2csc(Br)n2)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(F)c3F)cs2)CC1
Yield: 45.1 %

Procedure:
A solution of 2-bromo-4-(2,3-difluorophenyl)-1,3-thiazole (6.74 g, 24.4 mmol), tert-butyl piperazine-1-carboxylate (9.09 g, 48.4 mmol) and potassium carbonate (3.37 g, 24.4 mmol) in dimethylformamide (80 ml) was stirred at 120° C. for 13 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and crystals were collected by filtration to give 4.20 g (45.1%) of the desired product as a solid.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.F[C:21]1[CH:33]=[CH:32][C:24]([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:22]=1.[H-].[Na+].O>CS(C)=O>[C:4]1(=[O:14])[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]=[CH:11][N:12]([C:21]3[CH:33]=[CH:32][C:24]([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:22]=3)[CH:13]=2)[C:1](=[O:19])[C:2]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCCc1c[nH]cn1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCC(=O)c1ccc(-n2cnc(CCCN3C(=O)c4ccccc4C3=O)c2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5.10 g (20 mmol) of 4-(3-phthalimidopropyl)-imidazole followed by 3.92 g (20 mmol) of 3-(4-fluorobenzoyl)-propionic acid are added portionwise to a suspension of 1.20 g (40 mmol) of sodium hydride (80% on paraffin oil) in 50 ml of dimethyl sulphoxide. The reaction mixture is initially stirred at room temperature until gas evolution ceases and then at 100° C. for 17 hours. After cooling, the mixture is poured out on 50 ml of water and extracted with 3×50 ml dichloromethane. The aqueous phase is then adjusted to pH 5 with 2N hydrochloric acid and the precipitated solid is suction filtered and recrystallized from methanol.