Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])/[C:3](/[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:16][CH:15]=1)=[CH:4]\[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:6].[NH4+:30].[OH-]>CS(C)=O.CCOC(C)=O>[NH2:30][C@@:3]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[CH:16][CH:15]=1)([C:2]([F:28])([F:29])[F:1])[CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:6]
Reactant: [NH4+]
Reactant: Cc1ccc(C(=O)/C=C(/c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)C[C@](N)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Reaction time: 48 h
Yield: 101 %

Procedure:
To a solution of Intermediate 2E (2.1 g, 5.04 mmol) in DMSO (50 mL) was added 15 N aq NH4OH (25 mL). The mixture was stirred in sealed pressure vessel for 2 days. The reaction was diluted with EtOAc (60 mL), washed with water and sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography column (eluted with EtOAc in hexanes to provide racemic Intermediate 2F (2.2 g, 101%) as a white solid. LCMS Anal. Calc'd for C21H21F6NO2 433.39, found [M+H] 434.2. Separation of the individual enantiomers of Intermediate 2F was carried out using preparative chiral SFC method A: Racemic Intermediate 2F (2200 mg) provided Intermediate 2F, isomer 1 (817 mg) and Intermediate 2F, isomer 2 (790 mg). Enantiomeric purity determination of Intermediate 2F, isomer 1 and 2 was carried out using analytical SFC method A. Intermediate 2F, isomer 1: RT=2.2 min, 99% ee. Intermediate 2F, isomer 2: RT=2.8 min, 99% ee. X-ray crystal data collected for the camphorsulfonic acid salt of Intermediate 2F, isomer 1 showed the chiral center to have the R-configuration; therefore, the chiral center for Intermediate 2F, isomer 2 has the S-configuration.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=O)[N:16]=1)=[CH:8]2.[N:30]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][CH2:18][C:19]([NH2:30])=[O:21])[N:16]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(-c3nc(CCC(=O)O)cs3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(-c3nc(CCC(N)=O)cs3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-4-yl)propanoic acid (0.11 g), 1H-1,2,3-benzotriazol-1-ol (40 mg) and N,N-dimethylformamide (6 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (57 mg) at room temperature. The mixture was stirred for 20 min, and 28% aqueous ammonia (0.08 mL) was added. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.04 g, yield 36%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (4:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 200-201° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C@H:9]([CH2:17]C)[CH2:10][CH:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:4]([O:6][CH2:7][CH3:8])=[O:5].CCN(C(C)C)C(C)C.[O:28](C(OC(C)(C)C)=O)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=O>C(Cl)Cl>[C:32]([O:31][C:29]([NH:2][CH:3]([C@H:9]([CH3:17])[CH2:10][CH:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:28])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=CCCC(C)C[C@@H](CC)C(N)C(=O)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A solution of (3R)-ethyl 2-amino-3-ethyl-5-methylnon-8-enoate hydrochloride (2.99 g, 10.77 mmole) in DCM (20 mL) was added DIPEA (1.08 mL, 10.77 mmole) followed by (BOC)2O (2.39 mL, 10.77 mmole) at room temperature. The reaction mass was stirred at room temperature for overnight. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by column chromotography (Silica gel, 20% ethyl acetate in pet-ether) to get 2.3 g, (62.5%) of (3R)-ethyl 2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoate as an oily liquid. MS: MS m/z 342.4 (M++1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([C:22]([OH:29])([CH2:27][CH3:28])[C:23](OC)=[O:24])[CH:18]=[C:19]([F:21])[CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(OCC)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([C:22]([OH:29])([CH2:27][CH3:28])[CH2:23][OH:24])[CH:18]=[C:19]([F:21])[CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCC(O)(C(=O)OC)c1cc(F)cc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCC(O)(CO)c1cc(F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium aluminium hydride (0.345 g) was added to a solution of the ester so obtained in diethyl ether (70 ml) and the mixture was stirred at ambient temperature for 1 hour. Water (10 ml) was added dropwise and the mixture was filtered. The organic layer was dried (MgSO4) and evaporated to give (-)-2-(3-benzyloxy-5-fluorophenyl)butane-1,2-diol (2.2 g), as an oil.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:32]C(=O)C)([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:7][O:8]C(=O)C)(=O)C.[Li+].[OH-]>C1COCC1.O>[NH2:32][C:6]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([CH2:7][OH:8])[CH2:5][OH:4]
Reactant: CCCCCCc1ccc(-c2ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1ccc(-c2ccc(CCC(N)(CO)CO)cc2)cc1

Procedure:
Acetic acid 2-acetoxymethyl-2-acetylamino-4-(4′-hexyl-biphenyl-4-yl)-butyl ester (0.2 mmol) is dissolved in THF (1 mL) and treated with 2 N LiOH aqueous solution (0.5 mL). The resulting mixture is stirred at reflux for 1 h and diluted with H2O (10 mL). It is then extracted with EtOAc (3×5 mL) and the combined organic phase is washed with brine and dried over Na2SO4. After concentrating, the crude product is purified with LC-MS to give the desired product as a white solid. MS: (ES+): 356.2 (M+1)+.
Reaction SMILES: CO.C(B(CC)CC)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([CH:44]([CH3:46])[CH3:45])[N:20](/[CH:29]=[CH:30]/[C@@H:31]([OH:43])[CH2:32][C:33](=[O:42])[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1.[BH4-].[Na+]>C1COCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([CH:44]([CH3:46])[CH3:45])[N:20](/[CH:29]=[CH:30]/[C@@H:31]([OH:43])[CH2:32][C@@H:33]([OH:42])[CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:21]=2[C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[CH:13][CH:12]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)CC(=O)CC(=O)OC(C)(C)C
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Yield: 99.7 %

Procedure:
A solution of dry THF (16 ml) and dry methanol (4 ml) under nitrogen at room temperature was treated with a solution of triethyl borane (1.0M in THF, 2.32 ml). After 1 h the mixture was cooled to -78° and treated with a solution of 1,1-dimethyleth-1-yl (5S,E)-7-[4,5-bis-(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-5-hydroxy-3-oxo-6-heptenoate (1.075 g) in THF (4:1) (15 ml) plus washings (5 ml). After a further 1 h at -75° the mixture was treated with sodium borohydride (88 mg). After 21/2 h the mixture was quenched with saturated aqueous ammonium chloride solution (2 ml) and allowed to warm. The mixture was then diluted with water (100 ml) and extracted with ethyl acetate (3×70 ml). The combined extracts were dried and evaporated and the residue was azeotroped with methanol (3×30 ml). This gave a pale yellow solid (1.076 g) which was crystallised from ether-cyclohexane to give the title compound (739 mg) as white fluffy crystals, δ(CDCl3) 1.3-1.65 (m, 2H, CH(OH)CH2CH(OH)), 1.40 (d, J 7 Hz, 6H, --CH(CH3)2), 1.46 (s, 9H, --C(CH3)3), 2.35 (d, J 7 Hz, 2H, CH2CO2R), 3.15 (septet, J 7 Hz, 1H, --CH(CH3)2), 3.77, 3.81 (2s, 2H, CH(OH)CH2CH(OH), 4.12 (m, 1H, CH(OH)CH2CO2), 4.42 (m, 1H, =CHCH(OH)CH2 --), 5.30 (dd, J 14 and 7 Hz, 1H, N--CH=CH--), 6.67 (d, J 14 Hz, 1H, N--CH=CH--), 6.90 and 7.09 (2t, J 9 Hz each 2H, C-3 and C-5 protons of 4-fluorophenyls), 7.2-7.43 (m, 4H, C-2 and C-6 protons of 4-fluorophenyls).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][N:17]([CH3:42])[C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:38][CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34](O)[CH:35]=4)[C:30]3=[O:40])=[CH:25][C:24]=2[F:41])[CH2:19]1.N1C=CC=CC=1>ClCCl>[CH3:16][N:17]([CH3:42])[C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:38][CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:35]=4)[C:30]3=[O:40])=[CH:25][C:24]=2[F:41])[CH2:19]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2F)C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(OS(=O)(=O)C(F)(F)F)ccc4C3=O)cc2F)C1
Reaction time: 0.5 h

Procedure:
Trifluoromethanesulfonic anhydride (2.06 g) was added to a solution of 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (1.5 g) and pyridine (0.64 g) in dichloromethane (40 mL) at 0° C. After 30 minutes, the mixture was partitioned between water and dichloromethane, and the organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 501.50 (C22H23F4N3O4S) was obtained in this way; MS (ESI): 502 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH:25][C:26](=[O:28])[CH3:27])[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH:12]([NH:17]C(OC(C)(C)C)=O)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]=1)[CH3:2].[ClH:30]>O1CCOCC1>[ClH:30].[CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH:25][C:26](=[O:28])[CH3:27])[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH:12]([NH2:17])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1)NC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1cc(C(N)CC(C)C)no1)NC(C)=O
Yield: 100 %

Procedure:
2-Acetylamino-3-[3-(1-tert-butoxycarbonylamino-3-methyl-butyl)-isoxazol-5-yl]-propionic acid ethyl ester (7F) (5.95 g, 14.5 mmol) was stirred in 4N hydrochloric acid in dioxane (25 mL) at room temperature overnight. The product was concentrated and dried under high vacuum to give the title compound as a white solid (5.38 g, 100%). MS (CI) m/z 312.2 (M+1 for the free base).
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Tl+].[Cl:9][CH2:10][CH2:11][S:12](Cl)=[O:13]>CCOCC>[Cl:9][CH2:10][CH2:11][S:12]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=S(Cl)CCCl
Reactant: [O-]c1ccccc1
Agent: [Tl+]
Solvent: CCOCC
Product: O=S(CCCl)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of thallium (I) phenoxide (28.6 w) in dry ether (100 v) was rapidly treated with 2-chloroethanesulfinyl chloride, prepared as in Example I. The slurry was vigorously stirred for 1 hour at ambient temperature with exclusion of moisture. Removal of thallium(I) chloride by filtration and evaporation of the etheral filtrate solution gave an oil. The oil was then subjected to molecular distillation in a wiped-film apparatus at 70-75° (1 ×10-4 torr) to give phenyl 2-chloroethanesulfinate (122 w) as a mobile liquid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[S:31])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].I[CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH2:33][CH2:34][CH2:35][CH3:36])=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCCI
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCSC1=NC(c2ccc(C#N)cc2)C(C(=O)OCC)=C(C)N1c1cccc(C(F)(F)F)c1

Procedure:
Ethyl 4-(4-cyanophenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0.22 mmol), 1-iodobutane (45.0 mg, 0.25 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) are dissolved in 3 ml acetone and tired at room temperature overnight. The solvent is removed in vacuo and the product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])=[O:5])[CH3:2].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]O)[CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:37][C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1)=[O:15])=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)O
Reactant: OCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1cccnc1

Procedure:
The solution of 2.37 g of N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid, 0.61 g of 3-pyridylcarbinol and 1.15 g of dicyclohexylcarbodiimide in 25 ml of methylene chloride is stirred at room temperature for two days. The solid is removed, and the filtrate is diluted with 150 ml of ether and extracted with 0.5N hydrochloric acid. The acidic aqueous layer is separated, basified and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate, filtered, concentrated and flash chromatographed on silica gel eluting with ethyl acetate:ethanol (9:1) to yield 3-pyridylmethyl N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionate as an oil; NMR (CDCl3) δ 8.70 (m, 2H), 7.77 (m, 1H), 7.28 (m, 11H), 5.56 (t, 1H, J=7 Hz), 5.12 (s, 2H), 4.03 (q, 2H, J=8 Hz), 1.08 (t, 3H, J=8 Hz).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([S:15][C:16]3[CH:36]=[CH:35][C:19]4[N:20]=[C:21]([NH:23][C:24]([NH:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:25])[S:22][C:18]=4[CH:17]=3)=[N:13][N:14]=2)[N:11]=1)[CH3:4]>C(O)C>[CH2:3]([O:5][C:6]1[CH2:7][CH2:8][C:9]2[N:10]([C:12]([S:15][C:16]3[CH:36]=[CH:35][C:19]4[N:20]=[C:21]([NH:23][C:24]([NH:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)=[O:25])[S:22][C:18]=4[CH:17]=3)=[N:13][N:14]=2)[N:11]=1)[CH3:4]
Reactant: CCOc1ccc2nnc(Sc3ccc4nc(NC(=O)NCCN5CCOCC5)sc4c3)n2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC1=Nn2c(nnc2Sc2ccc3nc(NC(=O)NCCN4CCOCC4)sc3c2)CC1
Yield: 40.1 %

Procedure:
27 mg of sodium borohydride are added to a mixture of 179 mg of 1-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea in 10 cm3 of ethanol. The reaction is refluxed for 3.5 h, and then 108 mg of sodium borohydride are added gradually and the reflux is maintained for 48 h. The reaction mixture is concentrated to dryness under reduced pressure. The residue is purified by chromatography on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 mM), elution being carried out with a dichloromethane/methanol gradient of 99/1 to 93/7. 72 mg of 1-{6-[(6-ethoxy-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]#[N:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:19][OH:20]>>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:19][OH:20])[NH2:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C#N
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethylthiophene-2-carbonitrile (0.93 g, 3.3 mmol) that was obtained in Example 10 (10c) and a 40% aqueous solution of hydroxylamine (0.5 mL)). Subsequently, the crude product of the title compound thus obtained was purified by recrystallization from hexane (6:4) to afford the title compound (0.60 g) in a yield of 60% as a white crystalline solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[O:8][N:7]=1)(=O)=O)[CH3:2].[SH-].[Na+].C(=O)([O-])[O-].[K+].[K+].BrCC1[C:24]([C:33]([F:36])([F:35])[F:34])=[N:25][N:26]([CH3:32])[C:27]=1[O:28][CH:29]([F:31])[F:30]>CN(C)C=O.O>[F:31][CH:29]([F:30])[O:28][C:27]1[N:26]([CH3:32])[N:25]=[C:24]([C:33]([F:34])([F:35])[F:36])[C:2]=1[CH2:1][S:3][C:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[O:8][N:7]=1
Reactant: Cn1nc(C(F)(F)F)c(CBr)c1OC(F)F
Reactant: CCS(=O)(=O)C1=NOC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1OC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 6.7 g (35.0 mmol) of 3-ethanesulfonyl-5,5-dimethyl-2-isoxazoline in 50 ml of N,N-dimethylformamide was added 5.6 g (purity: 70%, 70.0 mmol) of sodium hydrosulfide, followed by 1 hour of stirring at room temperature. Thereafter, 4.8 g (35.0 mmol) of potassium carbonate and 10.8 g (35.0 mmol) of 4-bromomethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole were added thereto, followed by stirring at room temperature overnight. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 7.3 g (yield: 57.9%) of 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as white crystals (melting point: 39 to 40° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[CH3:18][NH:19][C:20]1[N:25]=[C:24]([C:26]2[C:27]([O:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CO>[CH3:18][NH:19][C:20]1[N:25]=[C:24]([C:26]2[C:27]([O:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:4][N:3]=4)=[CH:37][CH:38]=3)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(Oc3nnc(-c4ccccc4)c4ccccc34)cc2)n1

Procedure:
A mixture of 1-chloro-4-phenylphthalazine (0.0900 g, 0.374 mmol), 4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenol (0.110 g, 0.374 mmol), and potassium carbonate (0.129 g, 0.934 mmol) in 1 mL DMSO was heated in a sealed tube for 1 h. Upon cooling, a white precipitate formed. The material was partitioned between water and DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give a crude solid, which was suspended in MeOH, sonicated, filtered and dried to give N-methyl-4-(2-(4-(4-phenylphthalazin-1-yloxy)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a white solid. MS m/z=499 [M+H]+. Calc'd for C30H22N6O2: 498.5.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.Cl.[CH2:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])[CH:11]([CH3:13])[CH3:12]>>[CH2:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH3:8])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: CCC(C)CC(=O)O
Agent: Cl
Product: CCC(C)CC(=O)N[C@@H](C)C(=O)OCC(C)C

Procedure:
Following General Procedure BB and using 3-methylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[C:22]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccnc1N
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: COc1cccnc1NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 3-methoxypyridine-2-amine as the starting materials.