Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:12]=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.O>[Br:29][C:8]1[S:9][C:10]2[N:11]=[CH:12][N:13]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:14](=[O:16])[C:15]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1c2c(-c3ccccc3)csc2ncn1CC(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(-c3ccccc3)c(Br)sc2ncn1CC(F)(F)F
Temperature: 80 °C
Yield: 91.6 %

Procedure:
A mixture of 5-phenyl-3-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one (0.4 g, 1.29 mmol) and NBS (0.459 g, 2.58 mmol) in DMF (5 ml) was heated at 80° C. for 2 h. The reaction mixture was diluted with water (40 ml) and extracted with DCM (3×25 ml). The combined organic phases were washed with water (3×45 ml) and brine (30 ml), dried and concentrated to give the title compound (0.46 g, 91%). LCMS RT=1.46 min, M+H+=390.9/392.9.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[Br:24]Br.[OH-].[Na+]>CC(O)=O>[Br:24][C:3]1[C:4]([CH3:23])=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:6][C:2]=1[Br:1]
Reactant: BrBr
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)c(Br)c3C)c(C)nc12
Temperature: 110 °C
Yield: 55.3 %

Procedure:
To a solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (4.00 g, 10.20 mmol) and AcOH (40 mL) is added Br2 (0.57 mL, 11.21 mmol) and the solution heated at 110° C. overnight. Br2 (0.57 mL, 11.21 mmol) is added and the solution heated at 110° C. for 2 hours. The solution is poured into 5 M NaOH (200 mL) and ice (200 mL). The slurry is extracted with EtOAc (2×150 mL). The combined organic layers are washed with water (200 mL), 20% NaHSO3 (200 mL), sat. NaHCO3 (200 mL) dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (5%-15% EtOAc gradient) furnish the title compound (2.66 g, 5.64 mmol, 55%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.72-1.91 (m, 4H), 2.12 (s, 3H), 2.43 (s, 3H), 2.50 (s, 3H), 3.25-3.35 (m, 1H), 6.69 (s, 1H). LC/MS (m/z): calcd. for C18H21Br2N3S (M+H)+: 470.0; found: 470.3.
Reaction SMILES: [C:1]([S:5][C:6]1[N:11]=[C:10]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[C:1]([S:5]([C:6]1[N:11]=[C:10]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[CH:9]=[CH:8][CH:7]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Sc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)S(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
2-[6-(tert-Butylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.15 g, 0.46 mmol) was dissolved in chloroform (30 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.10 g, 0.46 mmol) in chloroform (10 ml) was added dropwise thereto. The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.12 g, 75%) as white crystals.
Reaction SMILES: C1[CH:6]=[C:5](Cl)[CH:4]=[C:3]([C:8]([O:10]O)=O)C=1.[C:12]([O:17]C(CC=C)C)(=[O:16])[C:13]([CH3:15])=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:12]([O:17][CH:5]([CH2:4][CH:3]1[O:10][CH2:8]1)[CH3:6])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(C)OC(=O)C(=C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OC(C)CC1CO1
Temperature: 23 °C
Reaction time: 6 h
Yield: 61.5 %

Procedure:
A solution of m-CPBA (32 g) in chloroform (150 ml) was cooled in cold water and then 4-penten-2-yl methacrylate (14 g) was added. The mixture was stirred at 23° C. for 6 hours. The post-reaction mixture was then poured into dilute potassium carbonate (300 ml) and the organic layer was separated. The organic layer was washed with three more portions of carbonate, finally with water and then dried. Remaining solvents were then removed and the residue was subjected to chromatography on silica gel. As a result pure 4,5-epoxypent-2-yl methacrylate (9.5 g) was isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1N.N(OC(C)(C)C)=O.[I:21]I>C(Cl)Cl>[I:21][C:4]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: II
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: COc1ccc(C(F)(F)F)cc1I
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-methoxy-5-(trifluoromethyl)aniline (500 mg, 2.62 mmol) in CH2Cl2 (10 mL) was added t-butyl nitrite (467 μL, 3.93 mmol). The reaction was stirred for 5 min prior to addition of iodine (1.3 g, 5.24 mmol), and then heated at 70° C. for 2 h. The reaction was cooled, diluted with CH2Cl2 (10 mL), washed with sat. Na2S2O3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (hexanes) to afford 2-iodo-1-methoxy-4-(trifluoromethyl)benzene as a light yellow solid. 1H NMR (CDCl3, 500 MHz): δ 8.05 (d, J=2 Hz, 1H), 7.61 (dd, J=8.7, 1.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NC1CCCCC1
Reactant: CC1(C)CN(Cc2ccccn2)c2ccc(O)cc21
Product: CC1(C)CN(Cc2ccccn2)c2ccc(OC(=O)NC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-(2-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (15.4 mg, 52%) having the following characteristics.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br.O>C1COCC1>[CH3:14][O:15][C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][S:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:25]
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1CSc1ccc(CC(=O)O)cc1
Reaction time: 0.5 h
Yield: 12 %

Procedure:
4-Mercaptophenylacetic acid (995 mg, 5.915 mmol) in THF (15 ml) was cooled in an ice-bath and sodium hydride (55-65%, 520 mg, ˜13 mmol) was added. The mixture was stirred for 30 minutes and then 2-bromomethyl-benzoic acid methyl ester (1.49 g, 6.507 mmol) in THF (5 ml) was added. The resulting mixture was stirred overnight and the temperature was allowed going up to room temperature. Water was dropped in and the mixture was stirred for ca. 20 minutes. It was then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜3, and then extracted with ethyl acetate. The organic extracts were combined, dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 20 g/70 ml) using DCM, then MeOH/DCM (1:99) as eluant gave 224 mg desired product, yield 65%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[F:16].Cl.[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:19][C@@H:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[O:13])=[CH:9][C:8]=1[F:16]
Reactant: Cn1ncc(Cl)c1-c1ccc(C(=O)O)cc1F
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1F
Reaction time: 1 h
Yield: 35.8 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzoic acid (100 mg, 0.43 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (151 mg, 0.43 mmol) [prepared according to Preparation 3], diisopropylethyl amine (0.4 mL, 2.14 mmol) in DCM (5 mL) was added PyBrop (330 mg, 0.71 mmol) in one portion. After 1 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (90 mg, 36%) as a white solid: LCMS (ES) m/z=585 (M+H)+.
Reaction SMILES: [CH:1]1(NC(C)C)CCCCC1.C([Li])CCC.[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:45][CH2:44][C@@:43]2([CH3:46])[C@H:23]([CH2:24][C@H:25]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C@@H:26]3[C@@H:42]2[CH2:41][C@H:40]([OH:47])[C@@:39]2([CH3:48])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@H:31]([CH3:38])[CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:22]1)=[O:20])[CH3:17].CI.Cl>C1COCC1>[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:45][CH2:44][C@@:43]2([CH3:46])[C@H:23]([CH2:24][C@H:25]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C@@H:26]3[C@@H:42]2[CH2:41][C@H:40]([OH:47])[C@@:39]2([CH3:48])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@H:31]([CH3:38])[CH2:32][CH:33]([CH3:1])[C:34]([O:36][CH3:37])=[O:35])[CH2:22]1)=[O:20])[CH3:17]
Reactant: CC(C)NC1CCCCC1
Reactant: CCOC(=O)[C@@H]1CC[C@@]2(C)[C@@H](C1)C[C@H](C(=O)OCC)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)[C@@H]1CC[C@@]2(C)[C@@H](C1)C[C@H](C(=O)OCC)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CC(C)C(=O)OC)CC[C@@H]12
Temperature: -78 °C
Reaction time: 5 h

Procedure:
To a solution of N-cyclohexyl-isopropyl-amine (2.8 ml: 0.017 mol) in anhydrous THF (120 ml), 11.4 ml (0.016 mol) of a butyllithium solution were added in 30'; the stirred mixture was then cooled (under nitrogen) to -78° C., and 3α,7β-diethoxycarbonyl-12α-hydroxy-5β-cholan-24-oic acid, methyl ester (2.5 g; 0.0045 mol), dissolved in 22 ml of anhydrous THF was added very slowly (45'). Fifteen minutes after the addition, CH3I (10.2 g; 0.072 mol) was added, and the mixture was brought to room temperature. After 5 hours the reaction was complete; the solution was acidified with a 10% aqueous solution of HCl and extracted with CHCl3 (3×80 ml). The chloroform solution was washed with water, dried on Na2SO4, and evaporated to dryness. The yield is almost quantitative.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[C:16]([CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:15][N:14]=[C:13]([C:21]3[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:23][C:24]4[O:28][C:27]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=4[CH:40]=3)[CH:12]=1)[NH:6]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:11]4[CH:12]=[C:13]([C:21]5[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])=[CH:23][C:24]6[O:28][C:27]([C:29]7[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=7)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=6[CH:40]=5)[N:14]=[CH:15][C:16]=4[CH2:17][C:18]([CH3:20])([CH3:19])[N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cc(-c4cc5c(F)cccc5[nH]4)c(C=C(C)C)cn3)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cc4c(cn3)CC(C)(C)n3c-4cc4c(F)cccc43)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 5-(4-(4-fluoro-1H-indol-2-yl)-5-(2-methylprop-1-en-1-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.156 mmol) and K3PO4 (166 mg, 0.781 mmol) in DMAc (0.8 mL) was stirred at 100° C. overnight. The mixture was then diluted with water (40 mL) and extracted with EA (20 mL*3). The organic layer was washed with brine (30 mL*3), dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:EA=1:1) to afford the product of 5-(11-fluoro-6,6-dimethyl-5,6-dihydroindolo[2,1-a][2,6]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (40 mg, yield: 40.0%). 1H-NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 7.86˜8.00 (m, 4H), 7.61 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.00˜7.18 (m, 4H), 6.72 (t, J=8.4 Hz, 1H), 6.01 (br s, 1H), 3.16 (s, 3H), 3.08 (br s, 2H), 2.93 (d, J=4.4 Hz, 3H), 2.77 (s, 3H), 1.69 (br s, 6H). MS (M+H)+: 641.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:25]=2)=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[N:25]=3)=[CH:17][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2ccc(-c3nc(CCN4CCCC4)c(C)o3)cc2)cc1OC

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 3,4-Dimethoxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 393.2 (M+1)
Reaction SMILES: C[O-].[Na+].C[O:5][C:6](=O)[CH:7]=[CH:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH2:25][CH2:26][CH2:27][OH:28])[C:14]([CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[N:15][C:11]=2[CH:10]=1.Cl.[NH2:33][OH:34]>CO>[OH:34][NH:33][C:6](=[O:5])[CH:7]=[CH:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH2:25][CH2:26][CH2:27][OH:28])[C:14]([CH2:16][CH:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])=[N:15][C:11]=2[CH:10]=1
Reactant: COC(=O)C=Cc1ccc2c(c1)nc(CC(C)c1ccccc1)n2CCCO
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(Cc1nc2cc(C=CC(=O)NO)ccc2n1CCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 6 %

Procedure:
Sodium methoxide (30% in methanol) (782 mg, 4.1 mmol) was added to a prestirred solution of 3-[1-(3-Hydroxy-propyl)-2-(2-phenyl-propyl)-1H-benzimidazol-5-yl]-acrylic acid methyl ester (130 mg, 0.34 mmol and hydroxylamine hydrochloride (242 mg, 3.4 mmol in MeOH (1.5 mL). The reaction mixture was continuously stirred for 40 minutes at room temperature and then poured into a solution of ice-water containing 1.0 mL concentrated hydrochloric acid. The mixture was extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and concentrated. The desired product was separated by reverse phase preparative HPLC. After lyopholyzation, 7.8 mg (6%) of N-Hydroxy-3-[1-(3-hydroxy-propyl)-2-(2-phenyl-propyl)-1H-benzimidazol-5-yl]-acrylamide was obtained as powder. HPLC: 96%; tR=(LC/PDA: Phenomenex Luna C18 2.0×150 mm 5μ column; 0.8 mL/min, gradient 5-65% B over 15.5 min, Solvent A: H2O with 0.1% trifluoroacetic acid; Solvent B: Acetonitrile with 0.1% trifluoroacetic acid; UV 254): 7.22 min; 92%. 1H NMR (400 MHz, DMSO-d6) δ 1.35 (3H, d, J=6.5 Hz), 1.83 (2H, m), 3.00-4.00 (6H, m), 4.33 (2H, t, J=7.1 Hz), 6.55 (1H, d, J=15.8 Hz), 7.19-7.33 (5H, m), 7.62 (1H, d, J=15.8 Hz), 7.70 (1H, d, J=8.60 Hz), 7.82 (1H, d, J=8.60 Hz), 7.92 (1H, s), 10.15 (1H, bs), 10.33 (1H, bs). MS(m/z): 380 [MH]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](O)c1ccccc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
To a 100 mL autoclave with a stirrer bar, acetophenone (1.2 g, 10 mmol) and {RuCl[(S)-daipena][(S)-xylbinap]}PF6 (the complex described in the Patent Literature 4) (13.3 mg, 0.01 mmol, 1/1000 molar fold of acetophenone) were added. After purging with a nitrogen gas, toluene (5 mL) and 1,8-diazabicyclo[5,4,0]undeca-7-ene (15.2 mg, 0.1 mmol) were added thereto. Subsequently, purging with a hydrogen gas, the mixture was stirred at 30° C. for 3 hours under hydrogen pressure 1 MPa. As a result of analysis of the reaction mixture by gas chromatography (Chirasil-DEX CB), it was found that the conversion rate is 1.4%.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[N:19]=[N:18][C:17]([NH:20][NH2:21])=[CH:16][C:15]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>ClCCCl>[Cl:13][C:14]1[C:15]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:16][C:17]2[N:18]([C:2](=[O:4])[NH:21][N:20]=2)[N:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NNc1cc(N2CCOCC2)c(Cl)nn1
Solvent: ClCCCl
Product: O=c1[nH]nc2cc(N3CCOCC3)c(Cl)nn12
Yield: 172.1 %

Procedure:
Triphosgene (750 mg, 2.5 mmol) was added to a stirred solution of 6-chloro-5-(morpholin-4-yl)pyridazin-3-ylhydrazine (1.42 g, 6.2 mmol) in 1,2-dichloroethane (60 ml) at room temperature under nitrogen. The mixture was then stirred and heated at reflux for 22 hours. Upon cooling the precipitate was collected by filtration. The solid was washed with diethyl ether and then dried in vacuo to give 6-chloro-7-(morpholin-4-yl)-2H-1,2,4-triazolo[4,3-b]pyridazin-3-one (1.1 g, 67%) which was used without further purification. Data for the title compound: 1H NMR (250 MHz, d6-DMSO) δ3.02-3.05 (4H, m), 3.72-3.76 (4H, m), 7.19 (1H, s), 12.57 (1H, br s); MS (ES+) m/e 256, 258 [MH+].
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:27]([O:29]C)=[O:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+]>O1CCOCC1.O>[C:1]([NH:6][C@H:7]([C:27]([OH:29])=[O:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: COCc1ccc(CCOc2ccc(C[C@H](NC(=O)C(C)C)C(=O)OC)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COCc1ccc(CCOc2ccc(C[C@H](NC(=O)C(C)C)C(=O)O)cc2)cc1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Methyl N-isobutyryl-O-{2-[4-(methoxymethyl)phenyl]ethyl}tyrosinate (0.7 g, 1.69 mmol) was dissolved in dioxane (6 ml). Lithium hydroxide monohydrate (0.25 g, 5.95 mmol) in water (6 ml) was added. The mixture was stirred overnight and then diluted with water and evaporated in vacuum to remove dioxane. The residue was acidified with 1M hydrochloric acid, pH ˜3 and then extracted twice with dichloromethane. The organic phase was washed with brine and dried with sodium sulfate. The solvent was then evaporated. 0.67 g desired product was obtained, yield 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:24]([F:27])([F:26])[F:25])[N:11](/[CH:20]=[CH:21]/[C:22]#N)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:41]CC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:24]([F:27])([F:26])[F:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:41])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#C/C=C/n1c(C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: O=C/C=C/n1c(C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1

Procedure:
From (E)-3-[4,5-bis(4-fluorophenyl)-2-trifluoromethyl-1H-imidazol-1-yl]-2-propenenitrile (484 mg) and diisobutylaluminum hydride (2.2 ml) in dry THF (15 ml) by the process as described for the preparation of Intermediate (4a) to afford a brown gum (0.53 g) which was purified by FCC eluting with System A (1:4) to afford the title compound (263 mg) as a yellow solid. νmax (Nujol) 1692 cm-1 (C=O).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1.[F:16][C:17]([F:35])([F:34])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=2)=[CH:20][CH:19]=1>>[F:16][C:17]([F:34])([F:35])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[CH2:30][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[CH:6][O:7][C:8]=3[CH:13]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc(COc2cccc(CCl)c2)cc1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Product: O=C(O)Cc1coc2cc(OCc3cccc(OCc4ccc(C(F)(F)F)cc4)c3)ccc12

Procedure:
The title compound was prepared in the manner analogous to step 1 of Example 80 using (6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester and 1-(4-trifluoromethyl-benzyloxy)-3-chloromethyl-benzene. MS m/z 471 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH:19]([O:21][CH2:22][C:23](N5CCOCC5)=[O:24])[CH2:18][CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:31])[CH2:3][CH2:2]1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH:19]([O:21][CH2:22][CH:23]([OH:24])[CH3:32])[CH2:18][CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:31])[CH2:2][CH2:3]1
Reactant: O=C(COC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1)N1CCOCC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)COC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,5,6,7-tetrahydro-1,3-benzoxazol-6-yl)oxy)-1-(morpholin-4-yl)ethanone (1.68 g) in THF (25 mL) was added methylmagnesium bromide (1 M THF solution, 5.85 mL). To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue in a mixed solvent of THF (10 mL)-methanol (10 mL) was added sodium tetrahydroborate (148 mg), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (920 mg).
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:40])[NH:19][C:20](=[O:39])[C:21]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33]OS(C)(=O)=O)[CH:23]=2)=[CH:9]1>>[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:40])[NH:19][C:20](=[O:39])[C:21]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33][S:1][C:2]3[S:3][CH2:4][CH2:5][N:6]=3)[CH:23]=2)=[CH:9]1
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: SC1=NCCS1
Product: Cn1cc(C2=C(c3cn(CCCSC4=NCCS4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Yield: 17.2 %

Procedure:
In an analogous manner to that described in Example 59, from 27 mg of 2-mercaptothiazoline and 100 mg of the product of Example 58, there were obtained 18 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(2-thiazolin-2-ylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione m.p. 170°-173° C.