Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:55])([F:54])[C:27]1[N:31]2[N:32]=[C:33]([N:36]3[CH2:41][CH2:40][CH:39]([C:42]4[C:50]5[C:45](=[CH:46][CH:47]=[C:48]([C:51]([OH:53])=O)[CH:49]=5)[NH:44][CH:43]=4)[CH2:38][CH2:37]3)[CH:34]=[CH:35][C:30]2=[N:29][N:28]=1.[CH3:56][NH:57][CH2:58][CH2:59][OH:60].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:60][CH2:59][CH2:58][N:57]([CH3:56])[C:51]([C:48]1[CH:49]=[C:50]2[C:45](=[CH:46][CH:47]=1)[NH:44][CH:43]=[C:42]2[CH:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:34]=[CH:35][C:30]3[N:31]([C:27]([C:26]([F:25])([F:54])[F:55])=[N:28][N:29]=3)[N:32]=2)[CH2:41][CH2:40]1)=[O:53]
Reactant: O=C(O)c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Reactant: CNCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCO)C(=O)c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
HATU (139 mg, 0.37 mmol) was added portionwise at ambient temperature to a stirred mixture of 3-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carboxylic acid (150 mg, 0.35 mmol), 2-(methylamino)ethanol (0.034 mL, 0.42 mmol) and DIPEA (0.073 mL, 0.42 mmol) in DMF (2.0 mL). The resulting solution was stirred for 2 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(2-hydroxyethyl)-N-methyl-3-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carboxamide (155 mg, 91%) as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][C:23]=2[CH:28]=O)=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][C:23]=2[CH:28]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-oxindole (106 mg, 0.5 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (125 mg, 1 equiv.) and piperidine (0.2 mL) in ethanol (2 mL) was heated in a sealed tube at 80° C. for 1 hr and then cooled. The precipitate which formed was collected by vacuum filtration, washed with ethanol and ethyl acetate and dried to give the title compound as an orange solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[N:22][CH:23]=1.[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([Cl:51])[C:37]=1[OH:52]>>[NH2:27][CH2:26][CH2:25][O:24][C:21]1[N:22]=[CH:23][C:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:40]4[CH:41]=[C:36]([Cl:35])[C:37]([OH:52])=[C:38]([Cl:51])[CH:39]=4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[CH:19][CH:20]=1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Product: NCCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cn1
Yield: 21.7 %

Procedure:
Following general procedure D, tert-butyl 2-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yloxy)ethylcarbamate (100 mg, 0.19 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (81 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (21 mg, 22% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.33-8.24 (m, 2H), 8.13-8.04 (m, 2H), 7.83 (dd, J=8.8, 2.8 Hz, 1H), 7.37 (s, 2H), 7.14 (d, J=8.8 Hz, 1H), 4.66 (t, J=5.1 Hz, 2H), 3.43 (t, J=5.1 Hz, 2H), 2.87-2.80 (m, 1H), 1.22-1.15 (m, 4H); ESI MS m/z 509 [C26H22Cl2N4O3+H]+; HPLC 99.7% (AUC), tR=11.26 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][NH2:13])[CH:7]=[CH:8][CH:9]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([Cl:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][C:15]1[N:20]=[C:19]([NH:13][CH2:12][CH2:11][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[C:18]([Cl:22])=[CH:17][N:16]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cccc(CCCN)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(CCCNc2nc(Cl)ncc2Cl)c1
Yield: 91.1 %

Procedure:
To a solution of 3-(3-methoxyphenyl)propan-1-amine hydrochloride (2.00 g, 9.92 mmol) and 2,4,5-trichloropyrimidine (1.19 mL, 10.4 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (4.80 g, 34.7 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a light brown gel (2.82 g, 91%). LCMS for C14H16Cl2N3O (M+H)+: m/z=312.0, 314.0.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH3:21][O:22][CH2:23]Cl>C1COCC1>[F:1][C:2]([F:17])([F:18])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=1)([O:8][CH2:21][O:22][CH3:23])[C:4]([F:6])([F:5])[F:7]
Reactant: COCCl
Reactant: C=Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
A solution of 1,1,1,3,3,3-hexafluoro-2-(4-vinylphenyl)-2-propanol (5.00 g, 18.51 mmol) in THF (10 mL)was slowly added to a mixture of NaH (60% dispersion, 968 mg, 24.20 mmol), washed with pentane, and THF (50 mL). The reaction mixture was allowed to stir at room temperature for 1 h, then cooled to −78° C. using a dry ice/acetone bath followed by the addition of chloromethyl methyl ether (1.50 mL, 19.75 mmol) in THF (5 mL). The reaction mixture was allowed to slowly warm to room temperature overnight, quenched with H2O, concentrated, and partitioned between ether/H2O. The combined extracts were washed with saturated NaHCO3, brine, dried (Na2SO4), and concentrated to provide a crude oil. This material was purified by Kugelrohr distillation (bp 65-9° C., 1.3 mm), followed by column chromatography on silica gel using 50:1 hexane/ethyl acetate to provide 1.96 g (34%) of a colorless oil; 1H NMR (CDCl3) δ 7.60 (d, 2ArH), 7.50 (d, 2ArH), 6.75 (dd, CH=), 5.85 (dd ═CHH), 5.40 (dd ═CHH), 4.85 (s, CH2), 3.60 (s, Me).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:32](=[O:47])[NH:33][C:34]2([C:37]3[CH:42]=[CH:41][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:39][CH:38]=3)[CH2:36][CH2:35]2)[C:5]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:14]=[C:15]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.ClCCl>ClCCl>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:14]=3)[CH2:9]2)=[C:4]([CH:3]=1)[C:32]([NH:33][C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:47]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)C3)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(N5CCNCC5)c4)C3)CC2)cc1
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
To a cooled solution of tert-butyl 4-(3-((1-(5-chloro-3-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (130 mg, 0.196 mmol) in dichloromethane (1 ml) a mixture trifluoroacetic acid/dichloromethane (3 ml/1 ml) was added and the resulting mixture stirred for 15 min. Solvents were evaporated in vacuo to afford a residue that was loaded on SPE-SCX (5 g) cartridge. Ammonia fractions after solvent evaporation afforded the title compound (D156) (105 mg)
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:13](=[O:14])[C:12](O)=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:10]2(=[O:23])=[O:22])=[CH:6][CH:5]=1.CN(C=O)C.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[Cl:35][C:12]1[C:13](=[O:14])[N:9]([CH2:8][C:7]2[CH:24]=[CH:25][C:4]([O:3][CH:2]([F:26])[F:1])=[CH:5][CH:6]=2)[S:10](=[O:23])(=[O:22])[C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1C(O)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C(Cl)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Yield: 61.4 %

Procedure:
2-[4-(Difluoromethoxy)benzyl]-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.98 g, ca.60% purity, 1.80 mmol)) was dissolved in DCM (40 mL) and DMF (0.14 mL) was added. Under an atmosphere of nitrogen, oxalyl chloride (0.46 g 3.61 mmol) was dropped in. The mixture was then heated to reflux for 5 h and then evaporated to dryness. Water (20 mL) was added and the reaction mixture was extracted with DCM (20 mL×3). The extracts were combined and washed with water (50 mL×3) and brine (20 mL), dried (MgSO4) and evaporated. The residue was purified by column chromatography (ISOLUTE SI, 20 g/70 mL), eluting with DCM:heptane (30:70), to give the title compound (0.442 g, 62%) as a semi-solid; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H), 7.48-7.58 (m, 5H), 7.11 (d, 2H), 6.51 (t, 1H), 4.86 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 155.8, 151.2, 143.5, 132.5, 130.8, 130.5, 129.4, 128.8, 127.2, 123.2, 119.5, 115.7 (t), 43.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:25][C:10]3=[CH:11][C:12]4[C:13]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29]([CH:26]5[CH2:28][CH2:27]5)=[O:30])=[CH:6][NH:5][N:4]=4)[NH:25][C:10]3=[CH:11][C:12]=2[C:13]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)C1CC1
Reactant: CCN1C(=O)C(CC)(CC)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(CC)(CC)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C4CC4)nc3cc21
Yield: 34.5 %

Procedure:
Cyclopropanecarboxylic acid[3-(5,7,7-triethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5,7,7-triethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (137.7 mg, 0.407 mmol) and cyclopropanecarbonyl chloride (46.8 mg, 0.448 mmol). 57 mg (34%) of the title compound were obtained.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>>[CH:1]1([O:7][C:15]2[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=2[C:13]#[N:14])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OC1C=CCCC1
Product: N#Cc1c(OC2C=CCCC2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example 126c from cyclohex-2-enol and 2,6-dinitrobenzonitrile as a brown solid (90%). MS 245 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1.[C:14](OCC)(=[O:19])[CH2:15][C:16]([CH3:18])=O.[OH-].[Na+]>O>[CH3:1][C:2]1[C:6]2[C:14]([OH:19])=[CH:15][C:16]([CH3:18])=[N:7][C:5]=2[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(O)c2c(C)nn(-c3ccccn3)c2n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A mixture of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine (1.8 g, 10 mmol) and polyphosphoric acid (4.2 g) was heated at 130° C. The mixture was stirred thoroughly at the same temperature, while ethyl acetoacetate (1.3 mL, 10 mmol) was added dropwise thereto, and the resulting mixture was stirred at the same temperature for 1 hour. The mixture was cooled to room temperature, iced water was added thereto. The mixture was neutralized with an aqueous sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=50:1 to 20:1), and recrystallized from ethyl acetate to give the title compound (0.72 g, 30% yield).
Reaction SMILES: [S:1]1[C:5](=[O:6])[NH:4][C:3](=[O:7])[S:2]1.[CH2:8](Br)[CH:9]=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([N:4]1[C:3](=[O:7])[S:2][S:1][C:5]1=[O:6])[CH:9]=[CH2:8]
Reactant: C=CCBr
Reactant: O=c1[nH]c(=O)ss1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCn1c(=O)ssc1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 111.8 %

Procedure:
Next, 4.0 g of the above 1,2,4-dithiazolidine-3,5-dione, 4.0 g of allyl bromide and 5.8 g of potassium carbonate were suspended in 65 ml of acetone, and the suspension liquid was stirred at room temperature for 6 hours, and then filtered. Then, the residual obtained by concentrating the filtrate was purified with a column to yield 5.8 g of N-allyl-1,2,4-dithiazolidine-3,5-dione. The N-allyl-1,2,4-dithiazolidine-3,5-dione was dissolved in 4.5 ml of chloroform, and 50 mg of 2,2′-azobisisobutylonitrile was added to this solution. The solution thus obtained was stirred at 60° C. for 4 days, and then 100 ml of acetone was added to the solution to precipitate a powder-like substance. The powder-like substance was recovered, washed with ethanol several times, and dried under a reduced pressure to yield 2.8 g of an allyl polymer. The reaction concerned is shown in the following formula (VII), G in formula (VII) being the allyl polymer. An infrared absorption spectrum of the allyl polymer G is shown in FIG. 5.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[S:10])[NH2:9])[CH3:2].Br[CH:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C(#N)C>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:12]2[N:9]=[C:8]([C:4]3[N:3]([CH2:1][CH3:2])[CH:7]=[CH:6][CH:5]=3)[S:10][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Reactant: CCn1cccc1C(N)=S
Solvent: CC#N
Product: CCn1cccc1-c1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 77 %

Procedure:
1-Ethylpyrrole-2-carbothioamide obtained in Reference Example 1 (1.85 g, 12 mmole) and α-bromo-4,4'-dimethoxydeoxybenzoin (cf. Aust. J. Chem., 8, 385, 1955) (4.02 g, 12 mmole) are dissolved in acetonitrile (120 ml), and the mixture is stirred at 60° C. for 50 minutes. After the reaction, the mixture is distilled under reduced pressure to remove the solvent. To the residue are added chloroform and aqueous sodium carbonate, and the mixture is shaken. The chloroform layer is taken, and the aqueous layer is further extracted with chloroform. The chloroform layers are combined, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue is recrystallized from n-hexane to give 4,5-bis(4-methoxyphenyl)-2-(1-ethylpyrrol-2-yl)thiazole (3.6 g, yield: 77%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:13][CH2:12][Cl:11])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: OCCCl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.1 %

Procedure:
To a solution of 4-hydroxyindole (4 g, 30 mmol), 2-chloroethanol (4.83 g, 60 mmol), triphenylphosphine (15.7 g, 60 mmol) in anhydrous tetrahydroufuran (40 ml) was slowly added diisopropyl azodicarboxylate (12.1 g, 60 mmol). The reaction was allowed to stir for 2.5 hours at room temperature, then poured into methylene chloride (250 ml), washed with water (3×100 ml) and dried over anhydrous sodium sulfate. This material was filtered and the solvent was removed under vacuum. Chromatography (20% hexanes-ethyl acetate) to remove triphenylphosphine, (20% methylene chloride-hexanes) afforded 2.94 g (50%) of product as a white solid: mp 69.5-72° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH3:21])[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:21])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(O)cc1C
Yield: 100 %

Procedure:
5 g (16.8 mmol) of the above prepared (E)-3-(4-benzyloxy-2-methyl-phenyl)-acrylic acid ethyl ester was dissolved in 50 ml of tetrahydrofuran and hydrogenated over 0.8 g of 10% of palladium on charcoal as catalyst at ambient temperature and atmospheric pressure. Filtering off the catalyst and evaporating the solvent yielded 3.5 g of the title compound as light yellow oil (100% of theory).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(N)cccc1F
Reactant: OCC1CCCCC1
Product: N#Cc1c(N)cccc1OCC1CCCCC1

Procedure:
Prepared as in Example 22b from cyclohexylmethanol and 2-amino-6-fluorobenzonitrile as a colorless oil (50%). 1H NR (400 MHz, CDCl3) δ 1.07-1.09 (m, 2H), 1.28-1.32 (m, 3H), 1.75-1.90 (m, 6H), 3.79 (d, J=6.4 Hz, 2H), 4.37 (s, 2H), 6.20 (d, J=8.4 Hz, 1H), 6.28 (d, J=8.4 Hz, 1H), 7.19 (t, J=8.4 Hz, 1H). MS 231 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[F:18])[O:8][N:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]([F:18])=[C:11]([C:9]2[O:8][N:7]=[C:6]([CH:4]=[O:3])[CH:10]=2)[CH:16]=1
Reactant: CCOC(=O)c1cc(-c2cc(Cl)ccc2F)on1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1cc(-c2cc(Cl)ccc2F)on1
Temperature: -78 °C
Yield: 84.4 %

Procedure:
In a 50 ml round bottom flask equipped with stir bar and drying tube added 5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (0.78 g, 2.89 mmol) and dichloromethane (10 ml). Cooled the solution down to −78° C. and to this stirred solution added diisobutylaluminum hydride (1M hexanes, 5.3 ml, 5.3 mmol). The resulting mixture was left stirring at −78° C. for 3 h. Reaction was quenched using sodium sulfate decahydrate. The resulting mixture was stirred at 63° C. for 15 min after which it was filtered through a celite pad. The filterate was concentrated in-vacuo to isolate an off-white solid, which was triturated with hexanes to isolate the title compound as a white solid (0.55 g, 84%). 1H-NMR (CDCl3), d (ppm): 10.2 (s, 1H), 7.99 (m, 1H), 7.44 (m, 1H), 7.20 (m, 1H), 7.10 (d, 1H). Step 2: 1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethanol: In a 50 ml round bottom flask equipped with stir bar added 5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carbaldehyde (0.5 g, 2.42 mmol) and tetrahydrofuran (6 ml). Cooled the mixture down to 0° C. and to it added methyl magnesium iodide (3M in diethyl ether, 3.23 ml, 9.67 mmol). The resulting mixture was left stirring at 0° C. for 3 h. Reaction mixture was quenched with hydrochloride acid (1N, aqueous, 10 ml), extracted with diethyl ether (3×50 ml). Combined organic phase was washed with water (50 ml), brine (50 ml), dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 10% ethyl acetate in hexanes to isolate the desired compound as clear oil (179 mg, 31%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][N:5]=[C:6]1[C:10](=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1.Cl.[NH2:17][OH:18].O>CN1CCCC1=O>[OH:1][CH2:2][CH2:3][O:4][N:5]=[C:6]1[C:10](=[N:17][OH:18])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1
Reactant: O=C1C(=NOCCO)Oc2ccccc21
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: OCCON=C1Oc2ccccc2C1=NO
Yield: 37.8 %

Procedure:
At 80° C., 10.1 g (0.05 mol) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] (VII-1) in 50 ml of N-methyl-2-pyrrolidinone are stirred with 3.5 g of hydroxylamine hydrochloride for 2 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is then chromatographed over silica gel using tert-butyl methyl ether/petroleum ether (1:1). The eluent is distilled off under reduced pressure, affording 4.2 g (29.6% of theory) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-oxime consisting of 62.4% of isomer A and 15.8% of isomer B (HPLC).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>CS(C)=O.O>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ncccc1C(F)(F)F
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Oc2ncccc2C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
2-Fluoro-3-(trifluoromethyl)pyridine (848 mg, 5137 μmol), cesium carbonate (2008 mg, 6164 μmol) and ethyl 4-hydroxybenzoate (854 mg, 5137 μmol) were combined in DMSO (12 mL) and heated to 80° C. overnight. After complete disappearance of starting material, the mixture was cooled to RT and diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product which was used without further purification.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:20])[NH:14][O:15][CH2:16][C:17]([OH:19])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]([CH3:45])[C:23]([N:25]([CH2:35][C:36]1[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[S:39][CH:40]=1)[C@@H:26]([CH3:34])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:24]>>[S:39]1[CH:40]=[C:36]([CH2:35][N:25]([C@@H:26]([CH3:34])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[C:23](=[O:24])[C@@H:22]([NH:21][C:17](=[O:19])[CH2:16][O:15][NH:14][C:13]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:20])[CH3:45])[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Reactant: O=C(O)CONC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(naphthalen-1-ylmethyl)ureidooxy)acetic acid (Compound VI-12) 113 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.