Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=1)=[O:7].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:22][N:5]([CH2:4][CH2:3][C:2]([F:19])([F:18])[F:1])[C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1)=[O:7]
Reactant: CI
Reactant: COC(=O)c1ccc(C(=O)NCCC(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCC(F)(F)F)C(=O)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a solution of methyl 6-[(3,3,3-trifluoropropyl)carbamoyl]nicotinate (2.4 g, 8.6 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% suspension in mineral oil) (1.3 g). The reaction mixture was stirred at ambient temperature for 1 h. Methyl iodide (3.42 g, 5.0 mL, 24.1 mmol) was added and the reaction mixture was stirred over night and then added water (20 mL). The reaction mixture was stirred for another 30 min and then extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with citric acid and the formed precipitate was filtered off and dried in vacuum oven to yield 1.12 g (47%) of the title compound; 1H NMR (400 MHz, CDCl3) δ ppm 9.26 (d, 1 H), 8.49 (d, 1 H), 7.78-7.91 (dd, 1 H), 3.80 (t, 1 H), 3.61-3.73 (m, 1 H), 3.16 (d, 3 H), 2.46-2.76 (m, 2 H); MS (ESI) m/z 277[M+H+].
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].N([O-])=O.[Na+].S(=O)(=O)(O)N.N(O)=O.[ClH:24]>>[Cl:24][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: NS(=O)(=O)O
Agent: O=NO
Agent: O=N[O-]
Product: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reaction time: 1 h

Procedure:
A suspension of 131.2 g (0.85 mole) of 2-amino-5-nitrophenol in 400 ml of 36% hydrochloric acid was maintained at a temperature of 10° C. or less with stirring. To this was added dropwise 150 ml of an aqueous solution containing 66.5 g (0.93 mole) of sodium nitrite over a period of about 1 hour. After completion of the dropwise addition, the mixture was further stirred at a temperature not exceeding 10° C. for 1 hour. To this mixture was added 3 g of sulfamic acid to decompose the excess nitrous acid. The suspension was added to 100 ml of a 20% hydrochloric acid aqueous solution containing 17 g of cuprous chloride with stirring. The stirring was continued for 1 hour.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1CCN2C(=NCCC2)CC1>COCCOC>[C:11]1(=[O:20])[N:10]([CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: Oc1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: O=C1c2ccccc2C(=O)N1COc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 10.76 g (55 mmol) of N-chloromethylphthalimide in 80 ml of DME, 8.23 ml (55 mmol) of 1,8-diazabicyclo[5,4,0]-7-undecene was added. The mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the reaction mixture was poured into water and extracted with ethyl acetate. The precipitate was filtered off. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.67 g of the desired compound (yield: 21%, colorless crystals).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([O:15]C)=[O:14])=[CH:12][C:6]=2[N:5]=1>>[CH3:2][NH:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:6]=2[N:5]=1
Reactant: CNc1nc2cc(C(=O)OC)ccc2[nH]1
Agent: Cl
Product: CNc1nc2cc(C(=O)O)ccc2[nH]1
Yield: 89.7 %

Procedure:
3 N Aqueous hydrochloric acid (14 mL, 42 mmol) was added to methyl 2-(methylamino)-1H-benzo[d]imidazole-5-carboxylate (2.9 g, 14 mmol) and the reaction was stirred at reflux overnight. The reaction was concentrated to give the title compound (2.4 g, 90%) as a yellow solid. 1H NMR (400 MHz, CD3OD, δ): 7.96-8.00 (m, 2H), 7.40 (d, J=8.4 Hz, 1H), 3.10 (s, 3H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:21][NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][CH2:35][CH2:36][NH:37][C:38]1[NH:39][CH:40]=[CH:41][N:42]=1)[N:29]=[CH:28]2)=[O:24])[C:18]([OH:20])=[O:19])=[O:15])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:21][NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][CH2:35][CH2:36][NH:37][C:38]1[NH:39][CH:40]=[CH:41][N:42]=1)[N:29]=[CH:28]2)=[O:24])[C:18]([OH:20])=[O:19])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)NC(CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCCC(=O)NC(CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Reaction time: 2 h
Yield: 112 %

Procedure:
2-(6-((Tert-butoxy)carbonylamino)hexanoylamino)-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (0.0322 g, 0.0551 mmol) was dissolved in methylene chloride (1 mL). Trifluoroacetic acid (1 mL) was added, and the reaction was stirred for 2 h. The reaction was concentrated to an oil under high vacuum. The oil was triturated with ether. The product was filtered, washed with ether, dissolved in 50/50 acetonitrile/water, and lyophilized to give 29.9 mgs (91%) of product. ESMS: Calcd. for C23H32N8O4, 464.25. Found, 485.2 [M+H]+1 Analytical HPLC, Method B, Rt=111.02 min, Purity=97%
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH3:22][O:23][C:24](=[O:28])[C:25](Cl)=[O:26]>>[CH3:22][O:23][C:24](=[O:28])[C:25]([NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:26]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Yield: 44 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) was converted, using chloro-oxo-acetic acid methyl ester instead of methoxyacetyl chloride, to the title compound (88 mg, 44%) which was obtained as a white solid. MS: m/e=369.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C[Al](C)C.C[O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[C:34]([Cl:36])[N:33]=[C:32]([NH2:37])[N:31]=3)[CH:26]=[CH:25][C:24]=12)=O.CCOC(C)=O.O>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[C:27]([O:29][C:30]4[CH:35]=[C:34]([Cl:36])[N:33]=[C:32]([NH2:37])[N:31]=4)[CH:26]=[CH:25][C:24]=23)=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cnn2cc(Oc3cc(Cl)nc(N)n3)ccc12
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nc(Cl)cc(Oc2ccc3c(C(=O)Nc4cccc(C(F)(F)F)c4)cnn3c2)n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
10.5 μl (0.084 mMol) 3-Trifluoromethyl aniline are dissolved in 2 ml toluene and cooled to 5° C. 126 μl Me3Al (2 M solution in toluene; 0.25 mMol) are added slowly via a syringe followed by a solution of 27 mg (0.084 mMol) 6-(2-amino-6-chloro-pyrimidin-4-yloxy)-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester in 1 ml THF. The reaction is stirred at rt for 1 h and then heated to 110° C. for 30 min. The reaction is submitted to aq. workup with EtOAc/H2O. The organic layers are combined, dried and concentrated to give the crude product which is further purified by flash chromatography (SiO2, 4 g column, CH2Cl2/MeOH; gradient 0-10% MeOH) to give the title compound as a white solid: m.p.: 219-221° C.; MS: [M+1]+=449.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH3:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:15][S:14][CH2:13][CH2:12][CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(CCCCSC)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSCCCCC1(C(=O)O)CCCC1
Temperature: 52.5 °C
Yield: 106 %

Procedure:
To a solution of 1-[4-(methylthio)butyl]cyclopentanecarboxylic acid methyl ester (18.8 mmol, 4.94 g) in a mixture of THF (38 mL) and methanol (38 mL) was added 1 N sodium hydroxide (38 mL)and the mixture was heated to 50-55° C. for 15 h. TLC analysis of the reaction mixture did not detect the presence of starting ester and the reaction was cooled to room temperature,. The volatiles were removed under reduced pressure and the residue was diluted with water (100 mL) and was extracted with diethyl ether (2×50 mL) to remove any neutral impurities. Then the separated aqueous layer was acidified with 1 N hydrochloric acid and the mixture was extracted with ethyl acetate (2×75 mL). The combined ethyl acetate extracts were washed with brine, dried (MgSO4), filtered, then concentrated in vacuo and the residue was dried under high vacuum to afford 4.31 g (92%) of 1-[4-(methylthio)butyl]cyclopentanecarboxylic acid as a low melting colorless solid. HR MS: Obs. mass, 216.1181. Calcd. mass, 216.1184, M+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CCOCC>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]#[C:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 90 °C
Yield: 95.3 %

Procedure:
Compound 5 (30 mg, 2 μmol Pd), 1-(4-bromo-phenyl)ethan-1-one (0.20 g, 1 mmol), phenylacetylene (0.16 g, 1.5 mmol), and triethylamine (3 mL) were sequentially added into a 15 mL septum-sealed test tube under protection of nitrogen. The mixture was then heated at 90° C. for 72 h. After it was cooled to the room temperature, 8 mL of anhydrous ether was added to precipitate compound 5. The mixture was centrifuged and the upper liquid layer was transferred via a syringe into a 20 mL round-bottom flask. Repeated the above precipitation procedure once. The combined liquid layer was concentrated under reduced pressure to give an oily residue. A saturated ammonium chloride solution (5 mL) was then added. The resulting mixture was extracted by ethyl acetate (10 mL×3), dried over anhydrous magnesium sulfate, filtrated, and concentrated to give a crude product. The crude product was further purified by column chromatography (silica gel, hexane/ethyl acetate=4/1) to give 0.21 g (98% yield) of 1-(4-acetylphenyl)-2-phenylethyne. 1H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 7.33–7.35 (m, 3H), 7.52–7.54 (m, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.2 Hz, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:18][C:19]([NH2:21])=[O:20].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CS(C)=O.C1COCC1.O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:18][C:19]([NH2:21])=[O:20])[CH3:32]
Reactant: CCOC(=O)CCCBr
Reactant: NC(=O)Cc1cn(Cc2ccccc2)c2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1
Temperature: 60 °C
Yield: 65.9 %

Procedure:
A solution of 280 mg (1.0 mmol) of 5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide in 30 mL of DMSO and 10 mL of THF was treated with 45 mg (1.1 mmol) of 60% NaH/mineral oil, and then with 0.16 mL (1.1 mmol) of ethyl 4-bromobutyrate. The mixture was heated in an oil bath at 60° C. for 2.25 hours. It was diluted with water, extracted with EtOAc, the EtOAc solution washed with water, saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica (CH2Cl2→3% MeOH/CH2Cl2)to give 260 mg (66% yield) of 4-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:23][CH:24]([O:28][CH2:29][CH3:30])[C:25]([NH2:27])=O)[CH3:22].CC(=O)OCC>C1COCC1>[CH2:21]([O:23][CH:24]([O:28][CH2:29][CH3:30])[C:25]([NH2:27])=[S:2])[CH3:22]
Reactant: CCOC(OCC)C(N)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(OCC)C(N)=S
Yield: 90.2 %

Procedure:
To a stirred mixture of P2S5 (45 g) in THF (300 ml) at 23°, sodium carbonate (21.5 g) was added. At the mixture, vigorously stirred, 2,2-diethoxyacetamide (10 g) was added. After 24 h a 10% aqueous solution of Na3PO4 (200 ml), EA (300 ml) and CH (300 ml) were respectively added. The aqueous layer was washed with EA and united to the organic layer. This was washed with water until clarification, dried and the solvent evaporated under reduce pressure. The crude residue was purified by flash chromatography (eluting with CH-EA 1:1) to give the title compound as a white solid (10 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][C:33]1[C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:35]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[C:34]=1[C:59]([O-])=[O:60])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([NH+](CC)CC)C.CCN(C(C)C)C(C)C.[C:78]([NH:81][NH2:82])(=[O:80])[CH3:79]>CN(C=O)C>[C:78]([NH:81][NH:82][C:59]([C:34]1[N:35]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[C:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:33]=1[O:32][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:60])(=[O:80])[CH3:79]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)[O-])n1-c1ccc(OC)cc1
Reactant: CC(=O)NN
Agent: CC[NH+](CC)CC
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: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)NNC(C)=O)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
HATU (739 mg, 1.94 mmol) was added to a solution of triethylammonium 3,4-bis(benzyloxy)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (5) (325 mg, 0.65 mmol), DIPEA (566 μL, 3.24 mmol) and acetohydrazide (53 mg, 0.71 mmol) in DMF (5 mL) at 0° C. The mixture was stirred for 30 min and allowed to warm to RT. The reaction was partitioned between water (10 mL) and Et2O (30 mL) and NH4OAc (aq.) (20 mL) was added, the organic layer was separated and washed with sat. NaHCO3 (aq.) (20 mL), brine (20 mL), dried (MgSO4), filtered and solvents removed in vacuo. The product was purified by silica gel chromatography (40 g, 0-80% EtOAc in isohexane) to afford ethyl 5-(2-acetylhydrazinecarbonyl)-3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (31) (196 mg, 100%) as a colourless oil: m/z 558 (M+H)+ (ES+).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:51]=[C:50]([N:52]1[CH2:53][CH2:54][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:66])[F:67])[CH:60]=2)[CH2:56][CH2:57]1)[CH2:49][NH:48][C:22]([C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=2)[NH:21][N:20]=1)=[O:24]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccc(O)cc2)[nH]n1
Reaction time: 8 h
Yield: 55 %

Procedure:
DIPEA (150 mg, 1.2 mmol) was added to a stirred solution of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid (70 mg, 0.34 mmol) in DMF (2 mL) followed by HOBt (48 mg, 0.36 mmol) and EDCI.HCl (69 mg, 0.36 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (116 mg, 0.34 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. The residue was purified by washing with 1% MeOH in EtOAc to afford 92 mg (55% Yield) of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 489, 96%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 9.8 (s, 1H), 8.02 (t, 1H), 7.5 (m, 3H), 7.28 (t, 3H), 6.8 (m, 3H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:19][O:20][C:21](=[O:34])[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([O:31][CH3:32])=[CH:24][C:23]=1F.CCN(CC)CC>CC#N.C(Cl)Cl>[CH3:19][O:20][C:21](=[O:34])[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1F
Reactant: Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
A mixture of 4-[3-(3,4-dichloro-phenyl)propyl]phenylamine (0.94 g, 3.3 mmol), 2-fluoro-4-methoxy-5-nitro-benzoic acid methyl ester (0.75 g, 3.3 mmol), and Et3N (0.46 mL) in CH3CN (30 mL) was heated to reflux for 120 hours. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 and washed with saturated NaHCO3. The organic layer was dried (Na2SO4) and concentrated to give a solid. Recrystallization with MeOH yielded 0.67 g (1.37 mmol, 42%) of the desired product.
Reaction SMILES: C([C:5]1[N:6](O)[C:7]([C:14]([O:16][CH2:17]C)=[O:15])=[C:8](C(F)(F)F)[N:9]=1)CCC.[N+](=C)=[N-].S([O-])([O-])(=O)=O.[Mg+2]>CO.C(OCC)C>[NH:9]1[CH:8]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:6]=[CH:5]1
Reactant: CCCCc1nc(C(F)(F)F)c(C(=O)OCC)n1O
Agent: C=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c[nH]cn1
Yield: 136.4 %

Procedure:
To a solution of 2-butyl-1-hydroxy-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid, ethyl ester (506 mg, 3.14 mmol) dissolved in a mixture of 5 mL of methanol and 10 mL of diethyl ether was added ethereal diazomethane until disappearance of starting acid was indicated by TLC. Anhydrous magnesium sulfate was then added and the solution filtered and concentrated in vacuo. Flash chromatography on 10 g of Merck silica gel eluted with 2:1, CHCl3 :hexanes, followed by 10:1, CHCl3 :Et2O afforded the title D compound (540 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([C:15]([NH:17][CH3:18])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.CCCCO.Cl>CCOC(C)=O>[CH3:18][NH:17][C:15](=[O:16])[C:10]1[C:9]([NH:8][C:6]2[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28](=[O:33])[CH2:27]4)[CH:7]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CNC(=O)c1ncccc1Nc1cc(Cl)ncc1C(F)(F)F
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CNC(=O)c1ncccc1Nc1cc(Nc2ccc3c(c2)CC(=O)N3)ncc1C(F)(F)F
Temperature: 160 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a high pressure vial was added 3-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylpicolinamide (0.205 g, 0.62 mmol) and 5-aminoindolin-2-one (0.138 g, 1.2 eq) and n-BuOH (5 mL). HCl (˜1.25M HCl in ethanol, 0.5 mL, 1.0 eq) was added to the above mixture. The vial was sealed and heated at 160° C. with stirring overnight in an oil bath. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude. The crude was dissolved in EtOAc and washed with saturated NaHCO3 solution. The organic layers were concentrated and the crude was purified by silica gel chromatography (20%˜100% EtOAc/Hex). The product was precipitated from EtOAc and filtered to obtain the desired product as the free base (isolated yield 56%). The product was converted to the HCl salt.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[BH4-].[Na+]>C(O)C>[OH:21][CH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=1)=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCSc1ccncc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
To a solution of 5.97 g (20.0 mmol) of 4-(3-phthalimidopropylthio)pyridine in 300 ml of ethanol, 7.57 g (200 mmol) of sodium borohydride was added, and stirred at room temperature for 24 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent:ethanol/ethyl acetate=1:10) to give 4.73 g of the desired compound (78.2% yield, colorless crystals), mp. 110°-111° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[N:12]([CH:17]=[CH:18][N:19]=2)[C:13]([CH3:16])=[CH:14][N:15]=1>C(Cl)Cl>[Br:1][C:17]1[N:12]2[C:13]([CH3:16])=[CH:14][N:15]=[C:10]([Cl:9])[C:11]2=[N:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(Cl)c2nccn12
Solvent: ClCCl
Product: Cc1cnc(Cl)c2ncc(Br)n12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
N-bromosuccinimide (348 mg, 1.96 mmol) is added to a solution of 8-chloro-5-methyl-imidazo[1,2-a]pyrazine (327 mg, 1.98 mmol) in DCM (6 mL) and the reaction stirred at room temperature for 2 h. Once the reaction is finished the reaction mixture is diluted with DCM and washed twice with 4 mL of Na2CO3 sat., dried (MgSO4), filtered and concentrated in vacuo to give a crude mixture that is purified by column chromatography using a gradient of (Pet.Ether40-60/AcOEt: 9/1 to 7/3) to give 3-Bromo-8-chloro-5-methyl-imidazo[1,2-a]pyrazine as a brown solid (335 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[CH3:1][C:2]1([CH3:20])[O:7][C:6](=[S:30])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(C#N)cs3)cc21
Product: CC1(C)OC(=S)Nc2ccc(-c3cc(C#N)cs3)cc21

Procedure:
The title compound was prepared in a manner similar to Example 16 using 5-(4,4-dimethyl -2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)thiophene-3-carbonitrile and Lawesson's reagent. The product was obtained in the form of yellow crystals: m.p. 258-259° C. 1H NMR (DMSO-d6) δ12.3 (s,l H ),8.54 (d, 1H, J=0.9 Hz) ,7.96 (s, 1H), 7.69-7.62 (m, 2H), 7.11-7.08 (d, 1H, J=8.3 Hz), 1.69 (s, 6H); MS (ESI) m/z 299 [M−H]−; Anal. Calcd. For C15H12N2OS2 ½H2O: C, 58.0; H, 4.24; N, 9.05. Found C, 58.33; H, 3.85; N, 8.39.