Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:9](=[O:20])[C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=2F)[C:7]#[N:8])[CH2:3][CH2:2]1.[H-].[Na+].CCCCCC>O1CCOCC1>[CH:1]1([N:4]2[C:15]3[C:10](=[CH:11][C:12]([F:18])=[C:13]([F:17])[C:14]=3[F:16])[C:9](=[O:20])[C:6]([C:7]#[N:8])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: N#CC(=CNC1CC1)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCC
Product: N#Cc1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 6 h
Yield: 91.4 %

Procedure:
A solution of 3-cyclopropylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile (12.0 g) in dioxane (60 ml) is added dropwise to a suspension of sodium hydride (1.9 g, in oil, 55-65 w/w%) in dioxane (40 ml) while maitainig the internal temperature between 16° C. and 18° C. on an ice bath. The mixture is stirred for 6 hours with heating while keeping the internal temperature around 45° C. The reaction mixture is poured into hexane (300 ml), and the resulting precipitate is filtered and washed with hexane and water to yield 1-cyclopropyl-3-cyano-1,4-dihydro-4-oxo-6,7,8-trifluoroquinoline (10.2 g) as a colorless powder, m.p. 217°-218° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[O:12])[N:4]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[O:12])[N:4]=1)(=[O:29])[CH3:28]
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(CO)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(COC(C)=O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 0.5 g of the compound from Example 5 was added 1 ml of acetic anhydride and 1 ml of pyridine. After 1 hour at room temperature, ice-water was added, the precipitated oil was triturated, filtered, and washed with water to afford 0.4 g of the title compound, m.p. 145°-150°.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]=1>>[CH3:7][C:6]1([CH3:8])[CH2:5][C:4]2([CH3:10])[CH:3]([CH:11]3[CH:15]2[CH2:14][CH2:13][CH2:12]3)[C:2](=[O:1])[CH2:9]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: C1=CCCC1
Product: CC1(C)CC(=O)C2C3CCCC3C2(C)C1

Procedure:
The second photochemical reaction consists in reacting isophorone with cyclopentene to yield 5,5,7-trimethyltricyclo[6.3.0.02,7 ]undecane-3-one: ##STR2##
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].CCl.[NH2:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][OH:13].Cl.[CH2:18](OC(=N)C)C>ClCCl>[CH3:1][C:2]1[O:13][CH2:12][CH:11]([C:14]([O:16][CH3:18])=[O:15])[N:10]=1
Reactant: CCOC(C)=N
Reactant: N[C@@H](CO)C(=O)O
Reactant: CCN(CC)CC
Agent: CCl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C1COC(C)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
Triethylamine (5.86 g, 58.01 mmol) was added to a suspension of L-serine methyl hydrochloride (4.5 g, 29.03 mmol) and ethylacetimidate hydrochloride (4.3 g, 34.95 mmol) in dichloromethane (40 mL) at 0° C. over a period of 20 min. The mixture was then stirred at ambient temperature for 18 h. The suspension was filtered and washed with diethyl ether. The solid which precipitated from the filtrate was again filtered and washed with diethyl ether. The resulting filtrate was dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 2-methyl-4,5-dihydrooxazole-4-carboxylate (3 g, 72%) as a liquid.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=1)[CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[OH:4].[C:29]1([C:40](O)=[O:41])[CH:30]=[CH:31][CH:32]=[C:33]2[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35][C:34]=12.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C>[C:29]1([C:40]([NH:1][CH:2]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:17]=2)[CH:3]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[OH:4])=[O:41])[C:34]2[CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][C:33]=2[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(C(O)C(N)Cc2cccc(OC(F)(F)C(F)F)c2)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
While stirring methyl 4-[(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoate (10.80 g, 26.91 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (5.06 g, 26.9 mmol) and 1-hydroxybenzotriazole hydrate (4.12 g, 26.9 mmol) in acetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.16 g, 26.9 mmol) was added and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and passed through silica gel. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether to give the objective substance.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18](OC)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O.C1(C)C=CC=CC=1>[C:19]1([C:18](=[O:25])[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:10])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)C(C(=O)c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 60.3 %

Procedure:
In a 500-ml four-necked flask were placed 16.0 g (0.40 mole) of 60% sodium hydride (an oil-added grade), 39.6 g (0.20 mole) of deoxybenzoin, 200.0 g of toluene, and 198.8 g (1.46 moles) of methyl benzoate. The mixture was then heated under reflux with stirring for 15 hours while distilling off methanol. After the reaction was over, the reaction mixture was cooled to 40° C. and 60.8 g (0.60 mole) of concentrated hydrochloric acid and 180.0 g of water were added in drops. The reaction mixture was transferred to a separatory funnel and an organic layer was separated. The organic layer was concentrated under reduced pressure to dryness. The residue was purified by reslurrying with methanol and a solid was recovered by filtration and dried under reduced pressure to give 36.2 g of 1,2,3-triphenylpropane-1,3-dione.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:31][CH:30]3[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]4[C:27]([C:33](O)=[O:34])([NH:28][C:29]3=[O:32])[CH2:26]4)[CH2:15]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[CH3:49][C:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:31][CH:30]3[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]4[C:27]([C:33]([NH:56][S:53]([C:50]5([CH3:49])[CH2:52][CH2:51]5)(=[O:55])=[O:54])=[O:34])([NH:28][C:29]3=[O:32])[CH2:26]4)[CH2:15]2)[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Reactant: CC1(S(N)(=O)=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 6.9 %

Procedure:
Compound 3j (120 mg, 0.233 mmol) was dissolved in DCM (10 ml). EDAC (54 mg, 0.28 mmol) was added and the reaction mixture was stirred at RT for 2.5 h. Methyl cyclopropanesulfonic amide (35 mg, 0.256 mmol) and DBU (73 μl, 0.489 mmol) were added and the reaction mixture was stirred at RT over night. 5% Citric acid was added and the organic layer was separated and washed with brine, dried, filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound (10.2 mg, 21%), MS (M+H)+632.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To an ice-cold mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (4.00 g, 3.43 mmol), and triethylamine (4.43 g, 43.8 mmol) in tetrahydrofuran (70 mL) was added 2,2,2-trichloroethyl chloroformate (3.06 g, 14.4 mmol) and the mixture was stirred at room temperature for 48 h. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was filtered through a pad of silica gel eluted with ethyl acetate to afford a white solid. The solid was triturated with hexane to give the title compound (2.54 g, 47%) as a white solid.
Reaction SMILES: C(O[N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:8][C:7]1=C=O)(C)(C)C.OC1C=C(OC)C=CC=1C(OC)=O.OC1CCN([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])CC1>>[C:50]([O:49][C:47]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11]1)=[O:48])([CH3:53])([CH3:52])[CH3:51]
Reactant: COC(=O)c1ccc(OC)cc1OC1CCN(OC(C)(C)C)C(=C=O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: COC(=O)c1ccc(OC)cc1O
Product: COC(=O)c1ccc(OC)cc1OC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using a procedure similar to that used in Example 21-C, methyl 2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-methoxybenzoate (10.38 g, 71%) was prepared from methyl 2-hydroxy-4-methoxybenzoate and 4-hydroxy-1-tert-butoxycarbonylpiperidine.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=[O:6].[CH2:12]([S:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]1[N:32]([CH3:33])[C:23]2=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:22]2[N:21]=1)[CH3:13].C(=O)(O)[O-].[Na+].[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([S:14]([C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]1[N:32]([CH3:33])[C:23]2=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]2[N:21]=1)=[O:6])[CH3:13].[CH2:2]([S:39]([C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]1[N:32]([CH3:33])[C:23]2=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]2[N:21]=1)(=[O:43])=[O:41])[CH3:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1ccsc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccsc1-c1nc2cc(C(F)(F)F)cnc2n1C
Product: CCS(=O)c1ccsc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.25 g of 3-chloroperoxybenzoic acid (69 to 75%) was added to a mixture of 0.25 g of 2-(3-ethylthiothiophen-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 5 ml of chloroform, under ice cooling, then the mixture was heated to room temperature and stirred for 1 hour. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.10 g of 2-(3-ethylsulfinylthiophen-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (16)) and 0.12 g of 2-(3-ethylsulfonylthiophen-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (17)).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:30])([CH3:29])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([S:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]([Cl:36])([Cl:35])[CH2:33]O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:31][C:32]([Cl:36])([Cl:35])[CH2:33][O:17][C:16](=[O:18])[CH:15]([S:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([CH3:30])([CH3:29])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13][CH:12]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)O)cc1
Reactant: OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid (4.79 g, 10.68 mmol) and 2,2,2-trichloroethanol (1.67 g, 11.22 mmol) in anhydrous DCM (300 mL) was first added EDCxHCl (2.66 g, 13.89 mmol) then DMAP (13 mg, 0.1 mmol) under nitrogen atmosphere at 0° C. After complete addition the cooling bath was removed and the reaction mixture was stirred at ambient temperature until no starting material was left. The mixture was diluted with water and aq. HCl (2N) and extracted with DCM. The combined organic layers were dried (MgSO4) and the solvent was evaporated under reduced pressure to afford the crude product which was directly proceeded to the next step (5.47 g, 88.3%). 1H NMR (400 MHz, CDCl3): δ 7.16 (t, 2H), 7.10 (d, 2H), 7.01 (t, 2H), 6.87 (t, 2H), 4.61 (q, 4H), 3.48 (dd, 1H), 3.12 (dd, 1H), 2.73-2.89 (m, 5H), 0.85 (s, 9H), 0.00 (s, 6H). Mass Spectrum: M−H+ 579.03.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([OH:30])=O)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([N:34](CC)[CH:35](C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CNC.C1COCC1>CN(C=O)C.CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([N:34]([CH3:35])[CH3:31])=[O:30])[N:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)O)n4)n3Cc3ccccc3)n12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)N(C)C)n4)n3Cc3ccccc3)n12
Reaction time: 0.03 h

Procedure:
To a solution of 3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]propanoic acid (7.0 mg, 0.017 mmol, from Step 1) in DMF (0.3 mL) was added N,N-diisopropylethylamine (12 μL, 0.070 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (12 mg, 0.031 mmol, Aldrich). After stirring for 2 minutes, 2.0 M dimethylamine in THF (0.070 mL, 0.14 mmol, Aldrich) was added. After 15 minutes, the reaction was diluted with MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (4.3 mg, 58%).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[NH:14][CH:15]=[C:16]([C:18]4[O:19][C:20]([CH3:23])=[CH:21][CH:22]=4)[N:17]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[NH:14][CH:15]=[C:16]([C:18]4[O:19][C:20]([CH3:23])=[CH:21][CH:22]=4)[N:17]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2c[nH]c(/C=C/c3nc4cccc(C)n4n3)n2)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2c[nH]c(CCc3nc4cccc(C)n4n3)n2)o1
Yield: 27.9 %

Procedure:
To a solution of 5-Methyl-2-{(E)-2-[4-(5-methyl-furan-2-yl)-1H-imidazol-2-yl]-vinyl}-[1,2,4]triazolo[1,5-a]pyridine (20 mg, 0.07 mmol) in methanol (20 mL) was added 10% palladium on carbon (20 mg). The reaction was shaken under 3 bar atmosphere of hydrogen overnight. Filtration and evaporation of the volatiles afforded the title compound (6 mg, 30%). LC-MS: m/z=308.3 (MH+), tR=0.41 minutes, method A.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]#[N:18])[CH:16]=[C:11]2[C:10]([CH2:19]N(C)C)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23]C(OCC)=O.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]#[N:18])[CH:16]=[C:11]2[C:10]([CH2:19][Cl:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)Cc1cn(C(=O)OC(C)(C)C)c2ncc(C#N)cc12
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cc(C#N)cnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5-cyano-3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (634, 2.60 g, 8.66 mmol) in toluene (60.0 mL) under an atmosphere of nitrogen was added ethyl chloroformate (0.828 mL, 8.66 mmol). The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (635, 400 mg, 16%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH3:2].C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:7]([C:8]([Cl:21])=[O:9])[CH:6]=1)[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
To a solution of 5-nitroisophtalic acid monoethyl ester (80 g) in DCM (700 ml) at 25° C. was added 2M oxalyl chloride solution in DCM (63 ml), and DMF (5 ml). The reaction was stirred for 2 h and then concentrated in vacuum. The residue was triturated with toluene and again concentrated in vacuum leaving the title compound (60 g). Rt=1.40 min for derivatised methylester (method D).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].F[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].[H-].[Na+].CN(C=O)C>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:17]([F:18])([F:20])[F:19]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: COCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
3-Methoxypropan-1-ol (217 mg, 2.40 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (500 mg, 2.40 mmol), and NaH (240 mg, 6.0 mmol) were combined in THF (10 mL) and DMF (1 mL) at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was partitioned between ethyl acetate and a 1M aqueous solution of hydrochloric acid. The layers were separated and then the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude material was purified by column chromatography utilizing a gradient of 0-5% methanol in dichloromethane to yield 4-(3-methoxypropoxy)-3-(trifluoromethyl)benzoic acid (213 mg, 32%) as a white solid. ESI-MS m/z calc. 278.1, found 279.3 (M+1)+; Retention time: 1.38 minutes (3 min run).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:11][C:12]([NH2:14])=[O:13]>C1COCC1.CN(C=O)C>[CH:6]([C:4]1[N:3]=[CH:2][N:1]([CH2:11][C:12]([NH2:14])=[O:13])[CH:5]=1)=[O:7]
Reactant: NC(=O)CBr
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)Cn1cnc(C=O)c1
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A solution of 1H-imidazole-4-carbaldehyde (1.92 g, 20 mmol) in anhydrous THF (32 mL) and DMF (8 mL) was treated with sodium hydride (60% dispersion in mineral oil, 880 mg, 22 mmol) for 5 mins. 2-Bromoacetamide (3.59 g, 26 mmol) was added and the reaction was stirred continuously overnight. The THF was concentrated, loaded on a silica column, and eluted with 20% methanol in dichloromethane. The solvent was evaporated to yield 2.70 g of the product as a white solid (88.2%). HPLC Method D, r.t.=1.5 min, (96.4% purity at 256 nm). LC/MS calculated mass=153.14, [M−H]−=152, [M+H]+=154.
Reaction SMILES: [C:1]12([NH:11][C:12]3[C:17](C(O)=O)=[CH:16][N:15]=[C:14]4[NH:21][CH:22]=[CH:23][C:13]=34)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([N:26](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:48]1[CH2:53]COCC1>>[C:1]12([N:11]3[C:12]4=[C:13]5[CH:23]=[CH:22][NH:21][C:14]5=[N:15][CH:16]=[C:17]4[NH:26][C:53]3=[O:48])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cnc2[nH]ccc2c1NC12CC3CC(CC(C3)C1)C2
Reactant: CCN(CC)CC
Reactant: C1COCCO1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: O=c1[nH]c2cnc3[nH]ccc3c2n1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
4-(Adamantan-1-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (17 mg) and triethylamine (15 μl) were dissolved in dioxane (0.5 ml). To the mixture was added diphenylphosphoryl azide (DPPA) (18 μl) at 120° C. under stirring. The mixture was stirred at the same temperature for 2 hours and cooled to ambient temperature. The obtained solid was collected by filtration and washed with acetonitrile to obtain (adamantan-1-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2(1H)-one (11 mg).
Reaction SMILES: FC1C=CC([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=CC=1.CN(C)[C@@H]1CCN(C(C2C=C(C)NC=2C=O)=O)C1>C(O)C.N1CCCCC1>[NH:12]1[C:13]2[C:9](=[CH:8][CH:16]=[CH:15][CH:14]=2)[CH2:10][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Agent: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[3-(3R)-dimethylamino-pyrrolidine-1-carbonyl]5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[3-(3R)dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]44-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (63.9, 56%).