Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][CH2:18][OH:19])=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH:9]=[C:10]3[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH2:12][CH2:17][C:18]=4[O:19][C:3]=1[C:4]=23
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccccc2CCO)c2c(Cl)c(Br)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]cc3c2c1OC1=C3C=CC=CCC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 23 %

Procedure:
2-{2-[5-Bromo-4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-phenyl}-ethanol was dissolved in DMF (20 mL) and sodium hydride (100 mg) was added until the gas evolution stops. The mixture was stirred at 80° C. for 12 h. The reaction was quenched with saturated ammonium chloride solution (5 mL) and concentrated. The solid was suspended in water (20 mL) and was applied to a Varian chemelut cartridge and eluted with ethyl acetate. The crude product was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes followed by mass triggered reverse phase HPLC to afford 5-Bromo-7,8-dihydro-2H-6-oxa-2,3-diaza-benzocycloocta[cd]indene (28.6 mg, 0.09 mmol, 23% yield). 1H NMR (500 MHz, MeCN-d3) δ 12.18 (s, 1H), 8.33 (s, 1H), 7.62 (d, J=2.5 Hz, 1H), 7.47 (m, 1H), 7.38 (m, 1H), 7.29 (m, 2H), 4.30 (t, J=6 Hz, 2H), 2.91 (t, J=6 Hz, 2H). MS: m/z 315.0/317.0 (M+H+) and 5-Bromo-2-(2-trimethylsilanyl-ethoxymethyl)-7,8-dihydro-2H-6-oxa-2,3-diaza-benzocycloocta[cd] indene (45 mg, 0.01 mmol, 26% yield).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7](C(OC(C)(C)C)=O)[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:4][CH:3]=1.[F:36][C:37]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][C:38]=1[C:39]#[N:40].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:39]([C:38]1[CH:41]=[C:42]([C:2]2[S:6][C:5]([NH:7][CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=3)=[N:4][CH:3]=2)[CH:43]=[CH:44][C:37]=1[F:36])#[N:40]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1ncc(Br)s1
Reactant: CC1(C)OB(c2ccc(F)c(C#N)c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CNc1ncc(-c2ccc(F)c(C#N)c2)s1)Cc1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To a solution of (S)-tert-butyl 1-(N-(5-bromothiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.20 g, 0.34 mmol) in 3 mL of dioxane in a microwave safe tube, was added 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.13 g, 0.52 mmol), sodium carbonate, 2 M in water (0.69 mL, 1.4 mmol), and tetrakis(triphenylphosphine) palladium (0.020 g, 0.017 mmol). The mixture was purged with nitrogen for 30 seconds and the tube was sealed. The tube was then heated to 120° C. in a Personal Chemistry microwave unit for 20 minutes. The mixture was diluted with 5 mL of water and extracted twice with 8 mL of EtOAc. The combined organic extracts were washed with 7 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure afforded tert-butyl (S)-1-(5-(3-cyano-4-fluorophenyl)thiazol-2-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate, mixed with the other two products. The crude mixture was carried on to the next reaction without any further purification.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH:13]([C@@H:16]2[CH2:18][C@@H:17]2[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:23]([O:22][C:20]([NH:19][C@H:17]1[CH2:18][C@H:16]1[CH:13]1[CH2:14][CH2:15][NH:11][CH2:12]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H]1C1CCN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H]1C1CCNC1
Yield: 100.1 %

Procedure:
To 10 ml of an ethanol solution of 340.4 mg (0.94 mmol) of 1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine was added 350 mg of 5% palladium-on-carbon, and the mixture was shaken in a hydrogen stream (3.5 kg/cm2) for 1.5 hours. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to give 213.0 mg (99.7%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([CH:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:7])#[N:2].[CH2:22]([Mg]Br)[CH3:23].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:1]([CH2:3][CH2:4][O:5][C:6]([CH2:8][C:9]1([CH2:22][CH3:23])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)=[O:7])#[N:2]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)OCCC#N)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1(CC(=O)OCCC#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.00 g (6.79 mmol) of tert-butyl 4-(cyanoethoxycarbonylmethylene)piperidine-1-carboxylate (WO 2006/001 752) in 33 mL of tetrahydrofuran are added dropwise, at −5° C. under argon, 4.53 mL (13.59 mmol) of a 3M solution of ethylmagnesium bromide in ether. The reaction medium is then stirred at room temperature for 12 hours. Ethyl acetate is added and the medium is cooled in a bath of ice/water, followed by addition of saturated ammonium chloride solution. The aqueous phase is separated out and extracted three times with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue is chromatographed on silica gel, eluting with a 95/5 mixture of cyclohexane and ethyl acetate to give 1.63 g of pure product in the form of a white powder.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5].[CH:12]([Mg]Br)=[CH2:13].Cl>O1CCCC1>[S:8]1[CH:9]=[CH:10][C:6]([C:4](=[O:5])[CH:12]=[CH2:13])=[CH:7]1
Reactant: CON(C)C(=O)c1ccsc1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)c1ccsc1
Temperature: -10 °C
Yield: 77 %

Procedure:
The product from step (a) (2.074 g, 12.1 mmol) was dissolved in anhydrous tetrahydrofuran (30 ml) and the solution cooled to −10° C. Vinyl magnesium bromide (1M, 14.5 ml, 14.5 mmol) was added dropwise, keeping the temperature below 0° C. The resultant solution was stirred at 0° C. for 2.5 h, then allowed to warm to room temperature. The reaction mixture was slowly poured into aqueous 2M hydrochloric acid (200 ml) and ice. Extracted with ethyl acetate (3×70 ml) and the combined extracts were washed with water (2×30 ml) and brine (20 ml), dried (magnesium sulphate) and evaporated in vacuo to give the title compound (1.288 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:54][C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[CH:57]=[CH:58][N:59]([C@@H:66]([CH3:70])[C:67]([NH2:69])=[O:68])[C:60]2=[O:65]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:54][C:55]2[CH:64]=[CH:63][CH:62]=[C:61]3[C:56]=2[CH:57]=[CH:58][N:59]([C@@H:66]([CH3:70])[C:67]([NH2:69])=[O:68])[C:60]3=[O:65])=[O:11])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: C[C@@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(Cl)cc3C(F)(F)F)cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A round bottom flask was charged with 2-(4-chloro-2-(trifluoromethyl)phenyl)acetic acid (0.13 g, 0.00056 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.3 g, 0.0009 mol), N,N-diisopropylethylamine (0.2 mL, 0.0009 mol), N,N-dimethylformamide (5 mL, 0.06 mol) and (S)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)propanamide (0.1 g, 0.0004 mol), and the reaction was stirred for 16 h at room temperature. The reaction was quenched with water and extracted with dichloromethane, washed with 2N HCl, saturated sodium bicarbonate solution, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (12 g, 0-10% MeOH/DCM) to yield the product as a white solid. MS m/z=452.4 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 10.11 (s, 1H), 8.07 (d, J=8.80 Hz, 1H), 7.79-7.76 (m, 3H) 7.64-7.60 (m, 2H), 7.49 (d, J=8.08 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.23 (bs, 1H), 6.71 (d, J=7.77 Hz, 1H), 5.50-5.45 (q, J=7.24 Hz, 1H), 4.06 (s, 2H), 1.55 (d, J=7.54 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][Mg]Br>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](=[O:5])[CH3:15]
Reactant: C[Mg]Br
Reactant: Cc1ccc(C(F)(F)F)cc1C(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(F)(F)F)ccc1C

Procedure:
The title compound was synthesized from 2-methyl-5-(trifluoromethyl)-benzoyl chloride via the reaction of the corresponding Weinreb amide with methyl magnesium bromide in THF.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19]([CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: O=S(=O)(CCCCBr)c1ccccc1
Product: O=C1CCc2ccc(OCCCCS(=O)(=O)c3ccccc3)cc2N1

Procedure:
Prepared analogous to Example 4 from 7-hydroxy-3,4-dihydro-carbostyril (see N. Shigematsu et al., Chem. Pharm. Bull. 1961, 970-975) and 4-phenylsulfonyl-butyl bromide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][NH:10][C:11]([N:13]=[CH:14]N(C)C)=[S:12])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22](=[O:25])[CH2:23]Br>>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:23]([C:22](=[O:25])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[CH3:19])=[CH:14][N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=NC(=S)NCCNC(=O)OC(C)(C)C
Reactant: Cc1ccccc1C(=O)CBr
Product: Cc1ccccc1C(=O)c1cnc(NCCNC(=O)OC(C)(C)C)s1
Yield: 75 %

Procedure:
The title compound was synthesised from [2-(3-Dimethylaminomethylene-thioureido)-ethyl]-carbamic acid tert-butyl ester and 2-methyl phenacylbromide (Literature: WO9907666) according to the procedure described for Example 25 in 75% yield. MS (m/e): 362.1 (MH+, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH2:5][C:6]1[CH:11]=[C:10]([C:12]2([CH3:17])OCCO2)[CH:9]=[CH:8][C:7]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][O:3][N:4]=[C:12]([C:10]1[CH:9]=[CH:8][C:7]([OH:18])=[C:6]([NH2:5])[CH:11]=1)[CH3:17]
Reactant: CON
Reactant: CC1(c2ccc(O)c(N)c2)OCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CON=C(C)c1ccc(O)c(N)c1
Temperature: 25 °C

Procedure:
A mixture of O-methylhydroxylamine hydrochloride (535 mg, 6.40 mmol), 2-amino-4-(2-methyl-1,3-dioxolan-2-yl)phenol D62 (250 mg, 1.28 mmol) and potassium carbonate (442 mg, 3.20 mmol) in ethanol (10 mL) was heated to reflux for 2 hr. The mixture was cooled to rt and concentrated to dryness under vacuum and the residue partitioned between DCM and water. The organic phase was separated washed with brine, dried (MgSO4) and concentrated to dryness in vacuo. The residue was purified using silica gel chromatography eluting with 0 to 10% MeOH in DCM. The title product was isolated as a pale brown solid, 224 mg, 97%.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[N:25](S(C2C=CC(C)=CC=2)(=O)=O)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1.O>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[NH:25][C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1
Reactant: COc1cc(OC)c2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)c2c(c1)c(-c1cc3cccnc3[nH]1)cn2C
Temperature: 80 °C
Yield: 35.4 %

Procedure:
3.3 ml of a 5N aqueous potassium hydroxide solution are added to a solution of 0.31 g of 2-(5,7-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 20 ml of methanol. The mixture is heated at around 80° C. for approximately 18 hours. The reaction medium is run into a mixture of 100 ml of ice plus, water, and extracted with three times 75 ml of ethyl acetate. The combined organic phases are washed with 100 ml of water and then with 100 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: dichloromethane]. 0.073 g of 2-(5,7-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14]C)(C)(C)[CH3:11]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:10](=[O:14])[CH3:11])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: COC(C)(C)C
Product: CC(=O)Nc1cc(Cl)ccc1O
Temperature: 22.5 °C
Yield: 92 %

Procedure:
143.6 g (1 mole) of 2-amino4-chlorphenol was suspended in 550 ml of methyl t-butyl ether under mild nitrogen purge. The mixture was heated to reflux until the material was dissolved. In 40 minutes 112.3 g of acetic anhydride was added. After the addition the mixture was cooled to 20-25° C. in one hour. After stirring for an additional hour the mixture was cooled to 0-5° C. under stirring and kept on this temperature for an additional hour. The product was filtered off, washed with 200 ml of methyl t-butyl ether twice and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 92%.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[C:20]1([CH2:30][C:31](O)=[O:32])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:31](=[O:32])[CH2:30][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc2ccccc12
Product: O=C(Cc1cccc2ccccc12)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product from Example 86A and 2-(1-naphthyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 8.18 (d, J=8.2 Hz, 1H), 7.95-8.01 (m, 3H), 7.88 (d, J=8.1 Hz, 1H), 7.70-7.77 (m, 1H), 7.61-7.66 (m, 4H), 7.54-7.60 (m, 3H), 7.51 (dd, J=8.2, 7.1 Hz, 1H), 4.19 (s, 2H); MS (ESI−) M/Z 438 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][C:21]2[N:25]([CH3:26])[N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[N:14]=1.O>CC(N(C)C)=O>[CH3:19][C:17]1[CH:18]=[C:13]([N:5]2[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]2)[N:14]=[C:15]([O:20][C:21]2[N:25]([CH3:26])[N:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[CH:16]=1
Reactant: Cc1cc(Cl)nc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(Oc2cc(C(F)(F)F)nn2C)nc(-n2cc(C(F)(F)F)cn2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
0.385 g of 4-trifluoromethylpyrazole is introduced under nitrogen in 10 ml of dimethylacetamide and at 0° C. 0.096 g of NaH is added. The mixture is allowed to come to RT over 30 min and then 0.757 g of 2-chloro-4-methyl-6-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine is added and the mixture is heated at 140° C. for 7 h, cooled to RT and poured into water. The product is extracted twice with ethyl acetate/heptane (1:1) and twice with ethyl acetate and then washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated. Chromatographic purification on silica gel gives 0.332 g of 4-methyl-2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(4-trifluoromethylpyrazol-1-yl)pyridine as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[CH:15]=[C:16]([C:31]([O:33]C)=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[CH:15]=[C:16]([C:31]([OH:33])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc([C@H]2CCCN2c2cccc(OC)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(N2CCC[C@@H]2c2cc(C(=O)O)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 74.8 %

Procedure:
Methyl 8-[(2R)-(1-(3-methoxyphenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylate (90 mg, 0.19 mmol) was reacted with sodium hydroxide (38.7 mg, 0.97 mmol) to give 8-[(2R)-(1-(3-methoxyphenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (64 mg, 73%) as a beige solid. Mass Spectrum: m/z [M+H]+=451.
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][CH:12]=1)(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:6][C:7]1[CH:8]=[C:9]([C:13](=[O:19])[CH2:14][CH2:15][C:16]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[O:18])[CH:10]=[CH:11][CH:12]=1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CCC(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)CCC(=O)c2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Under nitrogen, to a solution of the product of Step 1 (490 mg, 2.52 mmol) in DMF (10 mL), was added 1-methylpiperazine (505 mg, 5.04 mmol), HOBT (1.02 g, 7.6 mmol), HBTU (950 mg, 2.5 mmol), followed with 4-methylmorpholine (770 μL, 7.6 mmol). This mixture was then stirred at rt overnight. The reaction mixture was concentrated and the residue was purified with reverse phase HPLC (5% MeCN/H2O→50% MeCN/H2O), to afford the title compound as white solid (572 mg, 82%). MS (ES+) m/e 277 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:8][C:9]1[S:10][C:11]([CH:14]2[CH2:16][CH2:15]2)=[N:12][N:13]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:40]1[N:41]=[CH:42][NH:43][CH:44]=1)([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:40]1[N:41]=[CH:42][N:43]([CH2:8][C:9]2[S:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[CH:44]=1)([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:23])([CH3:19])([CH3:20])[CH3:18]
Reactant: CCOC(=O)C(CCCCNC(=O)OC(C)(C)C)(C(=O)OCC)c1c[nH]cn1
Reactant: ClCc1nnc(C2CC2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCNC(=O)OC(C)(C)C)(C(=O)OCC)c1cn(Cc2nnc(C3CC3)s2)cn1
Yield: 17.9 %

Procedure:
Together with 1.97 g (6.04 mmol) of cesium carbonate and 0.29 g (1.66 mmol) of 2-chloromethyl-5-cyclopropyl-1,3,4-thiadiazole, a solution of 0.60 g (1.51 mmol) of diethyl 2-(4-tert-butoxycarbonylaminobutyl)-2-(1H-imidazol-4-yl)malonate in 12 ml of DMF was heated at 75° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was taken up in ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. Chromatographic purification of the residue on silica gel (CH2Cl2:MeOH:water:acetic acid 95:5:0.5:0.5) gave 0.145 g (18%) of the title compound.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[N:10]=[C:11]([CH2:19][C:20]([NH2:22])=[O:21])[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.C[O:24][C:25](=O)[C:26]([C:28]1[C:36]2[C:31](=[C:32]([CH3:37])[CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=O.C1COCC1>O>[CH2:2]1[C:3]2([CH2:8][N:7]([C:9]3[N:10]=[C:11]([C:19]4[C:20](=[O:21])[NH:22][C:25](=[O:24])[C:26]=4[C:28]4[C:36]5[C:31](=[C:32]([CH3:37])[CH:33]=[CH:34][CH:35]=5)[NH:30][CH:29]=4)[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:1]1
Reactant: NC(=O)Cc1nc(N2CCNC3(CC3)C2)cc2ccccc12
Reactant: COC(=O)C(=O)c1c[nH]c2c(C)cccc12
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c(C3=C(c4nc(N5CCNC6(CC6)C5)cc5ccccc45)C(=O)NC3=O)c[nH]c12
Reaction time: 1.5 h

Procedure:
2-[3-(4,7-Diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetamide (4.95 g, 16.70 mmol) and (7-Methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (5.44 g, 25.05 mmol) are azeotroped twice with dry THF. Dry THF (100 ml) is then added, and under an atmosphere of argon KOtBu (1.0 M in THF, 50 ml, 50 mmol) is added dropwise during 20 min. After an additional 90 min, TLC analysis indicates complete conversion of starting materials. The reaction mixture is diluted with H2O and extracted twice with EtOAc. The combined organic layers are washed twice with saturated aq NH4Cl solution (back extracted), dried over Na2SO4 and concentrated. Purification by FCC(CH2Cl2/MeOH 100:0 to 98:2 to 96:4 to 94:6 to 92:8 to 90:10) yields the title compound, which is converted to its acetate salt by concentration of a EtOH/AcOH solution. 1H NMR (DMSO, 400 MHz) δ 0.26-053 (br, 4H), 1.89 (s, 3H, CH3COOH), 2.36 (s, 3H), 2.80 (br m, 2H), 3.15-3.48 (br m, 2H), 6.14 (d, J=8.2 HZ, 1H), 6.44 (dd, J=8.2/7.4 Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 7.00 (s, 1H), 7.02 (dd, J=8.2/8.2 Hz, 1H), 7.40 (dd, J=8.2/8.2 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.97 (d, J=2.9 Hz, 1H), 11.04-11.21 (br, 1H), 11.86 (d, J=2.9 Hz, 1H); ES-MS: 464 [M+H]+.