Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: Cc1cccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-2-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K11) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light brown substance (339 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:10]=[CH:11][C:3]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1cnc2[nH]ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(F)cnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (Adesis, 4.60 g, 27.0 mmol) in N,N-dimethylformamide (70 mL) was added 60% sodium hydride in mineral oil (1.186 g, 29.7 mmol) at 0° C. and the mixture was warmed to room temperature and stirred for 30 minutes. Benzenesulfonyl chloride (3.79 mL, 29.7 mmol) was added and after stirring 3 hours, the mixture was quenched with water and aqueous sodium bicarbonate. The suspension was filtered, washed with aqueous sodium bicarbonate, water, and heptanes, and vacuum oven-dried to give the title compound. MS (ESI+) m/z 311.0 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[C:3]1=O.[F:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[F:17][CH2:18][CH2:19][N:20]1[C:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])[C:3]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2
Reactant: O=C1C(Br)CCCC1C(=O)N1CCCCC1
Reactant: FCCNc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: O=C(C1CCCc2c1c1ccccc1n2CCF)N1CCCCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
A mixture of 2-bromo-6-(piperidine-1-carbonyl)-cyclohexanone (20; prepared according to example 3(b)) (500 mg, 1.7 mmol) and (2-fluoro-ethyl)-phenyl-amine (24) (890 mg, 3.5 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (2 mL) and dry zinc chloride (682 mg, 5 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with 2 N HCl (20 mL), water (2×20 mL) and aqueous potassium carbonate solution (2×20 mL) then dried and concentrated in vacuo. The crude material was triturated with diethyl ether to afford 151 mg (27%) of [9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (non-radioactive imaging agent 6) as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 21.6, 21.8, 24.7, 26.5, 26.9, 27.4, 37.3, 43.1 (d, JCF=45 Hz), 47.0, 82.1 (d, JCF=173 Hz), 108.5, 108.9, 118.6, 119.4, 121.0, 126.8, 136.2, 172.7.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH2:19].C(N(CC)CC)C.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH:19][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: COC(=O)CN
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)Cc1cccc([N+](=O)[O-])c1
Yield: 90.1 %

Procedure:
To a stirred solution of 3-nitrophenylacetic acid (10 g, 0.055 mol), glycine methyl ester hydrochloride (7.3 g, 0,058 mol), triethylamine (8.0 ml, 0.058 mol) and 4-dimethylaminopyridine (7.1 g, 0,058 mol) in dichloromethane (200 ml) was added, under nitrogen, 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide(11.1 g, 0.058 mol), the mixture was stirred at room temperature for 18 h then the solvent removed in vacuo. Ethyl acetate (300 ml) was added to the residue and the mixture partitioned with 1M hydrochloric acid (2×200 ml), saturated sodium bicarbonate solution (2×200 ml), water (100 ml) and brine (100 ml). The organic phase was separated then evaporated in vacuo. The residue was triturated with ether (200 ml) to afford the desired amide (12.5 g, 90%) as a white solid. mp 104°-105° C. 1H NMR (360MHz, CDCl3) δ3.71 (2H, s), 3.76 (3H, s), 4.06 (2H, d, J 5Hz), 6.06 (1H, br s), 7.53 (1H, dd, J=8 and 8Hz), 7.67 (1H, d, J =8Hz), 8.16 (2H, m).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6][C:7]([C:10]1[S:14][C:13]([NH2:15])=[N:12][N:11]=1)([CH3:9])[CH3:8]>C(OC(=O)C)C>[CH3:5][S:6][C:7]([C:10]1[S:14][C:13]([N:15]=[C:1]=[O:2])=[N:12][N:11]=1)([CH3:9])[CH3:8]
Reactant: CSC(C)(C)c1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CSC(C)(C)c1nnc(N=C=O)s1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A 300 milliliter, 3-neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotometer was charged with 50 milliliters of ethyl acetate and then with 20 grams of phosgene. An additional 50 milliliters of ethylacetate and 6.6 grams (0.035 mole) of 5-(1-methylthio-1-methylethyl)-2-amino-1,3,4-thiadiazole (prepared above) at a temperature of 0° C. was added. The resulting mixture was stirred for 17 hours at room temperature and then the flask was purged with nitrogen until no COCl2 was detected. The slurry was filtered, and the filter cake was dried in a vacuum oven to a m.p. of 161°-164° C., and the filtrate was topped on a roto-vac to yield more crystals with a m.p. of 161°-162° C., which were combined with the first crystals to yield 7.1 grams of 5-(1-methylthio-1-methylethyl)-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:21][C:19](=[O:22])[CH3:20])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 68.7 %

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.82 g) and potassium thioacetate (2.31 g) was heated to 60° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.80 g). To a solution of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (607 mg) in dry MeOH (5 mL) was added a solution of sodium methoxide in MeOH (25% wt, 0.59 mL). After stirring for 15 min, toluene-4-sulfonic acid 3-methoxy-propyl ester (described elsewhere, 571 mg) was added in MeOH. After 24 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to yield 4-(3-methoxy-propylsulfanyl)-piperidine-1-carboxylic acid tent-butyl ester. Treatment with mCPBA (as described above) yielded 4-(3-methoxy-propane-1-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)Nc1ccc(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
TFA (0.1 mL, 1.587 mmol) was added to a solution of 1-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3-(2,4-difluorophenyl)urea (15 mg, 0.030 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound in a 60% yield. 1H NMR (400 MHz, CD3OD): δ 8.38 (s, 1H), 8.05-7.99 (m, 1H), 764 (m, 3H), 7.56 (d, 1H, J=9.2 Hz), 7.26 (m, 2H), 7.01 (m, 1H), 6.92 (m, 1H); ESI-MS [M+H]+: 405.3.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][C:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][NH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:36]4[C:32]([CH3:31])=[N:33][NH:34][CH:35]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2c(-c3c[nH]nc3C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Yield: 15 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (100 mg, 0.191 mmol) in 1,4-dioxane (2 mL) was added 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (59.6 mg, 0.286 mmol), bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol) and potassium carbonate (79 mg, 0.573 mmol). Water (1 mL) was added and the mixture heated at 100° C. in a microwave for 15 min (×2). The solvent was removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase re-extracted with ethyl acetate (2×20 mL). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-80% ethyl acetate in cyclohexane and then further purified using MDAP (acidic conditions), to give the title compound (15 mg). LCMS (A) m/z: 525 [M+1]+, Rt 1.23 min (acidic).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C@@H:16]([NH:27]C(=O)OC(C)(C)C)[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:3]=1[C:35]([NH:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1)=[O:36].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:27][C@H:16]([C:4]1[C:3]([C:35]([NH:37][C:38]2[S:39][CH:40]=[CH:41][N:42]=2)=[O:36])=[C:2]([OH:1])[C:11]2[C:6](=[C:7]([C:12]([F:13])([F:15])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1c[nH]c2ccccc12)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.6 %

Procedure:
A mixture of 16.9 g of product of Example 11, 170 ml of methylene chloride and 85 ml of trifluoroacetic acid was stirred for 3 hours at ambient temperature and the solvents were eliminated under reduced pressure. The crude oil residue was crystallized from ether and after filtering, rinsing and drying under reduced pressure at 50° C., 16.4 g of 2-[(S) 1-amino-2-(1H-indol-3-yl)-ethyl]-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide were obtained in the form of trifluoroacetate melting at about 190° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[N:6]=1.[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1.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.[Pd].[Cu](I)I>[C:20]([C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[N:6]=1)#[C:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C#CCCCC
Reactant: O=C1c2ccccc2C(=O)N1OCc1csc(Br)n1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC#Cc1nc(CON2C(=O)c3ccccc3C2=O)cs1
Temperature: 25 °C
Reaction time: 21 h
Yield: 58.7 %

Procedure:
To a solution of 2-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1H-isoindole-1,3(2H)-dione (23.1 g, 68.1 mmol) in dry tetrahydrofuran (300 mL) were added 1-hexyne (11.2 g, 136 mmol), triethylamine (13.8 g, 136 mmol). The reaction mixture was degassed by blowing a flow of Argon through it, then palladium tetrakis(triphenylphosphine) (3.94 g, 3.41 mmol) and copper iodide (1.30 g, 6.81 mmol) were added. After stirring at room temperature for 21 h under argon, the mixture was concentrated in vacuo, diluted with water (800 mL) and ethyl acetate (900 mL), the organic layer was washed with water, dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded 2-{[2-(hex-1-yn-1-yl)-1,3-thiazol-4-yl]methoxy}-1H-isoindole-1,3(2H)-dione [13.6 g, yield 59%; HPLC/MS: m/z=341 (M+H); log P(HCOOH)=3.78].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[Br:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Br:10][CH2:11][CH2:12][CH2:13][C:14]([NH:7][C:6]1[CH:8]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:9])=[O:15]
Reactant: Nc1cc(Br)ccc1F
Reactant: O=C(Cl)CCCBr
Solvent: Cc1ccccc1
Product: O=C(CCCBr)Nc1cc(Br)ccc1F
Temperature: 100 °C

Procedure:
A solution of 5-bromo-2-fluoroaniline (10 g, 52 mmol) in toluene (150 ml) was treated with 4-bromobutyryl chloride (6.1 ml, 52 mmol) and then heated at 100° C. for 14 h. The reaction was cooled then washed with water, 10% sodium carbonate, 1N HCl and water, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The resulting tan solid was triturated with 5% ether in isohexane and collected by filtration to afford 4-bromo-N-(5-bromo-2-fluorophenyl)butyramide. This solid was dissolved in anhydrous N,N-dimethylformamide (150 ml) then treated with sodium hydride (1.4 g of a 60% dispersion in oil) added in portions over 5 min. The resulting mixture was stirred at 60° C. for 60 min, cooled and treated with methanol (10 ml). The reaction was diluted with water (1500 ml) and extracted with ether (2×400 ml). The organics were combined, washed with water (×3), brine, dried over anhydrous magnesium sulphate, filtered and pre-adsorbed onto silica. Chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (20-50%), gave 1-(5-bromo-2-fluorophenyl)pyrrolidin-2-one (9.1 g, 67%) as a straw-coloured solid: δH (400 MHz, CDCl3) 2.17-2.25 (2H, m), 2.55-2.59 (2H, m), 3.80-3.84 (2H, m), 7.20 (1H, dd, J 10.5 and 9), 7.33-7.37 (1H, m), 7.59 (1H, dd, J 7 and 2.5).
Reaction SMILES: [CH2:1]([C:4]1([CH2:10][OH:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].N1C=CN=C1.[CH2:17]([Si:19]([CH2:23][CH3:24])([CH2:21][CH3:22])Cl)[CH3:18]>CN(C)C=O>[CH2:1]([C:4]1([CH2:10][O:11][Si:19]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:17][CH3:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C=CCC1(CO)CCCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCC1(CO[Si](CC)(CC)CC)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1-allylcyclohexyl)methanol (1.0 g) in N,N-dimethylformamide (7 mL) were added imidazole (661 mg) and triethylchlorosilane (1.41 mL) at room temperature. After stirring the solution at room temperature for 3 hours, N,N-dimethylformamide was added thereto and it was extracted with hexane. The combined hexane layer was washed with acetonitrile and concentrated under reduced pressure to give the title compound (1.70 g). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(#N)C>[Si:13]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][Cl:1])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: OCCOCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCOCCCl
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethylene glycol mono-2-chloroethyl ether (6.2 g, 50 mmol) in acetonitrile (150 mg) were added imidazole (6.77 g, 99.54 mmol) and t-butyldimethylsilyl chloride (11.25 g, 74.65 mmol) at room temperature. The reaction mixture was stirred overnight at the same temperature. After the reaction was completed, the mixture was filtered through a filter paper, and concentrated under reduced pressure. Then, the concentrate was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=9:1) to give the title compound (11.0 g, yield 92%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][OH:20])[N:10]=1.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[Cl:21][C:6]1[CH:5]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][O:20][C:41](=[O:43])[CH3:42])[N:10]=1
Reactant: CC(=O)Cl
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCn1nc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)cc(C(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A solution of 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.43 mmol), N,N-diisopropylethylamine (0.23 mL, 1.29 mmol) and 4-N,N-dimethylaminopyridine (25.8 mg, 0.21 mmol) in methylene chloride (3.0 mL) cooled to 0° C. was treated with acetyl chloride (33.5 μL, 0.47 mmol). The reaction mixture was warmed to 25° C. over 3.5 h. The reaction mixture was then warmed to 40° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and then partitioned between methylene chloride (100 mL) and water (100 mL). The organics were then washed with a 1N aqueous hydrochloric acid solution (3×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. ISCO CombiFlash chromatography (40 g, 0.5-4.0% methanol/methylene chloride) afforded acetic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester (45.9 mg, 21%) as a yellow solid. ES+-HRMS m/e calcd for C20H16N6O6Cl2 (M+H+) 507.0581, found 507.0582.
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C([Cl:16])(=O)C>II>[Cl:16][CH2:2][CH2:1][O:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(OCC)OCC
Agent: II
Product: CCOC(=O)COCCCl
Temperature: 50 °C
Yield: 97.3 %

Procedure:
40 mL (224 mmol) of ethyl diethoxyacetate, 38 mL (536 mmol) of acetyl chloride and 0.11 g (0.45 mmol) of iodine are placed in a round-bottomed flask and heated at 50° C. for 24 hours. The reaction progress is monitored by NMR. The excess acetyl chloride is removed by evaporation under vacuum. 36.3 g (100%) of ethyl chloroethoxyacetate are obtained in the form of a liquid colored brown by the residual iodine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][C@H:19]1[CH2:24][NH:23][C@H:22]([CH3:25])[CH2:21][NH:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:20]3[CH2:21][C@@H:22]([CH3:25])[NH:23][CH2:24][C@@H:19]3[CH3:18])=[N:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: C[C@@H]1CN[C@@H](C)CN1
Product: C[C@@H]1CN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)[C@@H](C)CN1
Yield: 5.6 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and trans-2,5-dimethylpiperazine (114 mg, 1.0 mmol) were reacted according to GP4 to give 1.9 mg of the title compound (160FE33A). MS (ESI) 341 (MH+). Purity for MH+ (UV/MS) 100/82.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][CH3:13])[CH2:10][CH3:11].CCN(C(C)C)C(C)C.[CH2:24](Cl)[O:25][CH3:26].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:14][CH2:24][O:25][CH3:26])([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: CCC(O)(CC)c1ccc(C)cc1Br
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)(OCOC)c1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 11 h
Yield: 57 %

Procedure:
To a stirring solution of 3-(2-bromo-4-methylphenyl)pentan-3-ol (6.0 g, 23.3 mmol) in DCM (20 mL) at rt were successively added DIPEA (8.1 mL, 47.4 mmol) and MOMCl (2.7 mL, 35.5 mmol) over a 10 min period. The solution was stirred 11 h at rt followed by addition of aqueous NH4Cl solution (100 mL). The aqueous phase was segregated, and the organic one was washed with water (100 mL), brine, dried with anhydrous Na2SO4, filtered, and concentrated to give pure 2-bromo-1-(3-(methoxymethoxy)pentan-3-yl)-4-methylbenzene (4.0 g, yield 57%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC#N>[N:22]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: C1CNCCN1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: CC#N
Product: O=C(CN1CCNCC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 39.4 %

Procedure:
A slurry of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol) and piperazine (58 mg, 0.672 mmol) in MeCN (5 mL) was heated at reflux for 48 hrs. The resulting precipitate was filtrated, washed with MeCN (10 mL) and submitted to preparative LCMS to afford 2-(piperazin-1-yl)-N-(3-(quinoxalin-2-yl)phenyl)acetamide (46 mg, 39% yield). LCMS calculated for C20H21N5O (M+H): 348.42. found 348. 1H-NMR (DMSO-d6, 400 Mhz) δH: 9.92 (1H, br.), 9.52 (1H, s), 8.55 (1H, m), 8.13-8.20 (2H, m), 8.05-8.08 (1H, m), 7.82-7.98 (3H, m), 7.55-7.60 (1H, m), 3.25-3.40 (NH and 6H, br.), 2.80-2.88 (4H, br.).