Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Mg].[C:13]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].Cl>O1CCCC1.C(OCC)C>[OH:22][C:19]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH2:20][CH2:21][N:16]([C:13](=[O:15])[CH3:14])[CH2:17][CH2:18]1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc2ccccc2c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)N1CCC(O)(c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
2-Bromonaphthalene (24.75 g, 0.12 mol) in tetrahydrofuran (180 ml) was slowly added to magnesium (2.9 g, 0.12 mol) in tetrahydrofuran (20 ml) and the mixture stirred at room temperature for one hour. The resultant solution was slowly added to 1-acetyl-4-piperidone (16.9 g, 0.12 mol) in tetrahydrofuran (200 ml) at -78° C., and then allowed to stir to room temperature. The white suspension formed was hydrolysed with hydrochloric acid (120 ml, 1M) and the organic layer removed and concentrated in vacuo. The residue was taken up in dichloromethane, dried (MgSO4), and concentrated to leave a clear oil. Trituration of this oil with diethyl ether gave 1-(4-hydroxy-4-naphthalen-2-yl-piperidin-1-yl)ethanone (13.92 g, 43%) as a white solid; δH (CDCl3) 1.90 (4H, m, 2× piperidinyl CH2), 2.10 (2H, m, piperidinyl CH2), 2.15 (3H, s, COCH3), 3.20 (1H, m, piperidinyl H), 3.70 (1H, m, piperidinyl H), 4.60 (1H, br m, OH), 7.50 (2H, m, ArH), 7.60 (1H, dd, J 9.6, 1.6 Hz, ArH), and 7.90 (4H, m, ArH).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:12]O)[O:9]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:15][CH2:12][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[O:9]1
Reactant: OCC1CCc2ccc(O)cc2O1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc2c(c1)OC(CBr)CC2
Temperature: 0 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
A mixture of (7-hydroxychroman-2-yl)methanol (6.18 g, 34.3 mmol) and CBr4 (19.3 g, 58.3 mmol) in CH2Cl2 is treated with a solution of triphenylphosphine (9.0 g, 34.3 mmol) in CH2Cl2 at 0° C., stirred at 0° C. for 6 hr and concentrated in vacuo to give a residue. The residue is purified by column chromatography (silica gel, 60% CH2Cl2 in hexanes as eluent) to give the title product as an oil, 4.61 g (55% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][O:34][NH2:35])[N:27]([CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1>CN(C=O)C>[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][O:34][NH:35][C:11]([CH:8]3[CH2:10][CH2:9]3)=[O:12])[N:27]([CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1c(CONC(=O)C2CC2)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
Triethylamine (0.634 mL, 4.55 mmol) and cyclopropanecarbonyl chloride (0.248 mL, 2.73 mmol) were added to a solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 685 mg, 2.27 mmol) in DMF (5 mL). The cloudy mixture was stirred for 2 hours at room temperature, then was partitioned between water (20 mL) and dichloromethane (30 mL). The aqueous layer was extracted with dichloromethane (2×30 mL). The organic layers were combined and allowed to stand overnight at room temperature. Crystals formed and were isolated by filtration, washed with dichloromethane and acetonitrile, and dried in a vacuum oven to provide 442 mg of N-{[4-Amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}cyclopropanecarboxamide as a hydrate, white crystals, mp 209-210° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1([CH:18]([OH:21])[CH:19]=[CH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.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>[CH:13]1([C:18](=[O:21])[CH2:19][CH2:20][C:2]2[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([F:12])[CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#CCOc1ccc(Br)cc1F
Reactant: C=CC(O)C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#CCOc1ccc(CCC(=O)C2CCCC2)cc1F
Temperature: 140 °C
Yield: 90.8 %

Procedure:
A mixture of (4-bromo-2-fluorophenoxy)acetonitrile (2.5 g, 10.8 mmol), 1-Cyclopentyl-2-propen-1-ol (2.0 g, 16.2 mmol), dichlorobis(triphenylphosphine)palladium (II) (151 mg, 0.22 mmol), and sodium bicarbonate (1.08 g, 12.9 mmol) in N-methylpyrrolidinone (20 mL) was heated to 140° C. under N2 for 5 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a black oil. The oil was purified by flash column chromatography (Hexanes to 10% EtOAc in hexanes) to give the desired product (2.7 g, 93%). 1H NMR (CDCl3): δ 1.52-1.83 (m, 8H), 2.75 (m, 2H), 2.85 (m, 3H), 4.80 (s, 2H), 6.92-7.06 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][NH2:27])[CH:23]=[CH:24][CH:25]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=1)=[O:14]
Reactant: Cc1cccc(NN)c1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: Cc1cccc(NNC(=O)c2ccncc2Nc2ccc(I)cc2F)c1

Procedure:
was synthesized according to the procedure for General Method 1, outlined above, starting with 0.44 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.63 mmol of 3-methyl-phenylhydrazine. LC/MS [6.05 min; 463 (M+1)]
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:41][OH:42]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14]([NH:41][OH:42])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@@H](CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)NO)N2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 91.5 %

Procedure:
(3R)-3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide was prepared by the procedure of Example 1 from (3R)-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropanoic acid (14.6 g, 39.5 mmol), carbonyldiimidazole (7.1 g, 43.5 mmol) and hydroxylamine hydrochloride (3.3 g, 47.4 mmol) in tetrahydrofuran (50 mL) to afford (3R)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide as a white solid (13.9 g, 91% yield): mp, 257.0–259.5° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H, CH3), 3.11 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.67 (t, J=7.8 Hz, 1H, NCH), 6.90 (br s, 2H, Ar), 7.02 (br s, 1H, Ar), 7.86 (br s, 4H, Ar), 8.79 (br s, 1H, OH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.67, 34.22, 50.18, 55.44, 63.71, 111.73, 112.36, 119.65, 123.11, 131.18, 131.21, 134.56, 147.67, 148.53, 165.97, 167.61. Anal Calcd for C20H20N2O6: C, 62.49; H, 5.24; N, 7.29. Found: C, 62.79; H, 5.24; N, 7.23;
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23]>>[CH3:28][O:27][C:25]1[CH:24]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)cc(OC)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.153 mmol) and 3,5-dimethoxyaniline (35 mg, 0.23 mmol), similar to Example 180 and was isolated as a pale solid (30 mg, 52%). 1H NMR (CDCl3): 9.74 (d, J=1.5 Hz, 1H), 7.78 (m, 1H), 8.72 (d, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.10 (s, 1H), 6.53 (d, J=2.1 Hz, 2H) 6.39 (t, J=2.1 Hz, 1H), 3.83 (s, 6H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Al](C)C.N#N.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[CH3:23][C:21]1[N:10]([C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH:8]=2)[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=1
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2cccc(N3CCOCC3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.3 %

Procedure:
To a solution of 3-morpholinylaniline (3.42 g, 19.20 mmol) in CH2Cl2 (100 mL) was added trimethylaluminum (96 mL, 96 mmol, 1 M in toluene) carefully under N2. The reaction mixture was stirred at rt for 30 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (3.29 g, 19.20 mmol) in anhydrous CH2Cl2 (50 mL). The reaction mixture was stirred at rt overnight, then quenched with saturated NH4Cl aqueous solution (200 mL) and extracted with CH2Cl2 (200 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (0.73 g, 13%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]1[C:9]2([CH:13]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][NH:11][CH2:10]2)[CH2:8][CH2:7]1.C(N(CC)CC)C>C1COCC1>[CH3:1][S:2]([N:11]1[CH2:12][CH:13]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[C:9]2([CH2:8][CH2:7][CH2:6]2)[CH2:10]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NC1CNCC12CCC2
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(S(C)(=O)=O)CC12CCC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added dropwise to a stirred solution of (+/−)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (0.177 g, 0.783 mmol) in and triethylamine (0.436 ml, 3.13 mmol) in THF (9.78 mL) @ 0° C. under N2. Stirring @ 0° C. was continued for 1.5 hr. +/−MS after 1 hr 15 min looked the same as for 40 min, mostly desired product with a trace of sm. Additional methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added and stirring was continued for 50 minutes. +/−MS after 40 m indicated that the reaction had proceeded essentially to completion and no starting material was detected by mass spectrum analysis (m/e 303.4, M−H for desired product). The volatile solvents were removed under vacuum. Ethyl acetate and water were added, the organic layer was washed twice with water, followed by washing with brine, and the organic layer was separated, dried (Na2SO4), and concentrated under vacuum to yield 0.231 g of the crude product as a yellow viscous semi-solid. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 1:1 hexane:EtOAc yielded 0.197 g of the title compoud as a white solid. +/−MS: m/e 303.4 (M−H). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.61 (br. s., 1H), 4.10 (br. s., 1H), 3.49 (dd, J=10.6, 5.3 Hz, 1H), 3.43-3.36 (m, 2H), 3.29 (dd, J=10.6, 3.1 Hz, 1H), 2.84 (s, 3H), 2.18-2.08 (m, 1H), 2.05-1.86 (m, 5H), 1.47 (s, 9H).
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=1[NH:22][C:23](=O)[CH:24]=[CH:25][CH3:26])[CH2:3][C:4]([NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)=[O:5].CC(N(C)C)=O.[H-].[Na+].Cl>O>[OH:1][C:2]1[C:12]2[C:13](=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:16][CH:17]=2)[N:22]=[C:23]([CH:24]=[CH:25][CH3:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)=[O:5]
Reactant: CC=CC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC=Cc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 120 °C
Yield: 100 %

Procedure:
17.5 g of the product of Step A were added to a solution of 175 ml of dimethylacetamide and a mixture of 2.11 g of sodium hydride as a 50% dispersion in oil and 100 ml of dimethylacetamide and the mixture was heated at 120° C. for 30 minutes and was then cooled. The mixture was poured into a mixture of water and 2N hydrochloric acid and the mixture was vacuum filtered. The product was washed with water and dried under pressure at 80° C. to obtain 16.7 g of 4-hydroxy-2-(1-propenyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 265° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]2[C:9](=[O:27])[N:10]3[CH2:26][CH2:25][CH2:24][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[C:8]2[C:9](=[O:27])[N:10]3[CH2:26][CH2:25][CH2:24][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cccc2c1C(=O)N1CCC[C@H]1c1c(C(=O)OC(C)(C)C)ncn1-2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)c1cccc2c1C(=O)N1CCC[C@H]1c1c(C(=O)OC(C)(C)C)ncn1-2
Reaction time: 8 h

Procedure:
4.0 g (10.38 mmol) of t-butyl (S)-11,12,13,13a-tetrahydro-8-methylthio-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate are dissolved in 25 ml of methylene chloride, treated portionwise at room temperature with 2.0 g (about 10.4 mmol) of about 90% percent m-chloroperbenzoic acid and left to stand at room temperature overnight. Then, the solution is poured into 2 N sodium hydroxide, the methylene chloride phase is separated, dried over magnesium sulphate and evaporated. After recrystallization from ethyl acetate/hexane, there is obtained t-butyl (S)-11,12,13,13a-tetrahydro-8-methylsulphinyl-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 224°-225° as a diastereoisomeric mixture.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15](=[O:35])[CH:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15](=[O:35])[CH:16]([NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The product of part (c) was heated under reflux with tri-n-butyltin hydride (51.12 g) in toluene for 20 hours. The reaction was cooled and purified by column chromatography on silica using ethyl acetate/petroleum ether (1:4) to yield the title compound as a white solid (37.1 g), mp=138°-140° C.: found: C, 59.23; H,4.90; N, 5.28; C26 H24F6N2O3 requires C, 59.09, H, 4.96; N, 5.30%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH:10]1[C:14](=[O:15])[C:13]2([CH2:20][CH2:19][N:18]([O:21][CH3:22])[CH2:17][CH2:16]2)[N:12]([CH3:23])[C:11]1=[O:24].C(=O)([O-])O.[Na+].S(Cl)([Cl:33])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:33][C:10]1([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[Cl:1])[C:14](=[O:15])[C:13]2([CH2:20][CH2:19][N:18]([O:21][CH3:22])[CH2:17][CH2:16]2)[N:12]([CH3:23])[C:11]1=[O:24]
Reactant: O=S(=O)(Cl)Cl
Reactant: CON1CCC2(CC1)C(=O)C(c1cc(C)c(C)cc1Cl)C(=O)N2C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CON1CCC2(CC1)C(=O)C(Cl)(c1cc(C)c(C)cc1Cl)C(=O)N2C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(2-chloro-4,5-dimethyl-phenyl)-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]decane-2,4-dione (compound P2.26) (120 mg, 0.342 mmol) and sodium hydrogen carbonate (72 mg, 0.857 mmol) in dichloromethane (5 ml) at −5° C. was added sulfuryl chloride (0.026 ml, 43.3 mg, 0.321 mmol) in dichloromethane (0.5 ml) dropwise. The reaction mixture was stirred at 0° C. for 1.5 hour, poured on saturated aqueous sodium carbonate, the layers were separated, the water phase extracted with ethyl acetate (3×20 ml), the combined organic phases washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate). Yield: 120 mg of 3-chloro-3-(2-chloro-4,5-dimethyl-phenyl)-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]decane-2,4-dione (title compound P1.1) as a white solid, mp 93-94° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([F:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[Cl:21][C:3]1[C:2]([NH:1][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:29])=[CH:7][C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)=[C:5]([F:20])[CH:4]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: CCOC(=O)C(C)Br
Solvent: O
Product: CCOC(=O)C(C)Nc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 140 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A mixture of 0.12 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-23) and 70 μl of ethyl 2-bromopropionate was stirred at 140° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 80 mg (yield, 51%) of 3-{4-chloro-5-[1-(ethoxycarbonyl)ethylamino]-2-fluorophenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-90).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:22]([OH:24])=[O:23].CCOC(C)=O>CC(N(C)C)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[C:4]1[NH:18][C:19]2[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[CH:25]=[CH:26][C:27]=2[N:28]=1
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Reactant: Nc1ccc(C(=O)O)cc1N
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To mixture of 2-hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (22.35 g, 0.0975 mol) and 3,4-diamino-benzoic acid (17.2 g, 0.113 mol) was added DMA (120 mL) via a syringe and the resulting solution was stirred at 0° C. for 2 h, and at the room temperature for 3 h. The robber stopper was removed and the reaction mixture was heated at 110° C. for 14 h open to the air. The DMA was removed under reduced pressure and the residue was mixed with 200 mL EtOAc, and sonicated for 15 min. The mixture was filtered to get the solid precipitate, which was mixture with 150 mL EtOAc, and sonicated for 5 min. The resulting mixture was filtered to get the solid crude that was dried at 40° C. for 6 h under reduced pressure to afford a mixture of the title compound and DMA (ratio 1:1) (16.15 g, 38%). 1H NMR (DMSO-d6) δ 3.92 (s, 3H), 7.14 (m, 1H), 7.15 (s, 1H), 7.64 (d, J=6 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 7.84 (d, J=6 Hz, 1H), 7.91 (d, J=6 Hz, 1H), 8.19 (d, J=6 Hz, 1H), 8.21 (d, J=6 Hz, 1H), 8.29 (s, 1H). DMA also shows as 61.96 (s, 3H), 2.79 (s, 3H) and 2.94 (s, 3H). ESI-MS m/z 362.5 (MH+).
Reaction SMILES: C(OC(=O)[N:7]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1)[C:8]1[C:9]2[N:10]([N:26]=[CH:27][N:28]=2)[C:11]([C:14]2[CH:25]=[CH:24][C:17]3[C:18](=[O:23])[NH:19][S:20](=[O:22])(=[O:21])[C:16]=3[CH:15]=2)=[CH:12][N:13]=1)(C)(C)C>Cl.O1CCOCC1>[N:35]1([C:32]2[CH:33]=[CH:34][C:29]([NH:7][C:8]3[C:9]4[N:10]([N:26]=[CH:27][N:28]=4)[C:11]([C:14]4[CH:25]=[CH:24][C:17]5[C:18](=[O:23])[NH:19][S:20](=[O:22])(=[O:21])[C:16]=5[CH:15]=4)=[CH:12][N:13]=3)=[CH:30][CH:31]=2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2ccc3c(c2)S(=O)(=O)NC3=O)n2ncnc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NS(=O)(=O)c2cc(-c3cnc(Nc4ccc(N5CCOCC5)cc4)c4ncnn34)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
A suspension of (4-morpholin-4-yl-phenyl)-[5-(1,1,3-trioxo-2,3-dihydro-1H-1 λ6-benzo[d]isothiazol-6-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (100 mg, 0.173 mmol) in 4M HCl (2.5 mL) in dioxane is stirred at room temperature for 2 hours. The solvent is removed under vacuum and the residue is triturated with DCM, diethyl ether and petroleum ether to afford the title compound (84 mg, 100%). 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 3.25 (4H, m), 3.85 (4H, m), 7.20 (2H, d), 7.88 (2H, d), 8.16 (1H, d), 8.24 (1H, s), 8.58 (1H, d), 8.82 (2H, s), 8.96 (1H, s), 10.31 (1H, s). LCMS: Rt 2.31 min (95.7%), m/z (APCI) 478 (M+H)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[OH:5][C:6]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:25][CH3:26])[CH:20]=3)[C:15](=[O:27])[C:14]=2[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:28])[CH2:11]2.Cl>C(Cl)Cl>[OH:28][C:10]1([C:1]#[CH:2])[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:14]3[C:15](=[O:27])[C:16]4[C:21]([C:22](=[O:24])[C:23]=3[C:6]=2[OH:5])=[CH:20][C:19]([O:25][CH3:26])=[CH:18][CH:17]=4)[CH2:11]1
Reactant: COc1ccc2c(c1)C(=O)c1c(cc3c(c1O)CCC(=O)C3)C2=O
Reactant: CC[Mg]Br
Agent: Cl
Solvent: ClCCl
Product: C#CC1(O)CCc2c(cc3c(c2O)C(=O)c2cc(OC)ccc2C3=O)C1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Acetylene, purified by passing first through a trap cooled with ice and then through a trap containing concentrated sulfuric acid, is bubbled through 40 ml of anhydrous THF for 1 hour. Ethylmagnesium bromide (40 ml, 1M in THF, 40 mmol) is then added dropwise. After the addition, the solution is evaporated under reduced pressure and the residue is taken up with 80 ml of methylene chloride (CH2Cl2) distilled over P2O5. The ketone prepared in Example 1 (386 mg; 1.2 mmol), dissolved in CH2Cl2 (150 ml), is added dropwise to this solution, cooled to -40° C. The reaction mixture is stirred for 1 hour at between -40° C. and -20° C., then hydrolyzed with a 0.1N solution of hydrochloric acid and then extracted in the conventional manner with methylene chloride. Chromatography under pressure (CH2Cl2) makes it possible to separate the unreacted starting ketone (148 mg; 38%) from the ethynylcarbinol formed (165 mg; 43%).