Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:11].[NH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:24])[C:19]=2[OH:23])[C:14]1=[O:25]>C(O)C.[Pd]>[BrH:11].[C:1]1([CH2:7][CH2:8][CH2:9][NH:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:24])[C:19]=3[OH:23])[C:14]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1ccccc1
Reactant: NC1CCc2c(ccc(O)c2O)C1=O
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: O=C1c2ccc(O)c(O)c2CCC1NCCCc1ccccc1

Procedure:
In 300 volume parts of ethanol is dissolved 5 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide and, after the addition of 50 parts of β-phenylpropionaldehyde, catalytic reduction is carried out at ordinary temperature and pressure using palladium-on-carbon as a catalyst. When a stoichiometric amount of hydrogen has been absorbed, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The procedure yields 3.5 parts of 2-(3-phenylpropyl)amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide as colorless crystals melting at 215°-217° C.
Reaction SMILES: C([NH:8][C@@H:9]1[C@H:13]([F:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:8][C@@H:9]1[C@H:13]([F:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)[C@@H](NCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H](F)[C@@H](N)C1

Procedure:
(3S,4R)-tert-butyl 3-(benzylamino)-4-fluoropyrrolidine-1-carboxylate, 81 (16 mg, 0.054 mmol) was subjected to hydrogenolysis with 10 wt % Pd—C(10 mg) in ethanol (3 ml). The completed reaction mixture was filtered, concentrated and azeotroped with CDCl3 to provide (3S,4R)-tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate, 83 (8.3 mg, 0.041 mmol, 75.9% yield).
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=O)[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.[SH:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:15](=[O:17])[C@H:2]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[CH:7]=2)[CH:12]=1)[CH3:1]
Reactant: OCCCCS
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)SCCCCO)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a solution of naproxen (5.03 g, 21.9 mmol), 4-mercapto-l-butanol (2.32 g, 21.9 mmol) and N,N-dimethylaminopyridine (DMAP) (0.534 g, 4.37 mmol) in dichloromethane (200 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC) (5.03 g, 26.2 mmol) as a solid, in portions. The reaction mixture was stirred for 3 hours at room temperature, then partitioned between dichloromethane and water, and the water layer was washed with more dichloromethane. The combined organic layer was washed with water and brine, then dried over magnesium sulfate. The solution was concentrated under vacuum, and the residue was purified via column chromatography, 50% ethyl acetate/hexane. The appropriate fractions were combined, and the solvent removed by rotary evaporation to give an oil, 2.647 g, which contained 19% 4-mercapto-l-butanol by weight (product weight 2.07 g, 6.5 mmol, 30% yield): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=2.7 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.69 (d, J=1.0 Hz, 1H), 7.40 (dd, J=1.8, 8.5 Hz, 1H), 7.15 (dd, J=2.5, 8.8 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 4.02 (q, J=7.1 Hz, 1H), 3.92 (s, 3H), 3.61-3.64 (m, 2H), 2.87 (m, 2H), 1.61 (d, J=7.1 Hz, 3H), 1.59 (m, 2H), 1.41 (m, 2H); mass spectrum (API-TIS) m/z 319 (M+H+), 336 (M+18+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]1([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]1)=[O:15].Cl.[F:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:20][NH:29][CH2:28][CH2:27][F:26])([OH:19])[C:21]([F:23])([F:22])[F:24])=[O:15]
Reactant: Nc1c(C(=O)NCC2(C(F)(F)F)CO2)cnn1-c1ccc(F)cc1
Reactant: NCCF
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(C(=O)NCC(O)(CNCCF)C(F)(F)F)cnn1-c1ccc(F)cc1
Reaction time: 96 h
Yield: 128.5 %

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-pyrazole-4-carboxamide (1.03 g, 3 mmol) in anhydrous acetonitrile (10 ml) was added 2-fluoroethylamine hydrochloride (650 mg, 6 mmol, ca. 90% purity) and triethylamine (0.98 ml, 7 mmol) and the resulting suspension was shaken for 4 days. It was partitioned between ethyl acetate (70 ml) and water (20 ml), washed with saturated brine (20 ml), dried over sodium sulphate and evaporated to give a gum (1.57 g). This was purified on 100 g SiO2 using the Flashmaster 2 with 0-100°/0 ethyl acetate in cyclohexane 60 minute gradient as eluent. This gave the title compound (924 mg).
Reaction SMILES: S(N)(=O)([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=O>P(=O)(O)(O)O>[C:6]1([NH:9][CH2:5][CH2:6][NH2:9])[C:7]2[C:8](=[CH:4][CH:3]=[CH:8][CH:7]=2)[CH:3]=[CH:4][CH:5]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: O=P(O)(O)O
Product: NCCNc1cccc2ccccc12

Procedure:
35 ml of 2.5% sulfanilamide in 5% aqueous phosphoric acid in packed with 15 gr Freon 12 using 0.5 gr Emcol-14 as emusifier.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[NH:13][C:12]2=[O:22])=[CH:5][CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>CN(C)C=O>[O:21]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](=[CH:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:4][CH:5]=2)[C:12](=[O:22])[NH:13]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NC(=O)c2ccccc2C1=CNc1ccc(CO)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(NC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
To a suspension of 4-[(4-Hydroxymethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (294 mg, 1 mmol) in N,N-dimethylformamide (10 mL) is added methanesulfonyl chloride (0.77 mL, 10 mmol) and triethylamine (2.79 mL, 20 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. The crude product, methanesulfonic acid 4-[(1,3-dioxo-2,3-dihydro-1H-isoquinolin-4-ylidenemethyl)-amino]-benzyl ester (304 mg), thus obtained is used as such for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24](O)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:27]4[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]4)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1CCNCC1
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(C(=O)N2CCC(CCO)CC2)n[nH]1

Procedure:
The title compound was prepared as in the previous Example starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 4-piperidine ethanol. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-95:5). 1H NMR (400 MHz, CDCl3): 1.27 (3H, m), 1.57 (2H, m), 1.85 (3H, m), 2.81 (1H, m), 3.01 (2H, t), about 3.21 (1H, m), 3.76 (4H, m), about 4.41 (1H, m), about 4.67 (1H, m), 6.20 (1H, d), 6.59 (1H, d), 7.02 (1H, s), 7.29 (1H, broad s), 7.40 (1H, distorted d), 7.43 (1H, distorted dd), 7.75 (1H, d), 11.4 (1H, broad s).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:9]([C:18]#[N:19])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:9]([C:18]#[N:19])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)C)c(C#N)c2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)COc1ccc(-n2ncc(C(=O)O)c2Cl)cc1C#N
Temperature: 60 °C
Yield: 51.8 %

Procedure:
To a solution (10 ml) of ethyl 5-chloro-1-(3-cyano-4-isobutoxyphenyl)-pyrazole-4-carboxylate (1.05 g) in ethanol was added 1 N aqueous sodium hydroxide solution (3.6 ml) with string, and the mixture was heated at 60° C. for 1 hour. After the completion of the reaction, the reaction mixture was pouted into water and neutralized with acetic acid. The precipitated crystals were recrystallized from ethyl acetate to give 0.5 g of 5-chloro-1-(3-cyano-4-isobutoxyphenyl) pyrazole-4-carboxylic acid, melting point 216-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O[NH:18][C:19](=[NH:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:10][N:28]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)[N:18]=2)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: O=C(O)c1ccc(-c2ccccc2)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(Cl)c3)n2)cc1
Temperature: 122.5 °C

Procedure:
N,N-Dicyclohexylcarbodiimide (4 g, 0.019 mol) is added to a solution of 2-chlorobiphenyl-4-carboxylic acid (3 g, 0.013 mol), N-hydroxy-4-hydroxymethyl benzamidine (2.9 g, 0.017 mol) and N-hydroxybenzotriazole monohydrate (2.9 g, 0.019 mol) in N,N-dimethylformamide (40 mL). The reaction mixture is heated at 120-125° C. for 3 hrs. It is then cooled to 0-5° C., filtered and washed with dichloromethane (2×15 mL). The filtrate is evaporated under reduced pressure and the residue is treated with demineralized water (20 mL). It is extracted with ethyl acetate (2×20 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives a crude residue which is purified by column chromatography (silica gel 230-400, ethyl acetate:toluene, 1:9) to give {4-[5-(2-chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-phenyl}-methanol.
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CN(C)C=O>[CH3:3][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]1=[O:13])=[CH2:1]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCC(=O)OCC)c2ccccc21
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
A solution of 19 g of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one [described in J. Chem. Soc. Perkins, 1982, p. 261] in 150 ml of dimethylformamide was added with stirring at 20° C.±2° C. to 5.75 g of sodium hydride as a 50% suspension in oil and 10 ml of dimethylformamide and the mixture was stirred for another 30 minutes. 23.4 g of ethyl 4-bromo-butyrate were added to the mixture over 15 minutes and the mixture was stirred at room temperature for 4 hours and was poured into 800 ml of iced water. The mixture was extracted with ether and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure to obtain 33 g of ethyl 2,3-dihydro-3-(1-methyl-ethenyl)-2-oxo-1H-benzimidazol-1-butanoate.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][NH:6][C:7](=[O:11])[O:8][CH2:9][CH3:10])C.Cl.O>C1COCC1>[O:3]=[CH:4][CH2:5][NH:6][C:7](=[O:11])[O:8][CH2:9][CH3:10]
Reactant: CCOC(=O)NCC(OCC)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)NCC=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A solution of ethyl (2,2-diethoxyethyl)carbamate (2.0 g, 0.0097 mol.)) in 5 mL of THF at 0° C. was added HCl (10 mL, 2.0 eq) and then H2O (0.17 mL). The solution was then stirred for 4 h at 0° C. the solvent was evaporated at room temperature and solid NaHCO3 was added, filtration and concentration to give after silica gel chromatography ethyl (2-oxoethyl)carbamate as a colorless oil (0.36 g, 28%). 1HNMR (400 MHz), CDCl3: δ 1.19 (t, J=7.2 Hz, 3H); 4.05-4.10 (m, 4H); 5.44 (sbr, 1H); 9.60 (s, 1H).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1([OH:21])[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.[C:22](=[O:24])=[O:23].Cl>C1COCC1.O>[OH:21][C:11]1([C:7]2[S:6][CH:10]=[C:9]([C:22]([OH:24])=[O:23])[N:8]=2)[CH2:12][CH2:13][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:19][CH2:20]1
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc(C2(O)CCC3(CC2)OCCO3)n1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of n-butyllithium (17.1 mL of 1.6 M solution in hexane, 27.35 mmol) was added to 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (3.00 g, 12.43 mmol) in THF (50 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, dry ice (10 g, 227 mmol) was added to the lithiated compound solution and stirred for 2 h at −78° C. Water was added and the solution was warmed to room temperature. The mixture was then treated with 1N HCl to pH 3 to 4 and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated and chromatographed (EtOAc to 1% AcOH/EAOAc) to give 3.23 g of 2-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-1,3-thiazole-4-carboxylic acid. MS (EI) calcd: (M+H)+=286.1; found: 286.0.
Reaction SMILES: [C:1]([N:8]([CH3:27])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:29]1[CH:34]=[CH:33][C:32]([N:35]([CH3:38])[CH:36]=[O:37])=[CH:31][CH:30]=1>>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:29]3[CH:34]=[CH:33][C:32]([N:35]([CH:36]=[O:37])[CH3:38])=[CH:31][CH:30]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:27])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C=O)c1ccc(Br)cc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(B(O)O)ccc2F)CC1
Product: CN(C=O)c1ccc(-c2ccc(F)c(CNC3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1

Procedure:
The title compound was prepared from boronic acid (247) (300 mg, 0.79 mmol) and aryl bromide (51) (200 mg, 0.95 mmol) in accordance with Method B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH2:10][CH:11]=[CH:12][CH2:13][O:14][CH3:15]>O1CCCC1.[Pt]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCC=CCc1cc(Br)ccc1OC
Agent: [Pt]
Solvent: C1CCOC1
Product: COCCCCc1cc(Br)ccc1OC

Procedure:
A solution of 50 g of 4-methoxy-3-(4-methoxy-2-butenyl)-bromobenzene in 700 ml of tetrahydrofuran is hydrogenated for 2 hours under normal pressure and at room temperature in the presence of 2.5 g of 5% Pt/C. The reaction mixture is filtered. The filtrate is concentrated by evaporation. The evaporation residue obtained from the filtrate is purified by FC (1.6 kg of silica gel, hexane/ethyl acetate=20:1). Distillation under a high vacuum yields the title compound: Rf (hexane/ethyl acetate=10:1)=0.38; HPLC Rt =19.92 minutes; FAB-MS (M+H)+ =273.
Reaction SMILES: [O:1]([CH2:8][CH:9]=[CH:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[C].[Pd]>[O:1]([CH2:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1C=CCOc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1CCCOc1ccccc1
Reaction time: 24 h
Yield: 54.8 %

Procedure:
The thus-obtained methyl 2-(3-phenoxypropenyl)benzoate (0.261 g, 0.972 mmol) was dissolved in methanol (6 ml), 10% palladium carbon (0.022 g) was added, and a hydrogenation reaction was performed at room temperature for 24 hr. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 2-(3-phenoxypropyl)benzoate (0.144 g, 0.533 mmol, yield 55%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([CH2:23][CH2:24][O:25][C:26]5[CH:31]=[CH:30][C:29]([N:32]6[CH2:37][CH2:36][O:35][CH2:34][CH2:33]6)=[CH:28][CH:27]=5)[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:38]=2)=[CH:4][C:3]=1[O:39][CH3:40].Cl.Cl[CH2:43][C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:40][O:39][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([CH2:23][CH2:24][O:25][C:26]5[CH:31]=[CH:30][C:29]([N:32]6[CH2:33][CH2:34][O:35][CH2:36][CH2:37]6)=[CH:28][CH:27]=5)[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:38]=2)[CH:6]=[CH:7][C:2]=1[O:1][CH2:43][C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OCc1ccncc1
Temperature: 80 °C

Procedure:
A mixture of Example 474 (26.9 mg, 0.05 mmol) and 4-chloromethylpyridine hydrochloride (24.6 mg, 0.15 mmol) in DMF (1 mL) was treated with K2CO3 (34.6 mg, 0.25 mmol) and heated at 80° C. for 7 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to provide the title compound as the di-TFA salt. MS (ESI) m/e 629 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 9.77 (s, 1H), 8.79 (br s, 2H), 7.85 (s, 1H), 7.8 (d, J=4.1 Hz, 2H), 7.73 (d, J=8.5 Hz, 1H), 7.26 (dd, J=3.6, 1.9 Hz, 2H), 7.08-7.20 (m, 3H), 6.82-6.95 (m, 7H), 5.38 (s, 2H), 4.04 (t, J=6.8 Hz, 2H), 3.91 (s, 3H), 3.71-3.74 (m, 4H), 2.99-3.02 (m, 4H), 2.86 (t, J=6.8 Hz, 2H).
Reaction SMILES: [C:1]1([C:7](=[O:12])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17]C>>[C:1]1([C:7](=[O:12])[C:8]([O:10][CH2:11][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: CCCCCCO
Product: CCCCCCOC(=O)C(=O)c1ccccc1
Yield: 87 %

Procedure:
16.42 g (0.1 mol) of methyl phenylglyoxalate is transesterified as described in example 1.1, using 1-hexanol instead of methoxyethanol. 21.33 g (87%) hexyl phenylglyoxalate are obtained as a colorless liquid.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.CN(CCN(C)C)C.[CH3:33][Si:34]([CH3:37])(Cl)Cl>C1COCC1.CCOCC.O>[CH3:33][Si:34]1([CH3:37])[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[O:7][C:8]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: C[Si](C)(Cl)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si]1(C)c2ccccc2Oc2ccccc21
Reaction time: 16 h

Procedure:
At room temperature a solution of 8.00 g of diphenylether (47.0 mmol) in 35 ml of THF was added dropwise to a mixture of 41.4 ml of 2.5M n-butyllithium in hexane (103.4 mmol) and 16.7 ml of TMEDA (103.4 mmol). When all phenylether was added, the reaction mixture was stirred for 16 h. The ethereal solution of 2,2'-dilithiodiphenylether and a solution of 5.7 ml of dimethyldichlorosilane (47.0 mmol) in 75 ml of ether were added simultaneously to 40 ml of ether over 1 h. The reaction mixture was stirred for 16 hr. then hydrolyzed by addition of 30 ml of water. The hydrolyzed mixture was stirred for 2 hr. The organic layer was separated, and the aqueous layer was extracted with 30 ml of ether. The combined organic layers were treated with Norit, and dried with MgSO4. The solvent was removed in vacuo. Small crystals formed during the concentration. The semisolid oil was crystallized form methanol, resulting in white crystals of 10,10-dimethylphenoxasilin with a grassy odour. Yield: 4.82 g (45%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]([C:33](O)=[O:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[OH:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[C:26]([C:33]([NH2:37])=[O:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:21])[CH3:22])[C:7]3=[CH:6][C:5]=2[CH:4]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)C1c2cc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(=O)O)c(C(F)(F)F)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C1c2cc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(N)=O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (55 μmol) in anhydrous DMF (1 mL) was added HATU (42 mg, 0.11 mmol), NH4Cl (30 mg, 0.55 mmol) and N,N-diisopropylethylamine (100 μL, 0.55 mmol). The mixture was stirred at rt for 20 h. It was diluted with CH2Cl2 (10 mL) and washed with H2O. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic solution was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica chromatography and SFC separation to give isomers of 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=1.S(Br)([Br:20])=O.N1C(C)=CC=CC=1C>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Br:20])=[CH:12][CH:11]=1
Reactant: O=S(Br)Br
Reactant: OCc1ccc(-c2nc3ccccc3o2)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: BrCc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C

Procedure:
To 4-(benzoxazol-2-yl)benzyl alcohol (20.9 g; 100 mmol) dissolved in CH2Cl2 (330 ml) and cooled to 0°-5° C. is added thionyl bromide (9.2 ml; 120 mmol) and allowed to warm to room temperature after removing the bath. After 11/2 hours, 2,6-lutidine (11.6 ml; 100 mmol) is added to the mixture and warmed to 30° C. The reaction mixture is then diluted with CH2Cl2, washed with H2O 1×, 0.2M HCl 1×, NaHCO3 2×, brine, dried (MgSO4) and concentrated to dryness. The residue is recrystallized from EtOAc to obtain 4-(benzoxazol-2-yl)benzyl bromide as white-orange needles which is used directly in Step D.