Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:10]3=2)[CH:5]=[CH:4]1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:10]3=2)[CH:5]=[CH:4]1)[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2ccc3cc[nH]c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2ccc3c(c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 0 °C
Reaction time: 1 h
Yield: 124.7 %

Procedure:
Under N2, a flame-dried, 250-mL, three-necked flask was charged with sodium hydride (0.56 g, 13.9 mmol) and anhydrous DMF (20 mL) and cooled to 0° C. A suspension of tert-butyl 6,7,9,10-tetrahydroazepino[4,5-g]indole-8(1H)-carboxylate (2.66 g, 9.3 mmol) in anhydrous DMF (30 mL) was added and the mixture was stirred at 0° C. for 1 hour and then at room temperature for 30 m. Ethyl bromoacetate (2.06 mL, 18.6 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc and water and the organic layer was washed with water and the organic layer concentrated to give 4.32 g of a brown oil. Dissolving the oil in CH2Cl2 and filtration of the resulting precipitate removes unreacted starting material. Column chromatography of the filtrate (elution with 20–50% Et2O/hexane) gave 2.11 g (61%) of the title compound as a white solid: mp 111 –115° C.; 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=8 Hz, 1 H), 6.93–6.90 (m, 2 H), 6.48 (d, J=3 Hz, 1 H), 4.98 (s, 2 H), 4.24 (q, J=7 Hz, 2 H), 3.60–3.57 (m, 4 H) 3.17–3.13 (m, 2 H), 3.04–3.00 (m, 2 H), 1.44 (s, 9 H), 1.29 (t, J=7 Hz, 3 H); MS (EI), m/z 372 (M+); HRMS (FAB) calcd for C20H26N2O4+H 359.1971. found 359.1972. Anal. Calcd for C21H28N2O4: C, 67.72; H, 7.58; N, 7.52. Found: C, 68.06; H, 7.70; N, 7.73.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]([CH3:19])=[N:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>CO.CC(=O)OCC.[Pd]>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][C:11]=2[CH3:19])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: Cc1nc([N+](=O)[O-])ccc1N1CCN(C(C)C)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(N)ccc1N1CCN(C(C)C)CC1
Yield: 99.8 %

Procedure:
Stir 1-isopropyl-4-(2-methyl-6-nitro-pyridin-3-yl)-piperazine (2.52 g) and palladium over carbon 10% (600 mg) in methanol (38 mL) and EA (38 mL) under H2 (balloon) overnight. Filter over a celite pad and remove the solvent under vacuum. Purify by silica gel column chromatography eluting with DCM/methanol (0-10%) to afford 2.23 g of the title compound. MS (ES+): m/z=143 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CN1CC[CH2:19][C:18]1=O>C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.[Zn+2]>[CH:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)=[CH2:19]
Reactant: CN1CCCC1=O
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])c1ccc2ccccc2c1
Agent: [Zn+2]
Product: C=COc1ccc(C(=O)c2ccccc2)cc1
Temperature: 190 °C

Procedure:
A mixture of 650 g of 4-hydroxybenzophenone (98% by weight, Avocado, Research Chemicals Ltd.), 750 ml of N-methylpyrrolidone (>99% by weight, BASF AG) and 60 g of zinc naphthenate (Nusa; zinc salts of naphthenic acids, zinc content 12% by weight) was charged with stirring to a 2.5 l autoclave and flushed with nitrogen. After it had been heated to 190° C., injection was carried out first with nitrogen to 2 bar and then with acetylene to 20 bar. During the reaction, further acetylene was supplied to replace that consumed by reaction, so as to maintain a constant pressure of 20 bar. After a reaction time of 12 hours the batch was cooled to 20–25° C. (room temperature) and let down to atmospheric pressure. The solvent was distilled off under reduced pressure at a bridge temperature of from 70 to 80° C. with a pressure of 1 mbar (absolute). 310 g of Pluriol® E 600 (polyethylene glycol, trademark of BASF AG) were then added and the product was purified by a Sambay distillation at 1.2 mbar (absolute) and a bridge temperature of 163° C. This gave a total of 522 g of 4-vinyloxybenzophenone having a purity of from 96 to 99% by weight and a melting point of 58° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:15](I)[CH3:16]>O1CCCC1>[CH2:15]([N:10]1[CH2:11][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]1=[O:12])[CH3:16]
Reactant: CCI
Reactant: O=C1CC(c2ccccc2)CN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC(c2ccccc2)CC1=O
Yield: 57 %

Procedure:
A mixture of 4-phenyl-pyrrolidin-2-one (24.2 g; 0.15 mole) and sodium hydride (80% oil suspension)(5.4 g; 0.18 mole) in tetrahydrofuran (150 ml) is refluxed for 2.5 hrs. After cooling, ethyl iodide (29 g; 0.185 mole) is added thereto, and the resulting material is refluxed for another 5 hrs. The solvent is then evaporated off; the residue is taken up into chloroform, washed with water, dried and distilled. B.p.(0.2 mm Hg)=124°-126° C. Yield: 57%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:6])[CH3:5])[CH3:2].Br[C:8]1[CH:9]=[C:10]([S:15][C:16]2[CH:26]=[CH:25][C:19]([O:20]CC(O)=O)=[C:18]([CH3:27])[CH:17]=2)[CH:11]=[C:12]([OH:14])[CH:13]=1.[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:6])[CH2:5][O:20][C:19]1[CH:25]=[CH:26][C:16]([S:15][C:10]2[CH:9]=[C:8]([C:35]#[C:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:13]=[C:12]([OH:14])[CH:11]=2)=[CH:17][C:18]=1[CH3:27])[CH3:2]
Reactant: Cc1cc(Sc2cc(O)cc(Br)c2)ccc1OCC(=O)O
Reactant: CCOC(C)=O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccccc3)c2)cc1C

Procedure:
[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate (2.3 g; 5.79 mmol), phenylacetylene (1.9 mL; 17.4 mmol), bis(triphenylphosphine)palladium (II) chloride (0.33 g; 0.46 mmol) and copper iodide (0.07 g; 0.35 mmol) were dissolved in a mixture of triethylamine (7 mL) and DMF (8 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100° C. for 1 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid and ethyl acetate was added. The organic phase was separated, dried and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate:heptane 1:10→1:3). Yield: 1.2 g. HPLC-MS: m/z: 419 (M+); Rt: 2.52 min.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li+].CCC[CH2-].CCCCCC.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1.IC>C1COCC1>[Br:19][C:20]1[N:21]=[C:22]([F:26])[C:23]([CH3:1])=[CH:24][CH:25]=1
Reactant: Fc1cccc(Br)n1
Reactant: CC(C)NC(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(Br)nc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
To Diisopropylamine (22.001 mmol; 2240 mg; 3.13 mL) in THF (40 mL) at 0° C. was added N-Butyllithium (2.5 mol/L) in Hexane (24.001 mmol; 9.6 mL). The reaction was stirred at 0° C. for 0.5 h, and then cooled to −78° C. 2-bromo-6-fluoro-pyridine (20.001 mmol; 3520.0 mg) in THF (10 mL) was added dropwise. The mixture was stirred at −78° C. for 3 h. Iodomethane (22.001 mmol; 3122.8 mg; 1.37 mL) was added slowly. The mixture was allowed to warm to room temperature with stirring for 1 hour. The reaction was quenched with water (˜50 mL) and stirred overnight. The layers were separated. The organic layer was concentrated, and the residue was purified on silica eluted with 0 to 5% EtOAc in Heptane to afford 6-bromo-2-fluoro-3-methyl-pyridine as a white solid (2.08 g, 55%).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1.[CH3:34][C:35]#[N:36]>>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:33][C:35]([CH3:34])=[N:36][CH:32]=2)=[CH:27][CH:26]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CC#N
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: Cc1ncc(-c2ccc(Br)cc2)o1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic acid (6.6 ml) was added to a flask containing iodobenzene diacetate (12.2 g) and MeCN (200 ml) at rt. After 25 min. a solution of 4′-bromoacetophenone (5 g) in MeCN (50 ml) was added and the resultant mixture heated at reflux for 6 h. The reaction was allowed to cool to rt before the solvent was evaporated and the residue partitioned between saturated aqueous Na2CO3 (150 ml) and EtOAc (150 ml). The organic phase was washed with saturated brine (150 ml), dried (MgSO4) and evaporated to give an orange solid. The crude product was purified by column chromatography (silica gel, 50% EtOAc in hexane) to give the title compound (D15) as a pale yellow solid (3.5 g). LCMS electrospray (+ve) 239 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1ccncc1)c1ccc(F)cc1
Temperature: 150 °C

Procedure:
A mixture of 4-fluorophenylacetic acid (9 g, 58.4 mmol), 4-pyridinecarboxaldehyde (5.6 ml, 58.6 mmol), pyridine (6 ml) and acetic anhydride (6 ml) was heated at 150° C. for 1 h followed by evaporation and co-distillation with water. The resulting material crystallized on addition of ethanol. The solids were filtered and washed with ethanol and ethyl acetate to provide the title compound. MS (m/z): 244.0 (M+H)+; C14H10FNO2requir. 243.2 1H-NMR (DMSO-d6): d 8.43, 6.98 (2d, each 2H, Pyrid.), 7.73 (s, 1H, CH═), 7.21 (d, 4H, PhF).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:33])=[C:21]([C:23]2([CH:30]3[CH2:32][CH2:31]3)[NH:28][C:27](=S)[CH2:26][O:25][CH2:24]2)[CH:22]=1.C(OO)(C)(C)C.[NH3:40]>>[NH2:40][C:27]1[CH2:26][O:25][CH2:24][C:23]([C:21]2[CH:22]=[C:17]([NH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:14])=[CH:10][N:9]=3)=[O:13])[CH:18]=[CH:19][C:20]=2[F:33])([CH:30]2[CH2:32][CH2:31]2)[N:28]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reactant: N
Reactant: Nc1ccc(F)c(C2(C3CC3)COCC(=S)N2)c1
Agent: CC(C)(C)OO
Product: NC1=NC(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)(C2CC2)COC1

Procedure:
In an analogous manner to that described in example 6 (Method B), the condensation of 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (CAS 881409-53-6) and (RS)-5-(5-amino-2-fluoro-phenyl)-5-cyclopropyl-morpholine-3-thione followed by the treatment with tert-butyl hydroperoxide and ammonia yielded the title compound (23) as a white solid. Mass (calculated) C21H20F4N4O3 [452.406]; (found) [M+H]+=453.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[NH:5][C:4](=O)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl-].[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:20])[CH3:19]>CC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18](=[O:20])[CH3:19])[CH:3]=1
Reactant: COc1nc(N)cc(=O)[nH]1
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc(N)cc(CCCCOC(C)=O)n1
Temperature: 25 °C
Yield: 42 %

Procedure:
Alternative Method B. A mixture of 6-amino-2-methoxy-4-pyrimidone (30 g, 212.6 mmol), K2CO3 (44 g, 318 mmol), benzyltriethylammionium chloride (20 g, 88 mmol) and 4-bromobutyl acetate (60 g, 308 mmol) in acetone (800 ml) was heated at reflux overnight. After cooling to room temperature, the insoluble salts were filtered off and the solvent was removed. The residue was purified by chromatography on silica gel with CHCl3/MeOH (100:2-100:5) as eluent. After separation of 6-amino-2-methoxy-4-(4-acetoxybutyl)pyrimidine (22.8, yield 42%), 18.7 g (yield 34.5%) of 6-amino-2-methoxy-3-(4-acetoxybutyl)-4-pyrimidone was isolated as a white solid.
Reaction SMILES: [SH2:1].[CH3:2][S:3][C:4]1[S:5][C:6]([C:10]#[N:11])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:2][S:3][C:4]1[S:5][C:6]([C:10](=[S:1])[NH2:11])=[C:7]([NH2:9])[N:8]=1
Reactant: S
Reactant: CSc1nc(N)c(C#N)s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1nc(N)c(C(N)=S)s1
Temperature: 0 °C
Reaction time: 48 h
Yield: 54 %

Procedure:
20 parts of hydrogen sulfide are introduced, over 6 hours, into a mixture of 51.3 parts of 2-methylmercapto-4-amino-5-cyanothiazole, 0.2 part of triethylamine and 150 parts of dimethylformamide. The reaction mixture is left to stand for 48 hours and is then poured into 500 parts of ice water, and the product is filtered off. 33 parts of 2-methylmercapto-4-amino-5-thiocarbamoylthiazole (54% of theory) of melting point 192°-195° C. are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[N:5]=1
Reactant: C[C@H]1CCCN1c1nc(Cl)cc(Cl)n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H]1CCCN1c1nc(Cl)cc(-c2ccc(F)cc2)n1

Procedure:
Heat a mixture of 4,6-dichloro-2-(2-(S)-methylpyrrolidin-1-yl)pyrimidine (2.25 g, 9.74 mmol), 4-fluorophenylboronic acid (10.23 mmol), Pd(PPh3)4 (562 mg, 0.487 mmol), and a 2M potassium phosphate solution (9.74 mL) in dioxane (35 mL) under nitrogen at 80° C. for 16 h. Evaporate the mixture and add water (50 mL). Extract with EtOAc (3×50 mL), dry (Na2SO4), and evaporate. Purify by SiO2 flash chromatography, eluting with 9:1 hexanes:EtOAc to provide the title compound as an oil.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([C:13]#[C:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9]C=1>CN1CCCC1=O.O>[C:13]1([C:14]2[NH:15][C:16]3[C:17]([CH:1]=2)=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: FC(F)(F)Oc1ccc(NC#Cc2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)Oc1ccc2[nH]c(-c3ccccc3)cc2c1
Yield: 83.8 %

Procedure:
To a solution of potassium tert-butoxide (173 mg) in 1-methyl-2-pyrrolidone (3.7 mL) was added dropwise a solution of 2-phenylethynyl-4-trifluoromethoxyaniline (204 mg) in 1-methyl-2-pyrrolidone (3.7 mL) at room temperature under stirring, and the mixture was stirred for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (171 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]([N:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:22]=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:31]([N:20]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@@H:21]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C@@H:22]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:23])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O[C@H](c1ccccn1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -78 °C

Procedure:
Dissolve 2-bromopyridine (2.73 mL, 28.63 mmol) in THF (150 mL) and cool to −78° C. Add n-butyllithium (12.0 mL, 2.5 M in hexanes). Slowly add 2-(S)-dibenzylamino-3-phenyl-propionaldehyde (4.71 g, 14.31 mmol) in THF (15 mL) and stir 30 min. Quench reaction with saturated aqueous ammonium chloride. Remove cold bath and warm to room temperature. Wash organic layer twice with 5% aqueous citric acid, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with dichloromethane and ethyl acetate) to give the title compound as a residue (3.654 g, 62%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][N:25]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1)=[O:5])C.[OH-].[K+].O>CO>[CH2:44]([O:43][C:41]([N:25]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])=[CH:32][CH:31]=1)[CH2:24][CH2:23][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:11][C:10]=1[C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[O:42])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(NS(C)(=O)=O)cc3)C(=O)OCc3ccccc3)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OCc2ccccc2)c1
Reaction time: 10 h

Procedure:
A solution of 600 mg (0.862 mmol) of 3-(2-{benzyloxycarbonyl-[4-(4-methanesulfonylaminophenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester in 18 mL (9 mmol) of 0.50N potassium hydroxide in methanol was stirred at about 60° C. as 2.0 mL of water was added gradually. Stirring was continued at 60°-65° C. under nitrogen for 10 hours. The cooled mixture, which contained a white precipitate, was concentrated to small volume in vacuo. The residual suspension was partitioned between 25 mL of ethyl acetate and 25 mL of 0.5N hydrochloric acid. After the aqueous layer was separated, precipitation began in the ethyl acetate phase. Dilution with 25 mL of tetrahydrofuran redissolved the precipitate. The aqueous phase was back-extracted with 10 mL of ethyl acetate+10 mL of tetrahydrofuran. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residual solid was triturated with diethyl ether, collected on a filter, and washed with some additional ether to give (after drying) 573 mg (100%) of a powder, mp 211.5°-213° C.; virtually homogeneous by TLC(92.5:7.5 CH2Cl2 --MeOH). 500 MHz 1H NMR (DMSO-d6) was consistent with the assigned structure. Mass spectrum (ESI): m/e=668 (M+H).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[C:7](=O)(O)[O-].[Na+].Cl[S:13]([C:16]1[C:17]([O:27][CH3:28])=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21]([OH:23])=[O:22])(=[O:15])=[O:14].BrCC(O)=O>O>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([O:27][CH3:28])[C:16]([S:13]([CH3:7])(=[O:15])=[O:14])=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]
Reactant: COc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Reactant: O=C([O-])O
Agent: O=C(O)CBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c(S(C)(=O)=O)cc1C(=O)O
Reaction time: 1 h

Procedure:
A 0.90 g portion of sodium sulfite and 1.81 g of sodium bicarbonate were dissolved in 6 ml of water, and 2.00 g of 5-chlorosulfonyl-2,4-dimethoxybenzoic acid was added thereto, followed by 1 hour stirring. Next, 1.50 g of bromoacetic acid was added, followed by stirring at 75° C. After completion of the reaction, the reaction solution was poured into cool water, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 2,4-dimethoxy-5-methylsulfonylbenzoic acid, which was used in the next reaction without purification.
Reaction SMILES: C[Si]([CH2:5][C:6]([O-:8])=[O:7])(C)C.Cl[Si:10]1(Cl)[CH2:13][CH2:12][CH2:11]1>>[C:6]([O:8][Si:10]1([O:8][C:6](=[O:7])[CH3:5])[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:5]
Reactant: C[Si](C)(C)CC(=O)[O-]
Reactant: Cl[Si]1(Cl)CCC1
Product: CC(=O)O[Si]1(OC(C)=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30.0 g trimethylsilylacetate was added 16.0 g 1,1-dichlorosilacyclobutane. The reactants were stirred for one hour at 25° C. and fractional distillation performed on the reaction mixture. The title compound was isolated as a clear, colorless fluid. The yield was 14.6 g (81.4%). The structure of the product was confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy (NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([OH:14])=[N:12][S:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23]Br.O>C(#N)C>[Br:21][CH2:22][CH2:23][O:14][C:13]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:10][S:11][N:12]=1
Reactant: BrCCBr
Reactant: Oc1nsnc1-c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Clc1cccc(Cl)c1-c1nsnc1OCCBr
Yield: 148.1 %

Procedure:
In acetonitrile, were mixed and stirred 0.49 g of 3-(2,6-dichlorophenyl)-4-hydroxy-1,2,5-thiadiazole, 0.3 g of potassium carbonate, and 1.9 g of 1,2-dibromoethane at 80° C. for one hour. After spontaneous cooling, the reaction mixture was poured into water, and was extracted with diethyl ether. The diethyl ether layer was washed with dilute hydrochloric acid, 10% sodium hydrogencarbonate, and water successively,dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel chromatography to obtain 1.04 g of 3-(2-bromoethoxy)-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole.
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[N:18][C:17]=3C(C#N)=[CH:15][CH:14]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.[CH2:25]([OH:28])[CH2:26]O>CCOCC.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[N:18][C:17]=3[C:26]([C:25]([OH:28])=[O:1])=[CH:15][CH:14]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: [OH-]
Reactant: COc1cc(OC)cc(-c2ccc(C#N)c3nccnc23)c1
Reactant: OCCO
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COc1cc(OC)cc(-c2ccc(C(=O)O)c3nccnc23)c1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
KOH (6.0 g, 107 mmol, 10 equiv) was added to 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile (Step 179.3) (3.12 g, 10.7 mmol) in ethylene glycol (30 mL). The reaction mixture was stirred at 150° C. for 3 h (a solution was obtained), allowed to cool to rt, diluted with Et2O/H2O, and extracted with Et2O. The aqueous phase was acidified to pH 5 by addition of HCl. Vacuum filtration of the resulting suspension afforded 3.3 g of the title compound as a yellow solid: ESI-MS: 311 [M+H]+; tR=4.34 min (System 1).