Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[OH:15][CH2:16][C@H:17]([NH:25][C:26](=[O:30])[C:27](O)=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]([NH:25][C@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][OH:15])=[O:30]
Reactant: O=C(O)C(=O)N[C@@H](CO)Cc1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)N[C@@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
The mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.210 g; 0.890 mmol), (R)-2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoacetic acid (0.219 g; 0.979 mmol), HATU (0.339 g: 0.890 mmol) and N,N-diisopropylethylamine (0.389 mL; 2.23 mmol) in DMF (5 mL) was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in dichloromethane, the organic layer was washed with water, and was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) to yield 0.226 g (63%) of (R)—N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(1-hydroxy-3-phenylpropan-2-yl)oxalamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[I:11].C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.C(=O)=O.CC(C)=O.Cl>C1COCC1.O>[Cl:1][C:2]1([B:16]([OH:17])[OH:15])[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][CH:3]1[I:11]
Reactant: COc1cc(Cl)c(I)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC1=CC(Cl)(B(O)O)C(I)C=C1F
Yield: 32.8 %

Procedure:
To 1-chloro-4-fluoro-2-iodo-5-methoxy-benzene (10.0 g, 34.9 mmol) in THF (70 mL) was cooled to −78° C. was added triisopropylborate (8.9 mL, 38.4 mmol) followed by dropwise addition of n-butyl lithium (24 mL of a 1.6 M solution in hexanes, 38.4 mL). The solution was stirred and allowed to warm to room temperature over night by dissipation of the dry ice/acetone bath. 1N HCl (50 mL0 and water (50 mL) were added and the solution stirred at room temperature for 1 h. The solution was extracted with ethyl acetate. The organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated with 1:1 hexanes/diethyl ether and the solid collected by filtration to give 3.8 g (53%) of pure 1-chloro-4-fluoro-2-iodo-5-methoxyphenyl boronic acid: 1H NMR (400 MHz, CDCl3): δ 7.64 (d, J=11.7 Hz, 1H), 6.91 (d, J=7.3 Hz, 1H), 5.21 (br s, 2H), 3.90 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[CH:6]1[C:7]([CH2:8][S:14][C:13]([NH2:15])=[NH:12])=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1.[ClH:9]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: Cl
Product: N=C(N)SCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A mixture of 4-nitrobenzylchloride (Aldrich, 85.8 g, 0.5 mol) and thiourea (Aldrich, 38.1 g, 0.5 mol) in ethanol (250 ml) was heated to reflux, under nitrogen, for 2.5 h. The reaction mixture was allowed to cool to ambient temperature and the precipitate was filtered off. The solid was washed with ethanol and diethylether and then dried in vacuo to give the title compound as a white solid (112.4 g, 90.8%). δH [2H6]—DMSO 4.72 (2H, s); 7.74 (2H, d, 9.4 Hz); 8.25 (2H, d, 9.4 Hz); 9.41 (3H, bds).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]([C:16]#N)=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4].[OH-:18].[K+].Cl.[OH2:21]>C(O)C>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]([C:16]([OH:21])=[O:18])=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc2c(c(C#N)c1=O)CCCC2
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCCCn1cc2c(c(C(=O)O)c1=O)CCCC2
Yield: 70 %

Procedure:
2-Butyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-012) (260 mg, 1.13 mmol) was dissolved in water (6 mL)/ethanol (26 mL), to the reaction mixture was added potassium hydroxide (444 mg, 7.91 mmol), and the reaction mixture was heated under reflux for 24 h, and then cooled under ice-cooling. To the reaction mixture was added dropwise diluted hydrochloric acid (2 mol/L, 8 mL) and the reaction mixture was extracted with ethyl acetate (70 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crystal residue was recrystallized from hexane to give 2-butyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxylic acid (4-501-05) (197 mg, 70%) as a white crystal.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:25][NH2:26]>C(O)C>[CH3:25][NH:26][CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[CH3:12]
Reactant: CN
Reactant: COc1cncc(/C=C/CC(C)OS(=O)(=O)c2ccc(C)cc2)c1
Solvent: CCO
Product: CNC(C)C/C=C/c1cncc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A mixture of (4E)-5-(5-methoxy-3-pyridyl)-4-penten-2-ol p-toluenesulfonate (5.00 g, 14.41 mmol), methylamine (150 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 1.25 g (41.8%) of a colorless oil, bp 90-100° C. at 0.5 mm Hg.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)=[N:9][C:10]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH:55][C:56]([CH3:62])([CH3:61])[CH2:57][C:58](O)=[O:59]>CN(C)C=O>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:58](=[O:59])[CH2:57][C:56]([CH3:62])([OH:55])[CH3:61])[CH2:16][CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)=[CH:27][N:28]=1
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: CC(C)(O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)CC(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 16 h
Yield: 67.5 %

Procedure:
5-(9-Isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (150 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (128 mg, 0.67 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), and 3-hydroxy-3-methylbutanoic acid (79 mg, 0.67 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred for 16 hours. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (120 mg, 67%) as a white solid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.[Br:12]Br>CC(O)=O>[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][CH2:2][CH2:3][CH:4]2[NH2:11]
Reactant: BrBr
Reactant: NC1CCOc2ccccc21
Solvent: CC(=O)O
Product: NC1CCOc2ccc(Br)cc21
Temperature: 25 °C

Procedure:
A solution of chroman-4-ylamine (Step B) (2.550 g, 17.09 mmol) in AcOH (50 mL) at RT was treated with Br2 (3.01 g, 0.96 mL, 18.8 mmol) drop-wise. The reaction was stirred at RT until HPLC analysis showed complete consumption of starting material. The mixture was diluted with H2O (100 mL) and NaOH was added until the solution became basic. The aqueous layer was extracted with EtOAc until tlc analysis of the aqueous layer showed no evidence of the title compound. The combined organics were dried over MgSO4 and concentrated in vacuo to yield the crude compound, which was purified by flash column chromatography to afford the pure title compound. MS (APCI pos) 229 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:34][C:35]#[N:36]>CN(C)C=O>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:34][C:35]#[N:36])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3CC#N)CC1
Yield: 11 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), sodium hydride and bromoacetonitrile in N,N-dimethylformamide, to give the desired product as a brown gum (11%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
61.5 g (205 mmol) of tert-butyl (3-bromobenzyl)-N-methylcarbamate, 40 g (260 mmol) of 4-formylbenzeneboronic acid and 800 ml of toluene are introduced into a three-necked flask and under argon. 205 ml of an aqueous potassium carbonate solution (2 M) are added dropwise, the reaction medium is degassed with argon and 7 g of tetrakis(triphenylphosphine)-palladium(0) chloride are added and the mixture is heated at 90° C. for 24 hours. The reaction medium is poured into water, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulphate and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (70-30) mixture. After evaporation of the solvents, 38 g (57%) of the expected product are recovered.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:31]C2CCCCO2)/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([O:14]C3CCCCO3)[CH2:12][C:11](=[O:21])[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]1=2>C(O)(=O)C.O.C1COCC1>[S:1]1[C:5]([C@H:6]([OH:31])/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:21])[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]1=2
Reactant: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](OC2CCCCO2)[C@@H]1/C=C/[C@@H](OC1CCCCO1)c1cc2ccccc2s1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
(Z)-7-((1R,2R,3R)-2-((3R,E)-3-(Benzo[b]thiophen-2-yl)-3-(tetrahydro-2H-pyran-2-yloxy)prop-1-enyl)-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid (33) was dissolved in a 4:2:1 solution of acetic acid-water-THF (0.5 M). The solution was stirred for several days at room temperature until the reaction was complete, as judged by TLC. The crude product was purified by flash chromatography on regular silica gel using ethyl acetate-hexane-0.5% acetic acid as eluent to afford the title compound 14a; TLC: Rf=0.20 (silica on 10 mm aluminum plates, eluent: 40:60:1 hexanes-ethyl acetate-acetic acid); MS (−cESI) m/z 413 (M−1); LC/MS: Sample prep-diluent, methanol. Sample prepared in 100 μL, unknown final concentration, analytical method: column: Phenomenex Synergi Hydro-RP 4p 250×2.00 mm, flow rate 0.2 mL/min, detection UV (210 nm), column temperature 25° C., HPLC mobile phase: isocratic mobile phase consisting of 31.3% solvent A, 68.7% solvent B, Solvent A=10:90:0.1 methanol-water-acetic acid, Solvent B=90:10:0.1 methanol-water-acetic acid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(Cl)Cl.[OH:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1>C(OCC)C>[N+:1]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:18]([OH:19])[C:9]=1[OH:8])([O-:4])=[O:2]
Reactant: Oc1cc2ccccc2cc1O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: O=[N+]([O-])c1c(O)c(O)cc2ccccc12

Procedure:
Fuming nitric acid (4.2 ml) was added to methylene chloride (50 ml) and the resulting solution diluted with diethyl ether (100 ml): Then 3-methylbuthylnitrite (1.9 ml) was added and this final solution added at 25-30° C. to a solution of 2,3-dihydroxynaphthalene (16.0 g) in ether (100 ml).The reaction mixture was washed with water, extracted into potassium bicarbonate (1 M), acidified and finally extracted into ether. After column chromatography (SiO2, toluene-ethyl acetate-acetic acid 18:1:1) the product was crystallized from toluene. Yield: 1.5 g, melting point 141-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.5 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH —CH2Cl2 5:95 to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl) amide as a yellow solid (73 mg, 59%)
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4([C:28](O)=[O:29])[CH2:27][CH2:26]4)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:39][NH2:40]>>[CH3:39][NH:40][C:28]([C:25]1([C:21]2[CH:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:37])[CH3:38])([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)[CH:24]=[CH:23][N:22]=2)[CH2:27][CH2:26]1)=[O:29]
Reactant: CN
Reactant: C[C@@H](c1ccc(-c2ccnc(C3(C(=O)O)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CNC(=O)C1(c2cc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)ccn2)CC1
Yield: 59 %

Procedure:
The title compound was prepared from 1-[4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridin-2-yl]-cyclopropanecarboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 59% of theory; LC (method 3): tR=2.57 min; Mass spectrum (ESI+): m/z=528 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([NH2:19])=[C:13]([CH3:20])[C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(OCC)(=O)C.CCCCCC>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:1])=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccccc1
Yield: 80 %

Procedure:
By using 2,4,6,7-tetramethyl-3-phenyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 80%. Melting point: 242-245° C. (Ethyl acetate-hexane)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li].[CH3:14][C:15]1([CH3:22])[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[CH:16]1.[CH2:23]=[O:24].Cl>O1CCCC1.CCCCCC>[CH3:14][C:15]1([CH3:22])[CH2:20][CH:19]([CH2:23][OH:24])[C:18](=[O:21])[CH:17]=[CH:16]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: C=O
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1(C)C=CC(=O)C(CO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of diisopropylamine (7.27 g, 7 mmol) in anhydrous tetrahydrofuran (THF) was added drop wise a hexane solution (1.62 mol/l) of n-butyllithium (44.4 ml, 70 mmol) at −78° C. The solution was warmed to 0° C. and stirred for 1 hr at this temperature. After thus prepared lithium diisopopylamide solution was again cooled to −78° C., 4,4-dimethyl-2-cyclohexen-1-one (7.5 g, 60 mmol) was added dropwise and stirring was continued for 1 hr. Then, gaseous formaldehyde, generated by a thermal decomposition of paraformaldehyde (5 g) over an oil bath, was blown through the solution with a gentle stream of dry nitrogen gas and the reaction mixture was stirred for 2 hr. After standing over night at room temperature, 1N hydrochloric acid was added until the solution became weak acid. The solvent was removed and the residue was extracted with ether. After drying over anhydrous sodium sulfate and removal of the solvent, a mixture of 4,4-dimethyl-6-methylene-2-cyclohexen-1-one and 4,4-dimethyl-6-hydroxymethyl-2-cyclohexen-1-one was obtained (7.03 g). This mixture (3.0 g) was treated in reflxing benzene for 2 hr in the presence of catalytic amount of anhydrous p-toluenegulfonic acid and molecular sieve 3A (4 g). The solution was neutralized with 1N sodium bicarbonate and washed with brine. After drying over anhydrous sodium sulfate and removal of the solvent, crude 4,4-dimethyl-6-methylene-2-cyclohexen-1-one (Yoshixol) was obtained (2.35 g, overall yield 68%). The analytical sample was available. 2-cyclohexen-1-one was obtained (2.35 g, overall yield 68%). The analytical sample was available after purification by column chromatography or kugelrohr distillation but yield was much lowered. This NMR analysis of Yoshixol is following: IR(neat): 1670(C═O), 1620(C═C) cm-1. 1H NMR (60 MHZ, CCL4), d1.15 (s,6H, C(CH3)2), 2.57 (bs, 2H, CH2), 5.20, 5.93 (2 m, 2H, CH2=), 5.87 (d, J=10, 1H, 2-H), 6.63 (d, J=10 Hz,3-H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[C:12]1[N:17]=[C:16]2[C:18]([C:40]([O:42][CH3:43])=[O:41])=[CH:19][N:20]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]2=[N:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:51][CH2:52][CH2:53][C:54]([CH3:59])([N+:56]([O-:58])=[O:57])[CH3:55].O>CN(C=O)C>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:51][CH2:52][CH2:53][C:54]([CH3:59])([N+:56]([O-:58])=[O:57])[CH3:55])=[CH:10][CH:9]=2)[C:5]([C:12]2[N:17]=[C:16]3[C:18]([C:40]([O:42][CH3:43])=[O:41])=[CH:19][N:20]([C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:15]3=[N:14][CH:13]=2)=[N:6]1
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(C)c4ccc(O)cc34)nc12
Reactant: CC(C)(CCCCl)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(C)c4ccc(OCCCC(C)(C)[N+](=O)[O-])cc34)nc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
To a solution of methyl 2-(5-hydroxy-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (2.2 g, 3.9 mmol) in DMF (25 mL) was added K2CO3 (1.8 g, 12.8 mmol) and 1-chloro-4-methyl-4-nitropentane (1.0 g, 5.9 mmol), after the addition, the reaction mixture was heated to 100° C. with stirring for 4 hours. The reaction mixture was cooled to room temperature, H2O (25 mL) was added and product extracted with EtOAc (100 mL). The organic layer was washed with H2O (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give methyl 2-(1-methyl-5-(4-methyl-4-nitropentyloxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (1.8 g, 66.7%) as yellow solid. LCMS: (M+H)+=695.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:19])=[C:10]2[CH:17]=[C:16]([CH3:18])[S:15][C:11]2=[C:12]([CH3:14])[N:13]=1)=[O:7])CCC.[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>C[O-].[Na+].CO.Cl>[OH:19][C:9]1[C:8]([C:6]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:7])=[N:13][C:12]([CH3:14])=[C:11]2[S:15][C:16]([CH3:18])=[CH:17][C:10]=12
Reactant: CCCCOC(=O)c1nc(C)c2sc(C)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(O)c(C(=O)NCC(=O)O)nc(C)c2s1

Procedure:
4-Hydroxy-2,7-dimethyl-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (30 mg, 0.11 mmol, example 5-b-A) and glycine (75 mg, 1.0 mmol) were suspended in 2.0 mL of 0.5 N NaOMe in methanol. The resultant mixture was heated to 120° C. for 10 min. using a CEM microwave reactor. The reaction mixture was cooled, and diluted with 0.25 N HCl until pH<3. The mixture was extracted two times with ethyl acetate, and the organic fractions were dried over anhydrous magnesium sulfate and concentrated to 27 mg of a pale yellow solid. MS: (−) m/z 279.01 (M−1).
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.C[O:15][B:16](OC)[O:17]C>CCCCCC>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([B:16]([OH:17])[OH:15])=[CH:8][CH:9]=1
Reactant: COB(OC)OC
Reactant: Clc1ccc(Br)cn1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Cl)nc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
In a flask replaced by nitrogen, tetrahydrofuran solution (80 g) of 5-bromo-2-chloropyridine (9.6 g, 50.0 mmol) was charged, and cooled at 10° C., and then n-hexane solution of n-butyllthium (15% by weight, 24.6 g, 57.5 mmol) was added dropwise at 10° C. Next, at 10° C., trimethoxyborane (5.7 g, 55.0 mmol) was added dropwise. After 30 minutes from adding dropwise, cooling bath was removed off, and the reaction mixture was stirred at room temperature overnight. However, 6-chloro-3-pyridylboronic acid could not be obtained.