Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=3)[C@H:11]([CH2:24][N:25]3[CH:29]=[C:28]([C:30]([OH:32])=O)[N:27]=[N:26]3)[O:10][C:9]2=[O:33])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:67][N:68]1[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]1>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=3)[C@H:11]([CH2:24][N:25]3[CH:29]=[C:28]([C:30]([NH:67][N:68]4[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]4)=[O:32])[N:27]=[N:26]3)[O:10][C:9]2=[O:33])=[CH:4][CH:3]=1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cn(C[C@@H]2OC(=O)N(c3ccc(Cl)cc3)[C@H]2c2cc(F)cc(C(F)(F)F)c2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NN1CCCCC1)c1cn(C[C@@H]2OC(=O)N(c3ccc(Cl)cc3)[C@H]2c2cc(F)cc(C(F)(F)F)c2)nn1
Reaction time: 0.08 h
Yield: 36.6 %

Procedure:
(4S,5S)-1-((3-(4-Chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (40 mg, 0.082 mmol) is dissolved in CH3CN (2 mL) and is successively treated with DIEA (14 μL, 0.082 mmol) and HATU (31 mg, 0.082 mmol) at ambient temperature. After 5 minutes, 1-aminopiperidine (10 μL, 0.097 mmol) is added and the reaction stirred for 2 h as judged complete by LC-MS. The reaction is quenched with 1 mL 1M HCl and diluted with water and ethyl acetate. The organic layer is washed successively with NaHCO3, brine, dried over MgSO4, filtered and concentrated. Purification by flash chromatography on silica gel (0-5% methanol/dichloromethane) gives the title compound (17 mg, 37%) as a white film. 1H NMR (acetone-d6, 400 MHz) δ 8.49 (s, 1H), 8.39 (s, 1H), 7.72 (s, 1H), 7.66 (d, 1H, J=9.2 Hz), 7.52 (d, 1H, J=8.5 Hz), 7.45-7.49 (m, 2H), 7.30-7.33 (m, 2H), 5.85 (d, 1H, J=5.5 Hz), 5.21 (d, 2H, J=5.6 Hz), 5.11 (q, 1H, J=5.6 Hz), 2.89 (t, 4H, J=5.3 Hz), 1.65 (pentet, 4H, J=6.0 Hz), 1.48-1.51 (m, 1H), 1.39-1.45 (m, 1H). HPLC-MS calculated C25H23ClF4N6O3 (M+H+): 567.2, found: 567.2.
Reaction SMILES: Cl.O=[C:3]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13]2)[CH:4]([CH3:9])[CH2:5][C:6](O)=[O:7].O.[NH2:20][NH2:21]>C(O)C>[CH3:9][CH:4]1[C:3]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH2:14][CH2:13]3)=[N:21][NH:20][C:6](=[O:7])[CH2:5]1
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)CCN2
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2c(c1)CCN2

Procedure:
A solution of 27 g of 4-oxo-4-(indolin-5-yl)-3-methylbutanoic acid hydrochloride and 15 ml of hydrazine hydrate in 200 ml of ethanol was heated under reflux on a water bath for 2 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The precipitated crystals were filtered off, washed with water and recrystallized from ethanol to give 20 g of 5-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)indoline as white crystals, melting at 187°-189° C.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[C:6]=2[N:5]=[C:4]([CH3:14])[N:3]=1.O.[NH2:16][NH2:17]>>[CH2:12]([N:11]1[CH2:10][CH2:9][O:8][C:7]2[C:2]([NH:16][NH2:17])=[N:3][C:4]([CH3:14])=[N:5][C:6]1=2)[CH3:13]
Reactant: NN
Reactant: CCN1CCOc2c(Cl)nc(C)nc21
Solvent: O
Product: CCN1CCOc2c(NN)nc(C)nc21

Procedure:
Using the method of Example 87, 4-chloro-6,7-dihydro-8-ethyl-2 methylpyrimido[5,4-b][1,4]oxazine, from Example 102, was reacted with hydrazine hydrate to provide 6,7-dihydro 8-ethyl-4-hydrazino 2-methylpyrimido[5,4-b][1,4]oxazine.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:10][OH:11].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C1COCC1>[Cl:19][CH2:20][C:21]([NH:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:10][OH:11])=[O:22]
Reactant: NC(CO)c1cccc(F)c1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)NC(CO)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In step 2-2, triethylamine (8.15 mL, 58.6 mmol) in a single portion was added to a solution of 2-amino-2-(3-fluorophenyl)ethanol (7.57 g, 48.8 mmol) in THF cooled to 0° C. and chloroacetyl chloride (5.08 mL, 58.6 mmol) was added drop-wise. The mixture was cooled to 0° C. and stirred for 1 hour. The reaction mixture was quenched with water and the organic phase was washed with 0.5 N HCl, saturated NaHCO3, brine, and dried over MgSO4. The organic phase was concentrated and purified with flash chromatography (50% EtOAc/hexanes) to yield 2-chloro-N-(1-(3-fluorophenyl)-2-hydroxyethyl)acetamide (2-2) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:13][CH3:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.C(OCC)C>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH:12]=[CH:11][N:10]=[C:9]3[CH2:13][CH3:14])=[CH:6][CH:7]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: CCc1nccn1-c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCc1nccn1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Reaction time: 7 h
Yield: 75.6 %

Procedure:
1.9 g of 1-(4-aminophenyl)-2-ethylimidazole was added to a solution of 2.6 g of p-chlorobenzoyl chloride in 50 ml of toluene, and the mixture was refluxed with stirring for 7 hours. The reaction mixture was naturally cooled and diethyl ether was then added thereto. The precipitated crystal was recovered by filtration, washed sufficiently with ethyl ether and recrystallized from ethanol and then from water to obtain 2.5 g of the intended compound in the form of a hydrochloride. The melting point was 265° to 267° C. Elementary analysis values as C18H16ClN3O.HCl.1/2H2O were as follows.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[Br:12][C:13]1[CH:31]=[CH:30][C:16]([CH2:17][CH2:18][C:19]2[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=2[C:21](OCC)=[O:22])=[CH:15][CH:14]=1.[Cl-].[NH4+]>C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH2:18][C:19]2[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=2[CH2:21][OH:22])=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccccc1CCc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCc1ccccc1CCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Lithium aluminum hydride, 3.8 g. (0.1 mole), is wegihed under nitrogen, transferred to a dry, nitrogen-flushed reaction flask, and suspended in 300 ml. of absolute ether. The mixture is stirred at reflux for 30 minutes and then, after cooling to room temperature, a solution of 36.16 g. (0.108 mole) of ethyl 2-(4-bromophenethyl)-benzoate in 100 ml. of absolute ether is added dropwise. The mixture is stirred at room temperature overnight. The excess lithium aluminum hydride is decomposed by the addition of 5 ml. of ethyl acetate and the mixture then is hydrolyzed by the addition of 30 ml. of saturated ammonium chloride solution. The ethereal layer is separated and the aqueous layer re-extracted with ether. Evaporation of the combined, washed, and dried ethereal extracts under reduced pressure leaves the product as the residual solid, m.p. 72°-75.5° C. Recrystallization from hexane-cyclohexane affords purified material, m.p. 74°-75.5° C. A sample for analysis melts at 75°-76.5° C. after recrystallization from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](Cl)=[N:5][OH:6].[CH3:12][O:13][C:14](=[O:19])[CH2:15][C:16]([CH3:18])=O.C[O-].[Na+]>CO>[CH3:12][O:13][C:14]([C:15]1[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])=[N:5][O:6][C:16]=1[CH3:18])=[O:19]
Reactant: COC(=O)CC(C)=O
Reactant: ON=C(Cl)c1ccccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2Cl)noc1C
Yield: 59.6 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 2-chloro-N-hydroxybenzimidoylchloride (8.0 g, 42.10 mmol), methylacetoacetate (9.78 g, 84.20 mmol) and sodium methoxide (6.83 g, 126.30 mmol), a white solid required compound (6.32 g, 25.11 mmol, 60%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:19](OC)=[O:20])[CH:5]=[C:6]([CH:18]=1)[O:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=O.C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([O:7][CH2:8][CH2:9][NH:11][C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH:18]=1
Reactant: COC(=O)c1cc(Br)cc(OCC(=O)Nc2ccncc2)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cc(Br)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.6 %

Procedure:
A stiired solution of 2-(5-bromo-3-methoxycarbonyl-phenoxy)-N-pyridin-4-yl-acetamide (6.61 g) in anhydrous tetrahydrofuran (200 ml) was treated with a 1M diethyl ether solution of lithium aluminium hydride (56.1 ml) over a period of 20 min. A brown precipitate appeared and the mixture was stirred at room temperature for 6 h. The reaction mixture was treated with water (2 ml) 1M sodium hydroxide solution (2 ml), water (6 ml) and then with 2M hydrochloric acid (150 ml). The reaction mixture was extracted with ethyl acetate and then basified with 2M sodium hydroxide solution. The reaction mixture was reextracted with ethyl acetate. The first organic phase was washed with saturated aqueous sodium bicarbonate and combined with the second organic phase. The combined organic phase was washed with water and dried with brine and over sodium sulphate. Concentration of the organic phase gave a gum which was found to be unsatisfactory so the gum was partitioned between ethyl acetate and 2M hydrochloric acid. The aqueous layer was separated, basified to pH 10 and extracted with ethyl acetate. The organic phase was washed with water and dried with brine and over sodium sulphate. Concentration under reduced pressure gave the title compound as an off-white solid (1.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]#[N:20])[CH:15]=2)[CH:10]=1.[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)=[O:25].C1(C)C=CC=CC=1.C(O)C>C(=O)([O-])[O-].[Na+].[Na+].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.O>[C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:21]([O-:23])=[O:22])=[CH:3][C:2]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:24]=[O:25])[CH:18]=[CH:17]2)#[N:20]
Reactant: N#Cc1ccc2cc(Oc3ccc([N+](=O)[O-])cc3Br)ccc2c1
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: N#Cc1ccc2cc(Oc3ccc([N+](=O)[O-])cc3-c3ccccc3C=O)ccc2c1
Temperature: 25 °C

Procedure:
The compound (3-bromo-4-(6-cyano-2-naphthyloxy)nitrobenzene) (1 g) obtained in a previous production example, 2-formylphenyl boronic acid (610 mg) and tetrakis(triphenylphosphine)palladium (0) (150 mg) were heated to reflux and reacted for 6 hours in a mixture of 2 M sodium carbonate aqueous solution (10 ml), toluene (10 ml) and ethanol (10 ml). After cooling to room temperature, water was added and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (200 g, hexane:ethyl acetate=4:1) to obtain 880 mg of 4-(6-cyano-2-naphthyloxy)-3-(2-formylphenyl)nitrobenzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33](=[O:42])[CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40]C)=[O:39])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:24]([C:33](=[O:42])[CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCCCC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)CCCCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A 270 mg portion of methyl 6-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-6-oxohexanoate was dissolved in 3 ml of methanol, mixed with 3 ml of 1 M sodium hydroxide aqueous solution and stirred at room temperature for 4Hours. The reaction solution was concentrated under a reduced pressure, and 1 M hydrochloric acid was added to the residue until it became pH 3.0. After extraction with chloroform and subsequent washing with saturated brine, the organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 237 mg of 6-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-6-oxohexanoic acid as a colorless solid. FP: 559.
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.CC1(C)C(C)(C)OB([C:27]2[CH:44]=[CH:43][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:9]1[CH:8]=[C:7]([C:6]2[O:5][C:4]([CH3:17])([CH3:16])[C:3](=[O:18])[C:2]=2[C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:43][CH:44]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1Cl
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1Cl
Yield: 24.6 %

Procedure:
A solution of 4-bromo-5-(3-chloro-4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one 0.34 g, 1.021 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.37 g, 1.021 mmol), and Cs2CO3 (1.67 g, 5.130 mmol) in toluene (6 mL) and water (3 mL) was degassed. Then, Pd(dppf)Cl2 (0.167 g, 0.204 mmol) was added under an inert atmosphere and the solution was again degassed. Then the reaction mixture was refluxed for 1 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (20 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(3-chloro-4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (122 mg, 23%) as a solid. 1H NMR (500 MHz, d-DMSO): δ 8.42 (d, J=8.5 Hz, 1H), 8.02 (t, J=7.9 Hz, 2H), 7.79 (t, J=7.4 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.65-7.59 (m, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.22-7.18 (m, 3H), 7.12 (d, J=7.5 Hz, 2H), 5.40 (s, 2H), 3.91 (s, 3H), 1.46 (s, 6H). MS: [M+Na]: m/z=508.2, [M+H]: m/z=486.2. HPLC: 96%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12]C)=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:26][C:25]=2[CH3:39])[CH:21]=[CH:22][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>CN(C)C=O.O>[CH3:39][C:25]1[CH:26]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][O:1][C:2]2[CH:15]=[CH:14][C:5]3[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=3[CH:3]=2)[CH:19]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CCl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (10.0 g) and 3′-chloromethyl-2,6-dimethyl-4-[3-(methylsulfonyl)propoxy]biphenyl (17.6 g) in N,N-dimethylformamide (30.0 mL) was added tripotassium phosphate (16.8 g), and the mixture was stirred at 60° C. for 3 hr. 2.4M Aqueous sodium hydroxide solution (32.9 g) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled, water (100 mL) was added, and the mixture was extracted with toluene (50 mL). To the aqueous layer was added toluene (50 mL), and the mixture was extracted. To the obtained aqueous layer were added acetone (10 mL) and concentrated hydrochloric acid (17.6 mL), and the mixture was stirred at 30° C. for 1 hr, at 50° C. for 30 min, and at 25° C. for 2 hr. The precipitated crystals were collected by filtration, and washed with a mixed solution (50 mL) of acetone.water (3:7) and then water (50 mL). The obtained crystals were dried at 60° C. under reduced pressure to give [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid (24.3 g). 100% ee. (high performance liquid chromatography conditions)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[CH:17]([CH3:19])[CH3:18].F[C:21]1[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[CH:23][C:22]=1[CH3:31].O>CS(C)=O>[CH3:27][C:26]1[CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=[C:22]([CH3:31])[C:21]=1[O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)c1n[nH]c2ccc(O)cc12
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]nc(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
86 mg (0.624 mmol) of potassium carbonate are added to a solution of 110 mg (0.624 mmol) of 5-hydroxy-3-isopropyl-1H-indazole in 5 ml of DMSO and the mixture is stirred for 1 h. After addition of 106 mg (0.624 mmol) of 4-fluoro-3,5-dimethylnitrobenzene in portions, the mixture is then firstly stirred at room temperature for 2 h, then at 100° C. for 3 h. After cooling to room temperature, the mixture is added to 10 ml of water and the aqueous phase is extracted 3× with ethyl acetate. The combined organic extracts are washed with water and satd NaCl soln, dried over sodium sulphate and concentrated in vacuo. By purification of the resulting residue on silica gel (cyclohexane/ethyl acetate 3:1), 84 mg (41%) of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indazole are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:16]=[CH:15][C:14]([S:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)(=[O:19])=[O:18])=[CH:13][C:9]=1[C:10](O)=[O:11]>O1CCCC1.O>[Br:7][C:8]1[CH:16]=[CH:15][C:14]([S:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)(=[O:18])=[O:19])=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1cc(S(=O)(=O)n2ccc3ccccc32)ccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(Br)c(CO)c1)n1ccc2ccccc21
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 35.4 %

Procedure:
To a suspension of Lithium aluminium hydride (2.3 grams, 60.5 mmol) in tetrahydrofuran (20 mL) was added a solution of 2-bromo-5-(indole-1-sulfonyl) benzoic acid (17.64 grams, 46.42 mmol) (obtained from preparation 1) in tetrahydrofuran (30 mL) maintaining mass temperature at 0-5° C. The reaction mass was stirred at 0-5° C. for 4 hours. The progress of the reaction was followed by TLC. After completion of the reaction, the reaction mass was cooled to −10° C. Water (20 mL) was added water slowly under nitrogen atmosphere. The reaction mass was diluted further with water (300 mL) and filtered through hyflow bed. The clear filtrate was extracted with ethyl acetate (4×100 mL). The combined organic layer was washed with brine solution (2×50 mL), water (2×50 mL) and dried over anhydrous sodium sulphate and was concentrated under reduced pressure. The residual mass was purified by column chromatography, the eluent system being ethyl acetate and hexane (2:8) to obtain 6.025 gram the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH3:26])[C:20](=[O:27])[N:19]([CH2:28][C:29]([CH3:31])=[CH2:30])[C:18]=2[N:17]=1.[CH2:32]([Zn]CC)C.ClCI>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:17][C:18]2[N:19]([CH2:28][C:29]3([CH3:32])[CH2:31][CH2:30]3)[C:20](=[O:27])[N:21]([CH3:26])[C:22](=[O:25])[C:23]=2[N:24]=1
Reactant: CC[Zn]CC
Reactant: C=C(C)Cn1c(=O)n(C)c(=O)c2[nH]c(Cc3cncc4cc(OC)c(OC)cc34)nc21
Agent: ClCI
Solvent: ClCCCl
Product: COc1cc2cncc(Cc3nc4c(=O)n(C)c(=O)n(CC5(C)CC5)c4[nH]3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 18, 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3-(2-methyl-allyl)-3,7-dihydro-purine-2,6-dione (100 mg, 0.24 mmol) is suspended in 1,2-dichloroethane (30 ml). Diethyl zinc (1M hexane solution, 1.2 ml, 1.20 mmol) is added, followed by chloroiodomethane (0.174 ml, 0.24 mmol) and the reaction is stirred at ambient temperature for 1 hour, prior to quenching with saturated aqueous NH4 Cl. After extraction with chloroform, the organic phase is washed with water, dried over MgSO4 and evaporated. Purification by preparative HPLC affords 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3-(1-methyl-cyclopropylmethyl)-3,9-dihydro-purine-2,6-dione, [MH]+ 436.
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]3[S:43][CH:42]=[N:41][C:40]=3[CH:44]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[S:43]1[C:39]2[CH:38]=[CH:37][C:36]([C:6]3[C:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:27])=[N:14][C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=4)[N:7]=3)=[CH:44][C:40]=2[N:41]=[CH:42]1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C(C)C)nc2c1
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: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4scnc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (150 mg, 0.37 mmol) in dioxane (5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (288 mg, 1.1 mmol), K3PO4 (234 mg, 1.1 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 2%-5% ethyl acetate in petroleum ether to afford methyl 2-(benzo[d]thiazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (120 mg, 83%).