Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([C:14]([NH:16][C@H:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:39]>C(N(CC)CC)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([C:14]([NH:16][C@H:17]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[O:15])[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)(=[S:39])[NH2:2]
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)NC(=O)C1CN(c2ccc(C#N)cc2)C(=O)O1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)NC(=O)C1CN(c2ccc(C(N)=S)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.6 g of tert-butyl (2R)-2-[3-(4-cyanophenyl)-2-oxo-5-oxazolidinylcarbonylamino]-3-phenylpropionate [obtainable according to Example 8] are dissolved in a solvent mixture consisting of 30 ml of pyridine and 5 ml of triethylamine and the mixture is stirred for 1.5 h with ice cooling, with H2S gas being passed in continuously during this phase. The reaction mixture is subsequently stirred at room temperature for 24 h. Concentration by evaporation and customary workup give tert-butyl (2R)-2-[3-(4-thiocarbamoylphenyl)-2-oxo-5-oxazolidinylcarbonylamino]-3-phenylpropionate, m.p. 185°-186°.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:9]([CH2:13][OH:14])[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[CH2:32]([NH:39][C:10](=[O:11])[C@H:9]([N:8]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][OH:14])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To the suspension of (R)-2-(dibenzylamino)-3-hydroxypropanoic acid (285.34 g, 1.0 moL) in dichloromethane (2.86 L) was added HOBt (202.68 g, 1.50 moL), triethylamine (111.31 g, 1.1 moL), benzyl amine (117.86 g 1.1 moL) and EDC.HCl (230.04 g, 1.2 moL) at 0-5° C. under constant stirring. The reaction mixture was stirred at below 10° C. for 16 hours. When the reaction was considered complete, the agitation was stopped and the phases were allowed to separate. The organic phase was washed with water (856 mL), saturated sodium bicarbonate (2×713 mL), water (713 mL) and finally with a mixture of 2.85 mL of 30% HCl and 570 mL of water. The organic phase was concentrated under reduced pressure to a final volume of about 485 mL. MTBE (770 mL) was added and distilled again under reduced pressure to a final volume of about 485 mL. The reaction mixture was cooled to 20-25° C., and charged with heptanes (856 mL). The reaction mixture was heated to 28-32° C. and stirred for 1 hour, then cooled to 0-5° C. and stirred for 3 hours. The obtained mixture was filtered and the cake was washed with cold (0-5° C.) heptanes (285 mL). The resulting solid was dried under vacuum at 45-50° C. for 12 hours to provide (R)—N-benzyl-2-(dibenzylamino)-3-hydroxypropanamide as a white solid (353.82 g, yield 95%, HPLC purity >99.95%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:25])[CH:7]=[CH:8][C:9]=1[CH:10]([CH3:24])[C:11]([OH:23])([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1)[C:12]([F:15])([F:14])[F:13].Br[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([O:25][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=[CH:8][C:9]=1[CH:10]([CH3:24])[C:11]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1)([OH:23])[C:12]([F:15])([F:13])[F:14]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(O)(C(C)c2ccc(OCCc3ccccc3)cc2Cl)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 20.4 mg) was added to abs. DMF (2 mL). To this mixture was added a solution of 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (Example 73, 80 mg) in DMF (2 mL) over 15 minutes. The mixture was then allowed to stir for 30 min at RT. The mixture was cooled to 0° C. and a solution of 2-bromoethylbenzene ((0.033 mL) in DMF (1 mL) was added within 10 minutes. The mixture was then heated to 50° C. over night. The reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless oil (12 mg). MS (m/e)=450.2 (MH+).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C@H:8]([C:13]([O:15][CH3:16])=[O:14])[NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>>[Si:21]([O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C@H:8]([C:13]([O:15][CH3:16])=[O:14])[NH:9][CH2:10]2)=[CH:5][CH:4]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@H]1Cc2ccc(O)cc2CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Product: COC(=O)[C@H]1Cc2ccc(O[Si](C)(C)C(C)(C)C)cc2CN1
Yield: 79 %

Procedure:
Prepared as in Example 1c-JF from (R)-methyl 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (Example 13-2c) and tert-butylchlorodimethylsilane. Yield 79%, yellow oil (1.15 g, 79%). MS 322 (MH+).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.FC1C=CC=C(OCC#C)C=1F>C1COCC1.[Pd]>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1F)OCC=C2
Agent: [Pd]
Agent: C#CCOc1cccc(F)c1F
Solvent: C1CCOC1
Product: Fc1ccc2c(c1F)OCCC2

Procedure:
A mixture of 7,8-difluoro-2H-chromene and 1,2-difluoro-3-prop-2-ynyloxybenzene (43.2 g) is hydrogenated at RT for 1 h in 430 ml of THF in the presence of Pd/C (5% of Pd). The batch is evaporated to dryness, and the crude product is purified by column chromatography (SiO2, n-pentane: 1-chlorobutane=4:1), giving pure 7,8-difluorochroman as a pale-yellowish liquid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[N+:20]([O-])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]([NH2:20])=[CH:14][C:15]([F:19])=[C:16]([F:18])[CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCNc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNc1cc(F)c(F)cc1N
Reaction time: 2 h

Procedure:
To a stirred solution of N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5-difluoro-2-nitroaniline (37) in methanol (5 ml) was added 10% palladium on carbon (catalytic amount) portion wise at room temperature. The reaction mixture was allowed to stir under the atmosphere of hydrogen gas supplied by balloon at room temperature for 2 h. The reaction mixture was filtered through celite and filtrate was concentrated to afford the desired product N1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5-difluorobenzene-1,2-diamine (0.09 g; crude). LCMS (M+1=303).
Reaction SMILES: [N+:1]([C:4]1[C:8]([C:9]#[N:10])=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[OH:11]O.[OH-].[Na+:14]>CO>[Na+:14].[N+:1]([C:4]1[C:8]([C:9]([NH-:10])=[O:11])=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2]
Reactant: OO
Reactant: N#Cc1c[nH]nc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [NH-]C(=O)c1c[nH]nc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 4 h

Procedure:
A solution was made of 8 gm. of 1-sodium salt of 3-nitro-4-pyrazolecarbonitrile in methanol, and 75 ml. of 15% H2O2 was added, followed by 5 ml. of 6 N NaOH. The reaction mixture was heated to 45° C., at which point external cooling was needed to maintain the mixture at 45°-50° C. After the exothermic reaction had subsided, the mixture was held at 45°-50° C. and stirred for 4 hours. Then the mixture was cooled and the methanol was evaporated under vacuum. The liquid remaining was cooled in an ice bath and the product was separated by filtration and dried under vacuum. The dry product was determined to be 8 gm. of 3-nitro-4-pyrazolecarboxamide sodium salt, m.p.>300° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.[CH2:26]([O:28][NH2:29])[CH3:27].C(N(CC)CC)C>CO>[CH2:26]([O:28]/[N:29]=[C:22](/[C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)=[CH:14][N:15]=2)[N:18]=1)\[CH3:23])[CH3:27]
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: CCON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCO/N=C(\C)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a solution of 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone (50 mg, 0.16 mmol) in methanol (10 mL) was added O-ethylhydroxylamine hydrochloride (46 mg, 0.47 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at rt overnight. The solution was concentrated under reduced pressure and the residue was purified by prep-HPLC to afford 30 mg (53%) of the title compound as a white solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.82 (dd, 1H), 8.30 (d, 1H), 7.93 (m, 2H), 7.85 (d, 1H), 7.70 (d, 1H), 7.66 (s, 1H), 7.49 (q, 1H), 4.62 (s, 2H), 4.31 (q, 2H), 2.27 (s, 3H), 1.36 (t, 3H). LCMS (method C): [MH]+=364, tR=4.71 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][CH:2]([CH3:26])[CH2:3][N:4]([CH2:5][C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[S:37]([CH3:36])(=[O:39])=[O:38]
Reactant: CC(C)CNC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
A 250-mL round-bottomed flask was charged with di-tert-butyl (2S)-2-(((2-methylpropyl)amino)methyl)-1,4-piperazinedicarboxylate (0.77 g, 2.1 mmol), DMAP (0.0287 g, 0.235 mmol) and DIPEA (1.45 mL, 8.29 mmol) and CH2Cl2 (10 mL). Methanesulfonyl chloride (0.321 mL, 4.15 mmol) was added drop wise at room temperature. The mixture was stirred for 30 min and partitioned between water (30 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted with CH2Cl2 (30 mL) and the combined organic phases were washed with saturated aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 10 to 70% EtOAc in hexanes) to afford di-tert-butyl (2R)-2-(((2-methylpropyl)(methylsulfonyl)amino)methyl)-1,4-piperazinedicarboxylate (0.842 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=2.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1.C(=O)(O)[O-].[Na+].C(=O)=O>C(O)(=O)C.O>[N+:13]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:11]#[N:12])=[C:2]([N:1]3[CH:18]=[CH:22][CH:21]=[CH:20]3)[NH:3]2)=[CH:8][CH:7]=1)([O-:15])=[O:14]
Reactant: N#Cc1c(N)[nH]c2cc([N+](=O)[O-])ccc12
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(-n2cccc2)[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C

Procedure:
A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile (362 mg, 1.79 mmol) in acetic acid (5 mL) is treated with 2,5-dimethoxytetrahydrofuran (0.30 mL, 2.27 mmol), and the solution is heated to reflux for 14 h. After cooling to ambient temperature, the solution is poured into water (100 mL), and solid sodium bicarbonate is added until CO2 evolution ceased. The mixture is extracted with EtOAc (2×100 mL), and the extracts are washed with saturated brine, combined, dried over MgSO4, filtered and concentrated. The residual material is separated by silica gel chromatography (EtOAc/hexanes, 1/4) to afford 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile, compound 5, as a yellow solid (232 mg, 51%).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:24]1[O:25][CH:26]=[N:27][N:28]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:20]([C:15]1[CH:14]=[C:13]([CH2:12][CH:11]([NH2:10])[C:24]2[O:25][CH:26]=[N:27][N:28]=2)[CH:18]=[CH:17][C:16]=1[OH:19])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(CC(NC(=O)OCc2ccccc2)c2nnco2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(CC(N)c2nnco2)ccc1O
Yield: 96.9 %

Procedure:
To a solution of 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,3,4-oxadiazol-2-yl)ethylcarbamic acid benzyl ester (1.25 g, 3.16 mmol) in methanol (30 ml), 10% palladium carbon (130 mg) was added and stirred in a hydrogen atmosphere at room temperature for 1 day. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=100:10:1), giving the titled compound (0.80 g, 97%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:29]2[C:24](=[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[N:26]=[CH:27][CH:28]=2)[NH:23][C:22](=[O:37])[CH:21]=1>ClCCl>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:29]2[C:24](=[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[N+:26]([O-:9])=[CH:27][CH:28]=2)[NH:23][C:22](=[O:37])[CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccccc1-c1nccc2c(-c3ccc(F)cc3F)cc(=O)[nH]c12
Solvent: ClCCl
Product: Cc1ccccc1-c1c2[nH]c(=O)cc(-c3ccc(F)cc3F)c2cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
Meta-chloroperbenzoic acid (77%) (1.37 g, 6.12 mmol) was added portionwise to a solution of the title compound from Example 5 (1.40 g, 4.02 mmol) in dichloromethane (22 mL) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then, more dichloromethane was added (100 mL) and the solution was washed with 4% aqueous sodium bicarbonate (4×30 ml) and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield the title compound (1.40 g, 96%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[CH:6]3[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1.IC.[CH3:23]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[C:7](=[O:16])[C:6]3([CH3:23])[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CC1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CC12COCCN1c1nc(Cl)ncc1N(CC1CC1)C2=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a round-bottomed flask equipped with a magnetic stirrer was added 2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (745 mg, 2.53 mmol), DMSO (10 ml), iodomethane (0.189 ml, 3.03 mmol). The suspension was cooled to 0° C. and sodium 2-methylpropan-2-olate (292 mg, 3.03 mmol) was added. The reaction was removed from the ice-bath and stirred at 20° C. for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate 3 times and the organic layer washed with saturated NaCl. The organic layer was collected, dried with Na2SO4, filtered and the filtrate concentrated in vacuo to furnish a light-brown solid. The solid was washed with a small amount of ethanol followed by diethyl ether to afford 2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (641 mg, 2.228 mmol, 82% yield) as white solid. MS [M+H] found 309.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.I[CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH:16]([CH3:18])[CH3:17])[CH:5]=1
Reactant: CC(C)I
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC(C)C)c1
Yield: 67.7 %

Procedure:
A mixture of 2.0 g (10 mmole) of 3-hydroxy-4-nitro-benzoic acid methyl ester, 1.32 mL (13 mmole) of 2-iodopropane, 6.6 g (20 mole) of cesium carbonate and 60 mL of dimethylformamide was heated at 85 degrees overnight. The mixture was cooled, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with ethyl acetate-hexane (gradient, 100:0-70:30) gave 1.62 g of 3-isopropoxy-4-nitro-benzoic acid methyl ester as a yellow liquid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11](CC(O)=O)[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH2:1][C:2]([Cl:4])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(CC(=O)O)c1
Solvent: ClCCl
Product: COc1cccc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (57.1 g) is added to a stirred solution of 3-methoxyphenylacetic acid (49.85 g) in 300 ml of methylene chloride. The reaction mixture is stirred for 11/2 hr at RT, refluxed overnight, and then evaporated in vacuo. The residual product is used in the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)[CH3:2].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:16])=[O:12])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Ethylphenylacetic acid (3.0 g) (see Japanese Unexamined Patent Publication 63-233975) was dissolved in dichloromethane (15 ml), and thereto were added oxalyl chloride (6.0 ml) and N,N-dimethylformamide (one drop). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene to give a crude 4-ethylphenylacetyl chloride, which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:19]CCC(C1C=CC=CC=1)=O.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(=O)c1ccccc1
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(C)c1
Yield: 84 %

Procedure:
Compound 9e was synthesized by a procedure similar to that described for 9a using commercially available 3-methylpropiophenone (8e, 5.0 g, 0.033 mol), TBDMSOTf (8.5 mL, 36.1 mmol), and Et3N (7.5 mL) in CH2Cl2 (50 mL). After purification by column chromatography on silica gel, 7.45 g (84%) of 9e was isolated as colorless oil: 1H NMR (CDCl3) δ 7.31-7.24 (m, 2H), 7.23-7.17 (m, 1H), 7.10-7.05 (m, 1H), 5.22 (q, 1H, J=6.9 Hz), 2.37 (s, 3H), 1.76 (d, 3H, J=6.9 Hz), 1.03 (s, 9H), −0.03 (s, 6H); 13C NMR (CDCl3) δ 150.7, 140.1, 137.7, 128.4, 127.9, 126.8, 123.2, 105.9, 26.3, 21.8, 18.7, 12.1, −3.6. C16H26OSi.
Reaction SMILES: [OH:1][C@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1.[N:15]([O-])=[O:16].[Na+].O>C(O)(=O)C>[OH:1][C@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[C:11]=2[N:15]=[O:16])[CH:6]=[N:5]1
Reactant: O=N[O-]
Reactant: C[C@@H](O)Cn1ncc2ccc(O)cc21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](O)Cn1ncc2ccc(O)c(N=O)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 465.1 %

Procedure:
To a solution of 1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol (2.0 g, 1.04 mmol) in acetic acid (20 mL) was added sodium nitrite (0.72 g, 10.4 mol) and the mixture was stirred at room temperature for 1 hour. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2×200 mL). The combined extracts were washed with water (200 mL), and a saturated aqueous solution of sodium bicarbonate (200 mL), dried over magnesium sulfate, filtered and evaporated to a residue which was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a red solid (1.07 g, 47%): LC/MS m/z 222.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>C1COCC1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[B:18]([OH:23])[OH:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cccc2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(B(O)O)ccc2ccccc12
Temperature: -50 °C
Yield: 41.6 %

Procedure:
To a stirred mixture of 1-methoxynaphthalene (20.0 g, 126.6 mmol) in THF (100 mL) was added n-butyllithium (53.16 mL, 132.9 mmol, 2.5M solution in hexanes) at room temperature over 5 min. The reaction mixture was cooled to −50° C., and triisopropyl borate (43.8 mL, 35.7 g, 190 mmol) was added dropwise over 0.25 h. The resulting precipitate was broken up by the addition of THF (100 mL), and the mixture was allowed to warm to 0° C. with stirring. At this point the mixture was poured into 1N HCl (100 mL), the product extracted with ethyl acetate, the combined extracts dried over anhydrous sodium sulfate, and filtered. After concentrating the filtrate in vacuo at ambient temperature, the residue was partially dissolved in diethyl ether, triturated with hexane, and the resulting precipitate filtered and washed with hexane to afford 10.64 g (41%) of the title compound 1-methoxynaphthalene-2-boronic acid as an off-white crystalline solid (MW 202.02, C11H11BO3).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[I:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([N:21]3[CH:22]=[C:18]([I:17])[N:19]=[CH:20]3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Ic1c[nH]cn1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-methyl-pyridine (example A.51) (3.5 g, 12.8 mmol) and commercially available 4-iodo-imidazole (2.99 g, 15.4 mmol) according to the general procedure IVa. Obtained as a light grey solid (0.90 g, 16%). MS (ISP) 430.0 [(M+H)+], 432.1 [(M+2+H)+] and 434.0 [(M+4+H)+].