Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[OH:12].[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:3]([OH:12])[CH:4]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(N)c(O)c1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(NC(=O)c2ccncc2)c(O)c1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
A mixture of 1.44 g of 2-amino-5-tert-butylphenol, 1.07 g of isonicotinic acid, 2.17 g of WSC and 15 ml of pyridine was stirred while heating at 80° C. for five hours. The reaction mixture was cooled to room temperature, and then water was poured. Precipitated solid was filtered and washed with water and diethyl ether to give 1.22 g of N-(4-tert-butyl-2-hydroxyphenyl)isonicotinamide.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:11]=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[N:9]=1.C(=O)(O)[O-].[Na+].Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38]>O1CCOCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[N:11]=[C:10]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:37](=[O:38])[O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:28][CH:29]=2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
(4-{4-[(3S)-3-Methylmorpholin-4-yl]-6-[(phenylsulfonyl)methyl]pyrimidin-2-yl}phenyl)amine (2 g, 4.71 mmol) was dissolved in dioxane (20 mL). Sodium bicarbonate (594 mg, 7.07 mmol) was added, followed by phenyl chloroformate (0.593 mL, 4.71 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 20 mL DCM and 20 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (1.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4](/[C:9](=[N:18]\[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])/[CH3:10])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(=O)c1cc(Br)cnc1F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C/C(=N/[S@](=O)C(C)(C)C)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A mixture of 1-(5-bromo-2-fluoropyridin-3-yl)ethanone (11 g, 51 mmol), (R)-2-methylpropane-2-sulfinamide (12.2 g, 101 mmol) and titanium (IV) ethoxide (26.1 mL, 126 mmol) in THF (100 mL) was heated to reflux for 2 h. The mixture was cooled to room temperature, brine was added and the mixture was stirred for 10 min. The suspension was filtered through silica gel. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 0-20% EtOAc/hexanes) gave (R,Z)—N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (16 g, 50 mmol, 99% yield) as a bright yellow oil. LC/MS (ESI) m/z=321 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11]Br)[S:9][CH:10]=1)=[O:5])[CH3:2].[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:16]([O:28][CH3:29])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:27][C:24]2[CH:23]=[CH:22][C:21]([C:17]3[CH:18]=[C:19]([F:20])[C:14]([F:13])=[CH:15][C:16]=3[O:28][CH3:29])=[CH:26][CH:25]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Reactant: CCOC(=O)c1csc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)n1
Temperature: 130 °C
Yield: 89.5 %

Procedure:
A mixture of 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (prepared according to US 2004/0266856 A1) (3.0 g, 11.99 mmol), 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (3.09 g, 13.08 mmol), potassium carbonate (6.5 g, 47.03 mmol) and potassium iodide (1.1 g, 6.626 mmol) in DMF (25 mL) was heated under microwave conditions at 130° C. for 15 min. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3×150 mL). The organic layers were combined, washed with 1/1 water/brine (2×100 mL) and brine (100 mL), dried (MgSO4), filtered, concentrated and purified by flash chromatography (silica, 120 g, 20% to 100% ethyl acetate in hexanes) to give 2-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid ethyl ester (4.35 g, 89.5%) as an orange oil. LC-MS (ES) calculated for C20H17F2NO4S, 405.42; found m/z 406 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([F:25])[CH2:6][O:7][Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[BH4-].[Li+].[OH-].[Na+]>O1CCCC1>[Si:8]([O:7][CH2:6][CH:5]([F:25])[CH2:4][OH:3])([C:21]([CH3:24])([CH3:22])[CH3:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(F)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCC(F)CO)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 75.8 %

Procedure:
3-{[Tert-butyl(diphenyl)silyl]oxy}-2-fluoropropionic acid ethyl ester (17.98 g, 48.01 mmol) was dissolved in tetrahydrofuran (250 ml). Lithium borohydride (2.32 g, 96.02 mmol) was added to the solution under cooling on ice and the mixture was stirred for 24 hours. To the reaction solution was added 1N sodium hydroxide aqueous solution under cooling on ice to quench the reaction. The resulting solution was extracted with ethyl acetate, and the resultant was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 12.10 g (76%) of the title compound in the form of a colorless clear oily product.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([C:4](=O)[C:5]#[C:6][CH2:7][O:8]C1CCCCO1)[CH3:3].C[O-].[Na+].Cl.[NH2:21][OH:22].Cl.C(=O)([O-])O.[Na+]>CO>[C:2]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[O:22][N:21]=1)([CH3:16])([CH3:3])[CH3:1]
Reactant: CC(C)(C)C(=O)C#CCOC1CCCCO1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CC(C)(C)c1cc(CO)on1
Temperature: 70 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
4.49 g of 2,2-dimethyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexyn-3-one was dissolved in 20 ml of methanol, and 1.30 g of sodium methoxide and 1.53 g of hydroxylamine hydrochloride were added. The mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and then adjusted to pH 2 with concentrated hydrochloric acid. The mixture was stirred at room temperature for 18 hours. After aqueous saturated sodium hydrogen carbonate was added, the reaction mixture was extracted with ethyl acetate. The extract was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.12 g of (3-t-butyl-isoxazol-5-yl)methanol.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[C:27]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:34]Br)([CH3:30])([CH3:29])[CH3:28].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:1]=[C:2]1[C@H:7]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([O:39][Si:40]([C:43]([CH3:45])([CH3:44])[CH3:46])([CH3:42])[CH3:41])=[C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:32]=2)[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:3]1
Reactant: CC(C)(C)c1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(O[Si](C)(C)C(C)(C)C)c(C(C)(C)C)c2)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Yield: 71.3 %

Procedure:
According to example 142, 3.82 g of tert-butyl (2R, 3S)-(-)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate was alkylated with 3.86 g of 3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzyl bromide in 80 mL of anhydrous THF using 11.34 mL of 1 M sodium bis(trimethylsilyl)amide in THF. The crude product was subjected to flash chromatography on silica gel (85:15 hexane:EtOAc) to afford 4.85 g (71%) of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzyl)-4-morpholinecarboxylate as a white foam, m.p. 75-83° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([O:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[C:5](/[CH:19]=[CH:20]/[C:21](OCC)=[O:22])=[C:4]([CH3:26])[N:3]=1.C1(S)C=CC=CC=1.[Na].CCCCC=CCCCCC.C(N(C(C)C)CC)(C)C>>[NH2:1][C:2]1[N:3]=[C:4]([CH3:26])[C:5]2[CH:19]=[CH:20][C:21](=[O:22])[N:8]([C@H:9]3[CH2:14][CH2:13][C@@H:12]([O:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@H]1CC[C@@H](OCCO)CC1
Agent: CCCCC=CCCCCC
Agent: Sc1ccccc1
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc2c1ccc(=O)n2[C@H]1CC[C@@H](OCCO)CC1

Procedure:
A solution of (E)-ethyl 3-(2-amino-4-(cis-4-(2-hydroxyethoxy)cyclohexylamino)-6-methylpyrimidin-5-yl)acrylate (615 mg, 1.69 mmol), thiophenol (173 ul, 1.69 mmol), benzenethiol, sodium salt (248 mg, 1.69 mmol), 1,5-diazabicyclo-5,4,0)undec-5-ene (1.01 mL, 6.75 mmol) and diisopropylethyl amine (1.76 mL, 10.1 mmol) in N′,N-dimethylformamide (11.2 mL) was heated to 120° C. overnight. The reaction mixture was concentrated and the residue was partitioned between methyl tert-butylether (500 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated and washed with 50% brine, dried (Na2SO4), filtered and concentrated. The combined aqueous layers were extracted with chloroform (3×175 mL). Combined extracts were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with chloroform/7N ammonia in methanol (0-6%) to afford the title compound (411 mg, 77%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:12]1[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([S:19][CH3:20])[N:13]=1.[NH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[Cl:18][C:16]1[N:15]=[C:14]([S:19][CH3:20])[N:13]=[C:12]([NH:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:24][CH:23]=2)[CH:17]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(Nc2ccc(C(=O)OC(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
NaHMDS (41 mL, 1M in THF) was added into the solution of 4,6-dichloro-2-(methylthio)pyrimidine (4 g) and tert-butyl 4-aminobenzoate (3.96 g) in THF (200 mL). The reaction was stirred at room temperature for 16 hours, before being quenched by water (100 mL). The aqueous layer was extracted with EtOAc (3×100 mL)). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give tert-butyl 4-(6-chloro-2-(methylthio)pyrimidin-4-ylamino)benzoate which will be used without purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]([CH3:25])[C:21](OC)=[O:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.CCCCCC.C(OCC)(=O)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][C@H:20]([CH3:25])[CH2:21][OH:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.25 h
Yield: 109.1 %

Procedure:
Under argon atmosphere, Methyl(S)-3-(t-butyldiphenylsilyloxy)-2-metylpropionate (47) (1.0 g, 2.7 mmol) was dissolved in 50 ml of dry toluene, 1M DIBAL-H/hexane (5.7 ml, 5.7 mmol) was added to the resultant solution at 0° C., and the mixture was stirred for 15 min. Subsequently, the reaction mixture was further stirred for 45 min after the temperature was returned to room temperature. Ethyl acetate was added to the reaction mixture to decompose the excess DIBAL-H, and the resultant mixture was extracted with 0.5N HCl. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated. The obtained crude product was purified by column chromatography (30 g, 4-10% AcOEt-hexane) to obtain a colorless oily product (48) (968 mg, quant.).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[N:23][OH:24])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].ClN1[C:34](=[O:35])[CH2:33][CH2:32]C1=O.C(O)C#C.CCN(CC)CC>CN(C=O)C>[OH:35][CH2:34][C:33]1[O:24][N:23]=[C:22]([C:17]23[CH2:20][CH2:21][C:14]([C:7]4[NH:8][C:9]5[N:10]([CH2:11][CH2:12][CH3:13])[C:2](=[O:1])[N:3]([CH2:26][CH2:27][CH3:28])[C:4](=[O:25])[C:5]=5[N:6]=4)([CH2:19][CH2:18]2)[CH2:15][CH2:16]3)[CH:32]=1
Reactant: CCCn1c(=O)c2nc(C34CCC(C=NO)(CC3)CC4)[nH]c2n(CCC)c1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: C#CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2nc(C34CCC(c5cc(CO)on5)(CC3)CC4)[nH]c2n(CCC)c1=O
Temperature: 25 °C
Yield: 31.9 %

Procedure:
A solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]octane-1-carbaldehyde oxime (87 mg, 0.22 mmol) and N-chloro succinimide (1.2 eq, 0.27 mmol, 36 mg) in DMF (6 ml) was heated in an oil bath at 600C for 1.5 h. The reaction flask was removed from the bath and allowed to cool to rt and propargyl alcohol (2.0 eq, 0.44 mmol, 25 mg) was added. The flask was returned to the oil bath, Et3N (2.0 eq, 0.44 mmol, 44 mg) was added over a period of 1.5 minutes and the resulting mixture was heated at 60° C. for 3.5 h. The cool reaction mixture was evaporated in cacao to afford a solid residue that was purified by radial chromatography (2 mm plate) using a gradient of 2-10%0 MeOH in CH2Cl2 as eluent. Product-containing fractions were combined and concentrated to afford 31 mg (26%) of a white solid. MS: 442 (MH).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11]C)(=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH2:13][C:14]1[C:15]([C:20](OC)=[O:21])=[N:16][CH:17]=[CH:18][N:19]=1>CO>[CH3:9][O:8][C:6]([C:5]1[C:4]([OH:11])=[N:13][C:14]2=[N:19][CH:18]=[CH:17][N:16]=[C:15]2[C:20]=1[OH:21])=[O:7]
Reactant: COC(=O)c1nccnc1N
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(O)nc2nccnc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium methoxide (6.5 mL) (30% by weight in methanol) was dissolved in methanol (75 mL) at room temperature. Dimethyl malonate (3.7 mL) was added dropwise at ambient temperature over a period of 20 minutes and the reaction stirred at ambient temperature for 1 hour. Methyl 3-aminopyrazine-2-carboxylate (5.0 g) was added in portions at ambient temperature over a period of 40 minutes. The reaction mixture was heated to reflux for 3 days, and then allowed to cool. The solvent was concentrated. The residue was dissolved in water and acidified with concentrated hydrochloric acid (36% by weight in water). The precipitate was isolated, washed with water, methanol and ethyl acetate, and dried under high vacuum to give 6,8-dihydroxypyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester as a beige solid (4.16 g). 1H NMR (d6-DMSO): 3.80 (s, 3H), 8.59 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:21][S@:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[NH:24])=[O:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([N:24]=[S@@:22]([CH3:21])(=[O:23])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:8])=[CH:4][N:3]=1
Reactant: C[S@](=N)(=O)c1ccccc1
Reactant: Nc1ncc(C(=O)O)cc1I
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[S@@](=O)(=NC(=O)c1cnc(N)c(I)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 67.9 %

Procedure:
To a solution of 6-amino-5-iodonicotinic acid (330 mg, 1.3 mmol), N,N-diisopropylethylamine (0.44 mL, 2.5 mmol), and (S)-(+)-S-methyl-S-phenylsulfoximine (291 mg, 1.9 mmol) in 7.0 mL DMF at room temperature was added BOP (608 mg, 1.4 mmol). The solution was stirred 10 minutes and then heated at 60° C. for 5 hours. The mixture was dissolved in EtOAc, washed with Na2CO3 solution, H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown oil was purified by chromatography (silica gel, hexane/acetone). The product containing fractions were purified by chromatography one additional time (silica gel, EtOAc/MeOH). To give the title compound as a white foam (354 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:9][C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[Cl:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[C:29]([F:34])[C:28]=1[C:35]1[CH:39]=[C:38]([CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][N:43]=2)[O:37][N:36]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=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>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:8][CH2:9][C:10]=1[C:45]1[CH:44]=[N:43][C:42]([O:41][CH2:40][C:38]2[O:37][N:36]=[C:35]([C:28]3[C:29]([F:34])=[CH:30][CH:31]=[C:32]([F:33])[C:27]=3[Cl:26])[CH:39]=2)=[CH:47][CH:46]=1)=[O:4]
Reactant: CC1(C)OB(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)OC1(C)C
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
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: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A mixture of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957; 6.04 g, 15.5 mmol), 2-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (9.28 g, 20.7 mmol) and aq. 2M Na2CO3 (93.1 mL, 186 mmol) in DME (150 mL) was prepared, and Pd(PPh3)4 (1.00 g, 0.866 mmol) was added in portions. The mixture was heated to 80° C., and stirred at this temperature for 1 h. The mixture was allowed to cool to rt, and was diluted with EtOAc. The resulting mixture was washed with water and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:2→2:1) yielded the title compound (4.64 g, 40%). LC-MS: tR=1.34 min; ES+: 562.34.
Reaction SMILES: [C:1]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:8][N:7]1[CH3:20])([O:3][CH2:4][CH3:5])=[O:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:31]([CH:38]([CH3:40])[CH3:39])([CH2:34][CH2:35][CH2:36]I)[C:32]#[N:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[C:1]([C:6]1([CH2:36][CH2:35][CH2:34][C:31]([C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)([CH:38]([CH3:40])[CH3:39])[C:32]#[N:33])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:8][N:7]1[CH3:20])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1ccc(C(C#N)(CCCI)C(C)C)cc1OC
Reactant: CCOC(=O)C1Cc2cc(OC)c(OC)cc2CN1C
Product: CCOC(=O)C1(CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)Cc2cc(OC)c(OC)cc2CN1C

Procedure:
The resulting ester of formula 31 is then treated with an iodoalkane of formula 22 (see Scheme III, step 2) in the presence of a strong base to form an alkylated tetrahydroisoquinoline ester of formula 32. For example, 3-carboethoxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (31) is added to a solution of LDA in THF at -70° C. and allowed to stand for 5-60 minutes, preferably about 10 minutes. To this reaction mixture is then added 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22) in THF, and the resulting mixture allowed to warm to about 0° C. The mixture is then acidified, for example with dilute HCl, and the product extracted and purified to produce 3-carboethoxy-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (32).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[O:19]=[C:20]1[C:25]2=[CH:26][NH:27][C:28]([CH:29]=O)=[C:24]2[CH2:23][CH2:22][O:21]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[CH:29][C:28]3[NH:27][CH:26]=[C:25]4[C:20](=[O:19])[O:21][CH2:22][CH2:23][C:24]=34)[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-(2-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: COC([C:5]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]1=[O:12])=O.CN(C)C(=O)C.Cl.C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:5]2[C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][CH2:9]2)=[CH:19][CH:18]=1
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(C)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)C1=O
Temperature: 150 °C
Reaction time: 2 h

Procedure:
In 1-(4-chlorobenzyl)-3,3-dimethyl-2-oxocyclopentane carboxylic acid methyl ester (1.0 g, 0.00339 mol), N,N-dimethylacetamide (1 mL) and triethylamine hydrochloride (0.56 g, 0.00339×1.2 mol) were added and stirred at 150° C. for 2 hours. In the reaction liquid, toluene and saturated sodium bicarbonate water were added, and the mixture was partitioned. After extracting the aqueous layer using toluene, the organic layer was dried using anhydrous sodium sulfate and concentrated. Thereafter, the dried and concentrated product was purified using a silica gel column, and a target product was obtained.