Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]C(=O)C=2C=1O)[C:9]3=[O:44].[NH2:51][CH2:52][CH2:53][CH2:54][OH:55]>CO>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]/[C:52](=[N:51]\[CH2:4][CH2:3][CH2:2][OH:1])/[C:53]=2[C:54]=1[OH:55])[C:9]3=[O:44]
Reactant: NCCCO
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Solvent: CO
Product: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)/C(=N/CCCO)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.14 mmol) in methanol (3 mL) was added 3-aminopropan-1-ol (107 mg, 1.43 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 h. The reaction was quenched by adding saturated ammonium chloride solution (25 mL). Then it was extracted with chloroform (75 mL) and washed with water (2×25 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. The crude material was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-(3-hydroxypropylimino)-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (61.3 mg, 56.6%) as a dark blue solid: 1H NMR (500 MHz, CDCl3) δ 11.94 (s, 1H), 7.89 (s, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.48 (s, 1H), 6.12 (s, 1H), 5.27 (s, 1H), 5.02-4.99 (m, 1H), 4.74 (d, J=9.5 Hz, 2H), 4.12 (dd, J=14.2, 7.1 Hz, 2H), 3.83 (s, 3H), 3.81-3.72 (m, 9H), 3.68 (br s, 1H), 3.60 (s, 3H), 3.40 (s, 4H), 3.13 (t, J=9.1 Hz, 1H), 2.53 (s, 1H), 2.36 (s, 3H), 2.02-2.00 (m, 2H), 1.36 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 755 (M+H); HPLC 97.5% (AUC), tR=10.36 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[C:6]([O:10][C:11](=[O:33])[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:32])[C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23](Cl)=[C:22]([O:30][CH3:31])[CH:21]=2)[CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>CN(C)C=O>[C:6]([O:10][C:11](=[O:33])[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:32])[C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[C:23]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:22]([O:30][CH3:31])[CH:21]=2)[CH2:14]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: COc1cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc([N+](=O)[O-])c1Cl
Reactant: COCCN
Solvent: CN(C)C=O
Product: COCCNc1c(OC)cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-Methoxyethylamine (0.15 mL, 1.741 mmol) was added to a stirred solution of (R)-tert-butyl(1-(4-chloro-3-methoxy-5-nitrobenzoyl)piperidin-3-yl)carbamate (280 mg, 0.406 mmol) in N,N-dimethylformamide (DMF) (1.5 mL) at rt under nitrogen. The reaction mixture was heated to 80° C. and stirred under nitrogen overnight (16 h). LC/MS showed that the desired product had formed with 55% purity. Water (75 mL) and diethyl ether (75 mL) were added to the reaction mixture and the layers separated. The aqueous layer was further extracted with diethyl ether (2×50 mL). The organic layers were collected, dried (Na2SO4), passed through a hydrophobic frit and concentrated under vacuum to afford 330 mg of crude product as an orange oil. The crude product was dissolved in a minimum volume of DCM and purified by column chromatography (25 g silica). The column was eluted with a gradient of 60-100% ethyl acetate/cyclohexane. TLC was used to determine product fractions and the appropriate fractions were collected and concentrated under vacuum to afford—(R)-tert-butyl(1-(3-methoxy-4-((2-methoxyethyl)amino)-5-nitrobenzoyl)piperidin-3-yl)carbamate (165.7 mg, 0.366 mmol, 90% yield)
Reaction SMILES: BrBr.C(O[C@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)OC=C1)(=O)C.BrN1C(=O)CCC1=O.[O:30]=[CH:31][C@@H:32]([C@H:34]([C@@H:36]([C@@H:38]([CH2:40][OH:41])[OH:39])[OH:37])[OH:35])O.C(S)C.C(Cl)(=O)C1C=CC=CC=1>>[CH2:32]([C@@H:34]([OH:35])[C@H:36]([OH:37])[C@H:38]([OH:39])[CH2:40][OH:41])[CH:31]=[O:30]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: BrBr
Agent: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C1CCC(=O)N1Br
Solvent: CCS
Solvent: O=C(Cl)c1ccccc1
Product: O=CC[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Production of 2DG can be carried out using any known method. For example, 2-DG can be prepared from various starting materials such as D-glucose, D-mannose, calcium D-gluconate, D-arabinose, D-glucosamine hydrochloride, N-acetyl glucosamine, chitin, and chitosan and carboxymethylchitosan. Preparation methods vary with various starting materials. For example, D-glucose can be methylated and brominated, followed by debromination and acid hydrolysis to yield β-2DG. Bergmann et. al. (1992) Berichte der Deutschen Chemischen Gesellschaft Jahrg. 55:158-72. D-glucose or D-mannose can be treated with bromine and acetyl, followed by a Fischer procedure (Fischer et al. (1914) (Berichte der Deutschen Chemischen Gesellschaft Jahrg. 47:196-210), to yield 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol, which is reacted with bromine, then reduced to remove the acetyl group, yielding 2DG (Arita et al. (1972) Bull. Chem. Soc. Japan 45:567-69). The 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol intermediate can be treated with N-bromosuccinimide, followed by hydrogenation and deacetylation to yield 2DG. Monneret and Choay (1981) Carbohydr. Res. 96:299-305. D-glucose can be reacted with ethanethiol and benzoyl chloride, followed by dehydrogenation, reduction, and deprotection to give 2-DG. Wong and Gray (1980) Carbohydr. Res. 80:87-98). Glucal can be deacetylated by reacting with sulfuric acid to give 2-DG with an overall yield of 35%. Overend et al. (1949) J. Chem. Soc., 1:2841-45. D-arabinose can be treated with nitromethane and an acetylating agent, followed by treatment with diluted sodium hydroxide, to yield a-2-DG. Sowden and Fischer (1947)J. Am. Chem. Soc. 69:1048-50. D-arabinose can be condensed, reduced with acetone, then reacted with trifluoromethanesulfonic anhydride, to yield a product that is then reacted with sodium cyanide, followed by hydrogenation, reduction, and hydrolysis, yielding 2-DG. Shiue et al. (1979) Carbohydr. Res. 74:323-26.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
A 2 liter three necked flask equipped with a mechanical stirrer is charged with racemic 2-(4-nitrophenyl)propionic acid (40.55 grams, 0.208 mol) and ethyl acetate (1600.0 mL). To this solution at 30° C. was then added S(−)α-methylbenzylamine (13.49 mL, 0.104 mol) all at once. Reaction exothermed to 38° C. with massive formation of a white precipitate in less than 15.0 minutes. The reaction mixture was then heated at ethyl acetate reflux for 10.0 minutes and allowed to equilibrate to room temperature with stirring overnight. The precipitate was then filtered to give a semi-dried white product, (2R)-2-(4-nitrophenyl)propanoic acid, S(−)α-methylbenzylamine (wet cake=25.43 grams). Reslured the wet cake in ethyl acetate (1600.0 mL) at reflux for 10.0 minutes, stirred to room temperature overnight, and filtered the white precipitate, (2R)-2-(4-nitrophenyl)propanoic acid, S(−)α-methylbenzylamine, (wet cake=21.02 grams, ee=91.4%). Repeated the later again and dried the precipitate at 40° C. in a vacuum oven for 24.0 hours, (2R)-2-(4-nitrophenyl)propanoic acid, S(−)-α-methylbenzylamine, (18.02 g, 55%, ee=95%); 1H nmr (DMSO, 300 MHz) δ 1.31-1.32 (d, 3H), 1.37-1.38 (d, 3H), 3.56-3.60 (m, 1H), 4.184-20 (m, 1H), 7.27-7.53 (aromatic, 7H), 8.09-8.12 (aromatic, 2H); 13C nmr (DMSO, 300 MHz)) δ 19.91, 22.93, 48.45, 50.55, 123.71, 124.15, 127.15, 128.27, 129.06, 129.41, 129.76, 146.31, 153.36, 176.24.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[O:42][NH2:43]>C(Cl)CCl.C(N(CC)CC)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:43][O:42][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)=[O:20])=[CH:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6.1 g (E)-3-[1-(3-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid with 300 ml DMF and 2.6 g HOBt.H2O and 24.0 ml triethylamine is stirred at ambient temperature for 0.5 h. Then 9.8 g EDC.HCL is added and the suspension is stirred again at ambient temperature for 0.5 h. After that 2.0 g O-(tetrahydro-2H-pyran-2-yl)hydroxylamine are added and the suspension is stirred at ambient temperature for 24 h. The DMF is evaporated and the residue is extracted with ethyl acetate and water. The organic layer is dried over sodium sulfate. The title compound is isolated by flash chromatography. By this method 6.3 g of a yellow foam are obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1>>[Br:12][C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:23][CH2:24]2)=[N:17][CH:18]=1
Reactant: Cc1cc(Br)cnc1N1CCNCC1
Reactant: Cc1cc(F)ncc1C(=O)O
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Yield: 86.8 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (1.00 g) and 1-(5-bromo-3-methylpyridin-2-yl)piperazine (1.65 g) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (2.20 g) was obtained.
Reaction SMILES: CC(C)([O-])C.[K+].C[O:8][CH2:9][CH2:10][O:11]C.Cl[C:14]1[N:19]=[C:18]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:17]=[C:16]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[C:15]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH2:41]C>C(O)CO>[OH:8][CH2:9][CH2:10][O:11][C:14]1[N:19]=[C:18]([C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[N:17]=[C:16]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[C:15]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]
Reactant: COCCOC
Reactant: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(Cl)c1Oc1ccccc1OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: OCCO
Product: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Temperature: 85 °C

Procedure:
To a solution of potassium tert.-butoxide (366.5 mg) in ethylene glycol (5 ml) was added 1,2-dimethoxy ethane (5 ml) and n-propanesulfonic acid [6-chloro-5-(2-ethoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]amide (420 mg). The reaction mixture was heated to 85° C. for 7 days, concentrated in vacuo, poured onto water, acidified by 2N HCl and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The precipitated product was washed with diethylether, filtered and dried at HV to give n-propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (401 mg). LC-MS: tR: 3.67, [M+H]+: 462.26.
Reaction SMILES: [Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:19])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([NH:14]3)[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1.[CH:20](N(C(C)C)CC)([CH3:22])[CH3:21].C(Br)C=C.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:19])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([N:14]3[CH2:22][CH:20]=[CH2:21])[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1C2=C3CC1C(C)C1(C)C=NCC(Cl)=CC3=C1CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a stirred solution of 1.30 g of 10-chloro-6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[3,2-h][3]-benzazocine, and 24 ml of dimethylformamide was added 1.69 ml of diisopropylethyl amine. Upon cooling to 0° C., the mixture was cooled to 0° C. and 0.45 ml of allyl bromide in 5.0 ml of dimethylformamide was added, under nitrogen. The mixture was stirred an additional 3 hr at 0° C. and was poured into water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate and ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, filtered, and concentrated. The residue crystallized on standing. Recrystallization from ether with ether-pentane and pentane washing gave 0.75 g (47%) of product, mp 189°-191° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([S:19]([NH:18][C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:9]2[CH:10]=[C:6]([CH2:4][OH:3])[CH:7]=[N:8]2)(=[O:21])=[O:20])=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1cnn(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2cc(CO)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (synthesized according to general procedure D, 220 mg, 0.47 mmol) in THF (5 mL) was added LiAlH4 (1.0 mL, 2.4 M solution in THF) dropwise and the resultant reaction mixture was stirred for one hour at room temperature. Saturated Na2SO4 solution (3 mL) was subsequently added slowly at 0° C. and the precipitated solid was filtered through celite and washed thoroughly with EtOAc (100 mL). The filtrate was dried over Na2SO4, concentrated in vacuo, and purified by automated flash chromatography to afford the title compound: MS (ES) M+H expected 420.1, found 420.1.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:22][CH2:23][C:24]4[N:28](COCC[Si](C)(C)C)[N:27]=[N:26][CH:25]=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.Cl>[C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:22][CH2:23][C:24]4[CH:25]=[N:26][NH:27][N:28]=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nncc1COc1nn2c(-c3ccccc3)nnc2cc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2cc3nnc(-c4ccccc4)n3nc2OCc2cn[nH]n2)cc1
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 39.2 %

Procedure:
A mixture of the product from Step c (0.7025 g, 1.41 mmol) in ethanol (12 ml) and 2 M aqueous HCl (25 ml) was stirred at 60° C. for 5.5 h. The mixture was then neutralised by adding dropwise saturated aqueous Na2CO3. The resulting precipitate was collected by filtration, washed with water, then hexane, and dried under vacuum at 60° C. This was purified by recrystallisation (MeOH—CH2Cl2), then flash chromatography (silica gel, 3-5% MeOH/CH2Cl2) to afford 0.2044 g (39%) of the title compound as a white solid: mp 208-220° C.; 1H NMR (360 MHz, d6-DMSO) δ5.66 (2 H, s), 7.48-7.49 (3 H, m), 7.58-7.72 (5 H, m), 7.94 (1 H, br s), 8.40 (1 H, s), 8.47 (2 H, d, J=7.2 Hz), 15.10 (1 H, br s); MS (ES+) m/e 370 [MH]+; Anal. Found C, 65.07; H, 4.05; N, 26.01. C20H15N7O.0.1 H2O requires C, 64.72; H, 4.13; N, 26.41%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC=C)=[CH:9][C:8]=1[O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>C1(C)C=CC=CC=1.[Zn]>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:17][C:8]1[CH:9]=[C:10]([OH:13])[C:11]([C:25](=[O:27])[CH3:26])=[CH:12][C:7]=1[O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: C=CCOc1ccc(OCC(=O)OCC)c(OCC(=O)OCC)c1
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1cc(O)c(C(C)=O)cc1OCC(=O)OCC

Procedure:
The compound of example 65c (38 g; 112.5 mmol) was heated with acetyl chloride (9.74 ml; 137 mmol) and activated Zn (7.46 g) in toluene (250 ml) for 5 h (Synth. Commun. 1998, 28, 2203). to obtain the title compound which was processed as is routinely done and purified using flash chromatography (silica gel, 3% CH3CN in chloroform). Yield, 30 g (78.3%); MS (CI): 409 (M++29), 381(M+); analysis: C16H20O8 requires C, 56.47; H, 5.92; found: C, 56.05; H, 5.59%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:20]2[S:21][CH:22]=[C:18]([CH3:17])[N:19]=2)[CH:7]=1
Reactant: COc1ccccc1Oc1ccnc(Cl)c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1Oc1ccnc(Nc2nc(C)cs2)c1
Yield: 87.3 %

Procedure:
Using the method of Example 3, step B, 2-chloro-4-(2-methoxyphenoxy)pyridine (2.95 g, 12.5 mmol), 4-methylthiazol-2-amine (28.5 mL, 11.4 mmol), potassium phosphate (2.66 g, 12.5 mmol), Pd2(dba)3 (0.261 g, 0.285 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.181 g, 0.313 mmol) were reacted in toluene (30 mL) and water (8 mL) to provide 4-(2-methoxyphenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (3.12 g, 82.2% yield) as yellow solid. 1H NMR (CDCl3) δ 8.10 (d, 1H), 7.19 (m, 1H), 7.04 (dd, 1H), 6.95 (m, 2H), 6.42 (dd, 1H), 6.24 (d, 1H), 6.14 (d, 1H), 3.71 (s, 1H), 2.12 (s, 3H); Mass spectrum (apci) m/z=314 (100) (4+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11](=O)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:9][CH2:10][CH2:11][N:12]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CO[C@@H](c2ccc(F)cc2)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc([C@H]2CN(Cc3ccccc3)CCO2)cc1
Yield: 98.1 %

Procedure:
A solution of (6S)-6-(4-fluorophenyl)-4-(benzyl)morpholin-3-one (9.7 g) in tetrahydrofuran (30 ml) was added dropwise over 30 min to lithium aluminum hydride (2.6 g 70 mmol) in tetrahydrofuran (200 ml) at room temperature, and the reaction mixture was refluxed for 3 hrs. The reaction was quenched by addition of water (10.6 ml) and 15% aqueous sodium hydroxide solution (2.6 ml) at 0° C. The reaction mixture was filtered and the filtrate was concentrated to give (2S)-2-(4-fluorophenyl)-4-(benzyl)morpholine (9.05 g, yield 98% for 2 steps) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>CN1C(=O)CCC1>[OH:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([CH3:19])[CH:21]=3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: Cc1cccc(N)c1
Reactant: OCCOc1ccc(Nc2cc(Cl)ncn2)cc1
Solvent: CN1CCCC1=O
Product: Cc1cccc(Nc2cc(Nc3ccc(OCCO)cc3)ncn2)c1
Temperature: 140 °C
Yield: 20 %

Procedure:
A mixture of 6-chloro-4-[4'-(2-hydroxyethoxy)anilino]pyrimidine (1.0 g), 3-methylaniline (5 ml) and NMP (20 ml) was stirred and heated to 140° C. for 72 hours. The mixture was cooled and partitioned between ethyl acetate and water. The precipitate was removed by filtration, the ethyl acetate fraction chromatographed on silica and the combined products extracted with boiling ethyl acetate. The product was recrystallised from a mixture of ethyl acetate and hexane to give 4-[4'-(2-hydroxyethoxy)anilino]6-(3'-methylanilino)pyrimidine in 20% yield, m.p. 196°-199° C.;
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:36])([F:19])[F:37])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(OC(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(OC(F)(F)F)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][OH:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:18](OC)([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:19][C:18]1([CH3:20])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][O:15]1
Reactant: COC(C)(C)OC
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of methyl (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-hydroxypropanoate (22 g, 0.1 mol), 2,2-dimethoxypropane (20.8 g, 0.2 mol) and 4-methylbenzene-1-sulfonic acid (0.5 g) in toluene was heated with stirring at 110° C. overnight. The solvent was removed under reduced pressure. The residue was treated with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue distilled at 0.6 mbar to give 16.5 g of 3-tert-butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (yield was 63.6%) as an amber oil.