Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].C(O)C.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26]>C(N(CC)CC)C>[Cl:16][C:9]1[N:8]=[C:7]([CH3:17])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])[C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CN(C)CCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C
Reaction time: 0.17 h

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.5 Mol.) in 500 ml. of ethyl alcohol are heated at reflux temperature. 60 g. of triethylamine are added and then 51 g. of 3-(dimethylamino)propylamine are slowly dropped in with stirring. After the addition is completed, heating is continued for 10 minutes. The solvent is distilled off and the residue is treated with 200 ml. of water and made alkaline (pH 9-10) with sodium hydroxide. The mixture is extracted three times with 150 ml. portions of ether. The organic layers are combined, dried over calcium chloride and evaporated to dryness. The residue is recrystallized from methanol, yield 110 g. (64%), m.p. < 20°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:20][O:21][CH3:22])=[N:7][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)[C:9]=1[CH2:10][O:11][CH3:12])=[O:4].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/B(O)O)=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:20][O:21][CH3:22])=[N:7][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](/[CH:31]=[CH:30]/[C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH:14]=2)[C:9]=1[CH2:10][O:11][CH3:12])=[O:4]
Reactant: COCc1nn(-c2cccc(Br)c2)c(COC)c1C(=O)OC
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Product: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)OC

Procedure:
In analogy to the procedures described for intermediates 1A-E, the title compound has been obtained by i) condensation of methyl 4-methoxyacetoacetate with methoxyacetyl chloride to give 4-methoxy-2-(2-methoxy-acetyl)-3-oxo-butyric acid methyl ester; ii) methylation of 4-methoxy-2-(2-methoxy-acetyl)-3-oxo-butyric acid methyl ester with methyl trifluoromethanesulfonate to give (E and/or Z)-3,4-dimethoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester; iii) condensation of (E and/or Z)-3,4-dimethoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester with (3-bromo-phenyl)-hydrazine to give 1-(3-bromo-phenyl)-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester; iv) reaction of 1-(3-bromo-phenyl)-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester with (E)-2-(4-chlorophenyl)vinyl boronic acid to give 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester; v) saponification of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester to give the title compound as light brown solid. MS: 411.2 ([M−H]−, 1 Cl).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:29])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH2:27][CH3:28])[N:6]=2.[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:31]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:27]([C:19]1[N:18]([C:7]2[N:6]=[C:5]3[C:10]([N:11]=[C:3]([CH2:2][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:31]4)[N:4]3[CH3:29])=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=1)[CH3:28]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCl)n(C)c2n1
Reactant: C1CN(C2CNC2)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.4 %

Procedure:
To a solution of 8-chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (107 mg, 0.26 mmol) and 4-azetidin-3-ylmorpholine (44 mg, 0.31 mmol) in DMF (3 mL) was added K2CO3 (106 mg, 0.77 mmol). The resulting mixture was allowed to stir at room temperature for 16 h. The reaction mixture was dissolved in EtOAc, washed with H2O (×4) then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-5%). The resulting residue was further purified by Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH, followed by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 309 as a white solid (14 mg, 11%). LCMS (Method G): RT 5.74 min, [M+H]+ 518.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.98 (m, 1 H); 7.77-7.73 (m, 1 H); 7.27-7.23 (m, 2 H); 4.35 (m, 4 H); 3.89-3.82 (m, 6 H); 3.83 (s, 3 H); 3.72 (m, 4 H); 3.56 (m, 2H); 3.34 (q, J=7.5 Hz, 2 H); 3.15-3.03 (m, 3 H); 2.34 (m, 4 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:9][O:10][C:11]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[C:52]([O:58][CH3:59])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:45]([O:46][CH3:47])=[CH:44][C:43]([O:48][CH3:49])=[CH:42][C:41]=1[O:50][CH3:51])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH2:37])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH2:24])[CH:17]=1>>[CH3:59][O:58][C:52]1[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=[C:11]([O:10][CH3:9])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:41]([O:50][CH3:51])=[CH:42][C:43]([O:48][CH3:49])=[CH:44][C:45]=1[O:46][CH3:47])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH:37][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH:24][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])[CH:17]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NS(=O)(=O)C(F)(F)F)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NS(=O)(=O)C(F)(F)F)c2)c(OC)c1
Yield: 59.9 %

Procedure:
A solution of trifluoromethanesulfonyl chloride (10 mmol) and (E)-2,4,6-trimethoxy styryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method A. The product obtained was purified by column chromatography to give the desired product in 59.9% yield. (m.p. 144-46° C.)
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])=[CH:7][C:6]=1[O:16][CH3:17].[CH2:18](Br)[C:19]#[CH:20]>CO>[CH3:17][O:16][C:6]1[CH:7]=[C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])[CH:9]=[CH:10][C:5]=1[O:4][CH2:20][C:19]#[CH:18]
Reactant: COc1cc(CCNC=O)ccc1O
Reactant: C#CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#CCOc1ccc(CCNC=O)cc1OC

Procedure:
Sodium methoxide (32 ml of a 5.4 M solution in methanol, 0.17 mol) is added to a solution of N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-formamide (32 g, 0.16 mol) in methanol (400 ml). Propargyl bromide (20 g, 0.17 mol) is added and the mixture is refluxed for 4 hours. After evaporation the residue is taken up in ethyl acetate (400 ml) and washed with water (2×200 ml). The organic layer is dried over magnesium sulfate and evaporated. The residue is submitted to flash-chromatography to give the N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-formamide. 1H-NMR (300 MHz, CDCl3): 2.44 (t, 1H, C≡CH), 2.73 (t, 2H, CH2CH2), 3.51 (t, 2H, CH2CH2), 3.82 (s, 3H, OCH3), 4.69 (m, 2H, OCH2), 5.53 (bs, 1H, NH), 6.62-6.95 (m, 3H, CH arom.), 8.09 (s, 1H, CHO).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:19]C1C=CC(O)=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([I:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(OCCCCc2ccccc2)cc1
Reactant: Oc1ccc(I)cc1
Product: Ic1ccc(OCCCCc2ccccc2)cc1
Yield: 80 %

Procedure:
Using the preparative procedure for 4-(4-phenylbutoxy)bromobenzene, except using 4-iodophenol in place of 4-bromophenol, gave 4-(4phenylbutoxy)iodobenzene in 80% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.Cl>O1CCCC1>[CH3:1][N:2]1[C:6]([B:12]([OH:17])[OH:13])=[CH:5][CH:4]=[N:3]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1cccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nccc1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a stirred solution of 1-methyl-1H-pyrazole (2.49 mL, 30 mmol) in tetrahydrofuran (100 mL) was added butyllithium (2.5 M in hexane, 15.6 mL, 39 mmol) at −78° C. dropwise. After stirring for 1 hour, triisopropyl borate (27.6 mL, 120 mmol) was added and the reaction mixture was gradually warmed to room temperature for 16 hours. Hydrochloric acid (1 N aqueous solution) was added to the reaction mixture until pH 7 achieved. The mixture was extracted with dichloromethane:methanol (9:1, 5×200 mL). Combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to obtain crude residue. Purification was undertaken by flash column chromatography (ISCO™) eluting with dichloromethane:methanol (7:3, by volume) to afford the title compound as a white solid, 1258 mg, 33% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=1.C1C(=O)N([Cl:41])C(=O)C1>>[Cl:41][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH3:24])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Yield: 20 %

Procedure:
Following General Procedure H, (R)-tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethyl(methyl)carbamate (200 mg, 0.43 mmol) was reacted with NCS (69 mg, 0.52 mmol) to afford the desired product (43 mg, 20%) as a yellowish solid. ESI MS m/z 499 [C26H27ClN2O4S+H]+.
Reaction SMILES: C[O-].[Na+].[Na].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[N+:25]=[N-:26]>CO.O>[N:24](/[C:27](=[CH:17]\[C:16]1[CH:19]=[CH:20][C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1)/[C:28]([O:30][CH3:31])=[O:29])=[N+:25]=[N-:26]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)/C(=C/c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 58.7 %

Procedure:
Under argon, to a sodium methoxide solution (prepared from 2.5 g (108.7 mmol) of sodium and 70 ml of methanol) a mixture of 6.1 g (23.7 mmol) of 4-benzyloxy-3-nitrobenzaldehyde and 11.2 g (97.3 mmol) of methyl azidoacetate in 100 ml of methanol is added at 0° C. The mixture is stirred at 0° C. for 5 h, then diluted with 350 ml of water, the precipitated crystalls were filtered off, washed with water and dried to yield 4.93 g (59%) of the title compound. Mp.: 95-96° C. (water).
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[C:35](C2C=CC=CC=2CSCCO)=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[C:39]([C:14]2[CH:13]=[CH:12][CH:17]=[CH:16][C:15]=2[CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: CCOC(=O)c1ccccc1-c1ccccc1CSCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccccc1CSCCOc1ccccc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (5.0 g, 15.80 mmol, 1 eq.) in anhydrous THF was treated with phenol (2.08 g, 22.12 mmol, 1.4 eq.), triphenylphosphine (5.80 g, 22.12 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (4.47 g, 22.12 mmol, 1.4 eq.). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:9]=[C:14]([C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([Cl:10])[CH:12]=1)[NH:8]2
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Nc1ncnc(Cl)c1N
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cccc(-c2nc3c(Cl)ncnc3[nH]2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a mixture of 6-Chloro-4,5-diaminopyrimidine (0.70 g, 4.84 mmol) and 3-chlorobenzoic acid (0.76 g, 4.84 mmol) in the flask was added phosphoryl chloride (40.0 mL), and the resulting mixture was stirred for 16 h at 100° C. The reaction mixture was evaporated to remove excess phosphoryl chloride, and the residue was added to water (20 mL). The precipitate was filtered and purified by flash chromatography (0 to 5% Methanol/DCM) to afford the title compound (1.28 g, 31%) as a yellow solid. LC/MS: Rt=1.59 min, ES+ 265.0 (FA standard).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:34]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c[nH]c23)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A170) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12]1[O:17][CH2:16][N:15]([C:18]([CH3:30])([CH3:29])[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:14](=[O:31])[C:13]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)C>O.CO>[OH:10][CH2:11][C:12]1[O:17][CH2:16][N:15]([C:18]([CH3:30])([CH3:29])[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:14](=[O:31])[C:13]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)OCc2ccccc2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C(=O)OCc1ccccc1)N1COC(CO)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
A solution of potassium carbonate (0.96 g) in water was added in portions to a stirred solution of benzyl 2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (2.70 g) in methanol at 0° C. The mixture was stirred at ambient temperature for 1 hour and the solvent was evaporated under reduced pressure. The residue was acidified with 2 M hydrochloric acid, extracted with diethyl ether, the extract was dried (magnesium sulphate) and the solvent evaporated under reduced pressure to give benzyl 2-(2,3-dihydro-6-hydroxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (2.51 g) as a yellow gum, NMR (CDCl3) 1.6(s,6H), 4.15(s,2H), 5.1(s,2H), 5.3(s,2H), 7.26-7.42(m,10H).
Reaction SMILES: [Cl-].[Cl:2][CH:3]=[N+:4]([CH3:6])[CH3:5].C([Si](C(C)C)(C(C)C)[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)(C)C>C(Cl)Cl>[Cl-:2].[CH3:5][N+:4]([CH3:6])=[CH:3][C:13]1[CH:14]=[CH:15][NH:11][CH:12]=1
Reactant: C[N+](C)=CCl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Agent: [Cl-]
Solvent: ClCCl
Product: C[N+](C)=Cc1cc[nH]c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 127.8 %

Procedure:
10.60 g of (chloromethylene)dimethylammonium chloride and 6.25 g of N-(triisopropylsilyl)-pyrrole are suspended in 200 ml of CH2Cl2 under nitrogen at 0-5° C. The suspension is warmed to 60° C. and stirred for 30 minutes. Afterwards the mixture is cooled to ambient temperature. The suspension is filtered and washed with diethylether to give 5.67 g of the title compound as grey solid.
Reaction SMILES: [C:1]1([C@@:7]2([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9][C@H:8]2[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:30][N:20]([CH2:19][C@:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C@H:8]1[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 1,1-dimethylethyl [((1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]carbamate (7.5 g, 20.4 mmol), accessed via the method of 11B, and methyl iodide (14.4 g, 102.0 mmol, 5 eq) in 100 mL THF cooled to 0° C. was added 1M sodium bis(trimethylsilyl)amide in THF (30.6 mL, 30.6 mmol, 1.5 eq). The reaction mixture was stirred 8 h at 0° C. followed by 16 h at ambient temperature. The reaction mixture was partitioned between EtOAc and water, the phases separated, the aqueous phase extracted twice with EtOAc, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to an amber oil. The crude material was purified by flash chromatography (SiO2, eluted with EtOAc/hexanes (1:4)) to give the title compound (3.1 g, 8.1 mmol, 40%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.18 (m, 10H), 4.36-4.27 (m, 2H), 3.67-3.45 (m, 1H), 3.26-3.13 (m, 2H), 3.07-2.99 (m, 1H), 2.77-2.62 (m, 3H), 1.39-0.80 (m, 12H). ES-LCMS m/z 404.2 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].CS[C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=2[N:17]=1>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[N:13]=[CH:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=4)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=3[N:17]=2)=[CH:3][CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Reactant: Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Yield: 66.3 %

Procedure:
By following the general procedure of Examples 2 and 3, 524.2 mg (5.569 mM) of 4-aminopyridine was reacted with 687.4 mg (17.2 mM) of sodium hydride and 1983.8 mg (5.550 mM) of 2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one to provide 66.3% yield (85.8% purity) of 2-(pyridin-4-ylamino)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][C:5]=1[CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1.C1([O:27][C:28](=O)[NH:29][C:30]2[CH:35]=[C:34]([O:36][CH:37]([CH3:39])[CH3:38])[C:33]([C:40]#[N:41])=[CH:32][N:31]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:40]([C:33]1[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:35][C:30]([NH:29][C:28]([N:11]2[C:12]3[C:7](=[CH:6][C:5]([CH:14]4[CH2:18][CH2:17][O:16][CH2:15]4)=[C:4]([CH:3]([O:2][CH3:1])[O:19][CH3:20])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:27])=[N:31][CH:32]=1)#[N:41]
Reactant: COC(OC)c1nc2c(cc1C1CCOC1)CCCN2
Reactant: CC(C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1nc2c(cc1C1CCOC1)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of (racemic) 7-(dimethoxymethyl)-6-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine (Intermediate 337, 230 mg, 0.45 mmol), phenyl(5-cyano-4-isopropoxypyridin-2-yl)carbamate (Intermediate 96, 405 mg, 1.36 mmol) and DMAP (170 mg, 1.36 mmol) in DMF (2.7 ml) was stirred at 90° C. After 1 h, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried over Na2SO4 and evaporated. The crude material was applied to a 12 g RediSep silica column and purified by normal phase chromatography, eluting with eluting with a gradient from 1% to 100% EtOAc/heptanes. Product-containing fractions were combined and evaporated. The resulting material was applied to a 12 g RediSep silica column and purified by normal phase chromatography, eluting with eluting with a gradient from 1% to 50% MeOH/DCM. Product-containing fractions were combined and evaporated to give the title compound as a white solid. (UPLC-MS 6) tR 1.28; ESI-MS 482.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:36]>CN(C)C=O.O.Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:36])[CH:15]=[C:14]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)OCc4ccccc4)cc23)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)OCc4ccccc4)cc23)c(OC)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A solution of methyl 4-(5-benzyloxycarbonylindol-3-ylmethyl)-3-methoxybenzoate (46.1 g) in N,N-dimethylformamide (200 mL) was added to a slurry of sodium hydride (2.83 g) in N,N-dimethylformamide (300 mL) at 5° C. under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 5° C., then was treated with iodomethane (16.6 g), allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was then poured into ice/water (400 mL), diluted with water (250 mL) and 1N hydrochloric acid (250 mL). The resulting aqueous solution was extracted with ethyl acetate. The combined organic extract was washed (1N hydrochloric acid, water, brine), dried (MgSO4), filtered and evaporated. The residue was triturated with warm diethyl ether and filtered to give methyl 4-(5-benzyloxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate as an ivory solid (42.4 g, 89%); partial NMR (300 MHz, CDCl3): 3.75 (s, 3H, NCH3), 3.87 (s, 3H, CO2CH3), 3.90 (s, 3H, OCH3), 4.12 (s, 2H, CH2), 5.36 (s, 2H, OCH2), 6.82 (s, 1H, indole-H(2)), 8.38 (d, 1H, indole-H(4)).