Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)=[CH:7]2.O1CCCC1.[C:25]([C@H:29]1[CH2:34][CH2:33][C@H:32](O)[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Br:1][C:2]1[C:11]([O:12][C@H:32]2[CH2:33][CH2:34][C@H:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:30][CH2:31]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)=[CH:7]2
Reactant: CC(C)(C)[C@H]1CC[C@H](O)CC1
Reactant: C[C@@]1(c2ccc3c(Br)c(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Br)CC1
Reaction time: 0.08 h

Procedure:
(R)-4-(5-Bromo-6-hydroxy-naphthalen-2-yl)-4-methyl-oxazolidin-2-one (2.16 g, 6.70 mmol) was dissolved in tetrahydrofuran (22.50 mL, 277.4 mmol) in a capped 250 mL round-bottom flask equipped with a magnetic stir bar. trans-4-tert-Butyl-cyclohexanol (2.095 g, 13.41 mmol) and triphenylphosphine (3.517 g, 13.41 mmol) were added and the mixture was stirred for 5 minutes. Diisopropyl azodicarboxylate (2.640 mL, 13.41 mmol) was then slowly added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, diluted in methylene chloride and adsorbed onto silica gel under reduced pressure, then purified by flash chromatography (0-55% EtOAC in hexanes) to give 1.37 g of the title compound (45% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:40]1[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]2[C:41]1=[O:50].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][N:40]3[C:44](=[O:45])[C:43]4[C:42](=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:41]3=[O:50])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Nc1nc2c(c3c1ncn3CCCCO)CCCC2
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nc2c(c3c1ncn3CCCCON1C(=O)c3ccccc3C1=O)CCCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
A cloudy solution of 4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (1.0 g, 3.8 mmol), triphenylphosphine (1.49 g, 5.7 mmol) and N-hydroxyphthalimide (0.93 g, 5.7 mmol) in tetrahydrofuran (50 mL) was cooled to approximately 0° C.; then diisopropyl azodicarboxylate (1.33 mL, 6.8 mmol) was added dropwise. The reaction was allowed to warm to ambient temperature and was stirred for 5 hours. The solvent was removed under reduced pressure, and the resulting solid was purified by chromatography on silica gel (gradient elution with 0-10% methanol in dichloromethane with a small amount of concentrated ammonium hydroxide added) to provide 600 mg of 2-[4-(4amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:14]=[C:13]([CH2:23]O)[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:56]I>C1C=CC=CC=1.CCOCC>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[CH:12]=[C:13]([CH2:23][I:56])[N:14]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:16]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: OCc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2cc(CI)nc(NC3CCCC3)n2)cc1
Yield: 59.6 %

Procedure:
[6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-(cyclopentylamino)-4-pyrimidinyl]methanol (215 mg, 0.49 mmol) was dissolved in a mixture of benzene (4 mL) and ether (8 mL). Imidazole (134 mg, 2.0 mmol) and triphenylphosphine (191 mg, 0.73 mmol) were added sequentially. A solution of iodine (179 mg, 0.71 mmol) in ether (5 mL) was added dropwise to the reaction mixture over 10 minutes. The resultant solution was stirred for an additional 20 minutes then diluted with 10 mL of ether. The mixture was filtered to remove solids. Concentration followed by flash chromatography (4:1 hexanes:ethyl acetate) provided 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-(iodomethyl)-2-pyrimidinamine (160 mg, 60%) as a solid. Rf 0.47 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.38 (d, 1H), 7.67 (m, 2H), 7.28 (m, 1H), 7.18 (t, 2H), 7.03 (d, 1H), 6.38 (s, 1H), 5.19 (d, 1H), 4.35 (m, 1H), 4.02 (s, 2H), 2.10 (m, 2H), 2.67 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:11]2[C:18]([CH3:19])=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=3CC3C=CC=CC=3)[NH:16][C:12]=2[N:13]=[CH:14][N:15]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][C:10]1[C:11]2[C:18]([CH3:19])=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[NH:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: Cc1c(-c2cccc[n+]2Cc2ccccc2)[nH]c2ncnc(Cl)c12
Reactant: Nc1cccc(Cl)c1
Solvent: CC(C)O
Product: Cc1c(-c2ccccn2)[nH]c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
With the exclusion of air, 529 μl (5.0 mmol) of 3-chloro-aniline are added to approximately 1.2 mmol of 4-chloro-5-methyl-6-(N-benzyl-pyridinium-2-yl)-7H-pyrrolo[2,3-d]-pyrimidine in 10 ml of isopropanol and the reaction mixture is boiled under reflux for 3 hours. The reaction mixture is concentrated by evaporation and the residue is chromatographed over silica gel. Elution with methylene chloride/ethanol (7:3) and methylene chloride/methanol (7:3) yields first 4-(3-chloro-anilino)-5-methyl-6-(pyrid-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (A) and then 4-(3-chloro-anilino)-5-methyl-6-(N-benzyl-pyridinium-2-yl)-7H-pyrrolo[2,3-d]pyrimidine bromide (B). A is also obtained by heating B. A: m.p. 251-252° C.; 1H-NMR (200 MHz, DMSO-d6): 12.75 and 9.25 (2sb), 8.75 (d, J=5, 1H), 8.35 (s, 1H), 8.05-7.85 (m, 3H), 7.66 (d, J=8, 1H), 7.45 (m, 2H), 7.29 (d, J=8, 1H), 2.84 (s, 3H); FAB-MS: (M+H)+ =336. B: m.p. 171-172° C. (intense foaming); 1H-NMR (200 MHz, DMSO-d6): 12.65 (sb), 9.48 (d, J=6, 1H), 8.80 (t, J=8, 1H), 8.59 (sb, 1H), 8.43 (s, 1H), 8.3 (m, 2H), 7.94 (m, 1H), 7.72 (d, J=8, 1H), 7.40 (t, J=8, 1H), 7.28 (m, 3H), 7.17 (d, J=8, 1H), 6.94 (m, 2H), 5.93 (s, 2H), 2.27 (s, 3H); FAB-MS: (M+H)+ =426.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]4[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 12.2 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(trifluoromethyl)phenylboronic acid (20 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative HPLC twice to give pure 2′-amino-1′-methyl-2-phenyl-6-(4-(trifluoro methyl)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (2.87 mg, 12%). 1H-NMR (MeOD): 2.46 (m, 1H), 2.60 (m, 1H), 3.32 (s, 3H), 5.25 & 5.85 (m, 1H), 7.14 (m, 1H), 7.37-7.54 (m, 6H), 7.66-7.78 (m, 5H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][N:14]1C(=O)C2=CC=CC=C2C1=O>O1CCCC1.ClCCl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH2:13][NH2:14])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(SCCN)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.04 g (43.4 mmol) of NaH was dissolved in 40 ml of tetrahydrofuran at 0° C. To the resulting solution, 4 ml of 4-methylthiophenol dissolved in dry tetrahydrofuran was added slowly. The resultant mixture was stirred at an ambient temperature for 20 minutes and 8.0 g (31 mnol) of N-(2-bromoethyl)phthalimide obtained in step 1 dissolved in dry tetrahydrofuran was added. The mixture was stirred overnight at an ambient temperature and then refluxed for 2 hours. The reaction mixture was distilled under a reduced pressure to produce a residue, which was dissolved in dichloromethane. Then, the resultant solution was washed with water and with an aqueous sodium chloride solution. The organic layer was dried and dichloromethane was removed under a reduced pressure. The residue was recrystallized from a mixture of ethyl acetate/hexane to obtain 6.86 g of the title compound as a yellow solid. The solution remaining after the recrystallization was purified by column chromatography (eluent; ethyl acetate: hexane=1:6) to obtain additional 1.40 g of the title compound. Therefore, a total of 8.26 g (yield 90%) of the title compound was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:14])=O>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([Cl:14])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC(C)C(=O)O
Product: CCCCCC(C)C(=O)Cl

Procedure:
Employing 5 g. of 2-methylheptanoic acid and 7.6 ml. of oxalyl chloride and using the procedure of Preparation A2, 3.3 g. of the desired product was obtained, b.p. 32°-34 ° C./0.6 torr.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:37]1([NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:27]=[C:28]([N:30]5[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]5)[CH:29]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCC(C)CC4)c3)c3ccccc23)n1
Reactant: NC1CCCC1
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(Oc4ccnc(NC5CCCC5)n4)c4ccccc34)c2)CC1

Procedure:
Compound is prepared from 3-fluoro-5-(4-methylpiperidin-1-yl)-N-(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)benzamide (0.2 mmol) and cyclopentylamine (10 mmol) according to conditions described in Step 4 of Example 3 and general procedure C. A yellow solid (13 mg); Mp: 88-90° C.; 1H NMR (300 MHz, CDCl3) δ 0.98 (d, J=6.6 Hz, 3H), 1.23-1.87 (m, 13H), 2.77-2.85 (m, 2H), 3.76 (d, J=12.3 Hz, 2H), 4.08-4.15 (m, 1H), 5.15 (bs, 1H), 6.04 (s, 1H), 6.76 (d, J=12.3 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 7.26-7.30 (m, 2H), 7.49-7.55 (m, 2H), 7.87-7.97 (m, 3H), 8.07-8.11 (m, 1H), 8.20 (s, 1H); MS 540 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6](I)[C:5]([CH3:13])=[N:4]1)[CH3:2].[Cu][C:15]#[N:16].CCOC(C)=O>CN(C=O)C>[C:15]([C:6]1[C:5]([CH3:13])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])#[N:16]
Reactant: CCn1nc(C)c(I)c1C(=O)OC
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1nc(C)c(C#N)c1C(=O)OC
Yield: 91.4 %

Procedure:
To a flask, methyl 1-ethyl-4-iodo-3-methylpyrazol-5-ylcarboxylate (1.00 g, 0.003 mol) was dissolved in 10 mL of DMF and copper (I) cyanide (0.46 g, 0.005 mol) was added in batches. After heating to reflux for 1 h, the mixture was separated by filtration. The filtrate was diluted with 50 mL of water, and then extracted with 50 mL of ethyl acetate. The organic layer was washed with 50 mL of saturated aqueous sodium bicarbonate solution and 50 mL of saturated brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Column chromatography (EtOAc:P.E.=1:10 as eluent) gave 0.53 g of the title compound as a yellow oil (yield 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([O:27][CH3:28])([CH3:26])[CH3:25])=[O:20].FC(F)(F)S(O[C:35]1[C:46]([CH3:47])=[N:45][C:38]2[N:39]=[C:40]([NH:43][CH3:44])[N:41]=[CH:42][C:37]=2[CH:36]=1)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:35]2[C:46]([CH3:47])=[N:45][C:38]3[N:39]=[C:40]([NH:43][CH3:44])[N:41]=[CH:42][C:37]=3[CH:36]=2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([O:27][CH3:28])([CH3:25])[CH3:26])=[O:20]
Reactant: COC(C)(C)CCNC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1F
Reactant: CNc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
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: C1COCCO1
Solvent: O
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)OC)c(F)cc3C)c(C)nc2n1
Temperature: 55 °C
Yield: 21.1 %

Procedure:
Combine 1-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-methoxy-3-methylbutyl)urea (0.17 g, 0.431 mmol), 7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (0.139 g, 0.431 mmol) and NaHCO3 (0.109 g, 1.293 mmol) in dioxane (6 mL) and H2O (1.5 mL). Sparge the mixture with argon. Treat with tetrakis(triphenylphosphine)palladium (0.025 g, 0.022 mmol), sparge again with argon and heat at 55° C. overnight. Add an additional portion of tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmol) and heat at 65° C. overnight. Cool the mixture to RT, remove solids by filtration, and wash solids with dioxane. Combine filtrates, dilute with EtOAc, wash with saturated NaHCO3 and brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex). Dissolve in DCM, wash with saturated NaHCO3 and brine, dry over Na2SO4, concentrate to dryness. Treat with 1:1 MeCN/H2O, freeze in −78° C. bath and lyophilize to obtain the title compound (40 mg, 21% yield) as a pale yellow solid. MS (ESI) m/z: 441.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[N:10]1([CH2:15][CH2:16][CH2:17][NH2:18])[CH:14]=[CH:13][N:12]=[CH:11]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>ClCCl>[N:10]1([CH2:15][CH2:16][CH2:17][NH:18][C:7]([C:4]2[S:3][C:2]([Br:1])=[N:6][CH:5]=2)=[O:9])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)c1cnc(Br)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1)c1cnc(Br)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromothiazole-5-carboxylic acid (0.4 g, 1.923 mmol), 3-(1H-imidazole-1-yl)propan-1-amine (0.265 g, 2.115 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.935 g, 2.115 mmol) were mixed in dichloromethane (7 ml), treated with Hunig's base (0.705 ml, 4.04 mmol) and stirred at 25° C. for 2 hours. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 2-20% methanol/dichloromethane) afforded the title compound.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[C:13]([C:16]1[C:17]([CH3:29])=[C:18]([CH:24]=[CH:25][C:26](=[O:28])[CH3:27])[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])(=[O:15])[CH3:14].[OH-].[Na+]>C(O)C.O>[C:13]([C:16]1[C:17]([CH3:29])=[C:18]([CH:24]2[CH2:25][C:26](=[O:28])[CH:27]=[C:3]([OH:4])[CH2:2]2)[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])(=[O:15])[CH3:14]
Reactant: CC(=O)C=Cc1c(C)cc(C)c(C(C)=O)c1C
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1c(C)cc(C)c(C2CC(=O)C=C(O)C2)c1C
Yield: 79 %

Procedure:
Diethyl malonate (10.16 g; 69 mmole) was added to a solution of sodium metal (1.46 g; 63 mmole) in anhydrous absolute ethanol (50 ml) and the mixture was heated to reflux temperature. A mixture of 1-(3-acetyl-2,4,6-trimethylphenyl)but-1-en-3-one (14.60 g; 63 mmole) in anhydrous absolute ethanol (50 ml) was added over a period of 2 minutes and the mixture was heated under reflux for a period of 2 hours. A 30% aqueous solution of sodium hydroxide (100 ml) was added and the mixture was heated under reflux for a further 41/2 hours. The solution was poured into water (200 ml) and the aqueous mixture was washed with diethyl ether (2×100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and warmed gently until the evolution of carbon dioxide ceased. The aqueous mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The product, 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxycyclohex-2-en-1-one (13.55 g; 84.0%), was obtained as a glassy solid. Proton magnetic resonance spectrum (D6 -dimethylsulfoxide; δ in ppm): 2.20 (3H, s); 2.24 (3H, s); 2.38 (3H, s); 2.45 (3H, s); 2.45-3.40 (4H, m); 3.90 (1H, m); 5.25 (1H, s); 6.85 (1H, s); 11.0 (1h, br.s).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].[H][H]>[Pd].[O-]S([O-])(=O)=O.[Ba+2].CN(C)C(=O)C>[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3]
Reactant: [H][H]
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc2c(c1)COC2=O
Temperature: 60 °C
Yield: 65.1 %

Procedure:
In a hydrogenator, 23 l of N,N-dimethylacetamide, 1.65 Kg (8.39 moles) of 5-chlorocarbonylphthalide (prepared for example as described in J. Chem. Soc., 1931, 867–871) and 200 g of 5% Pd/BaSO4 are charged Hydrogen is then charged at 3 bar thereinto and the mixture is heated at 60±3° C. for a total of 48 hours. The mixture is cooled and, after removal of the catalyst by filtration, the filtrate is concentrated under vacuum at 75° C. up to a solid residue. The product is dispersed with 8 l of deionized water and, at 5÷10° C. under stirring, the pH of the mixture is adjusted to 7.0÷7.5 by addition of 2.3 l of 10% ammonium hydroxide solution After a 30-minute stirring, the product is filtered, washed with deionized water and dried under vacuum at 50° C. to give 885 g (65%) of desired product having m.p.=163÷165° C. (in J. Chem Soc. 1925, page 2290 a m.p.=159÷160° C. is given).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:35])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])=[C:18]([CH2:33][OH:34])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:38][C@H:39]1[CH2:44][CH2:43][CH2:42][CH2:41][N:40]1[C:45]1[N:49]2[CH:50]=[C:51]([O:54][C@H:55]3[C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[C@@H:58]([NH2:65])[CH2:57][CH2:56]3)[CH:52]=[CH:53][C:48]2=[N:47][N:46]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:65][C@@H:58]2[C:59]3[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=3)[C@H:55]([O:54][C:51]3[CH:52]=[CH:53][C:48]4[N:49]([C:45]([N:40]5[CH2:41][CH2:42][CH2:43][CH2:44][C@@H:39]5[CH3:38])=[N:46][N:47]=4)[CH:50]=3)[CH2:56][CH2:57]2)=[O:35])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:24]([CH3:26])[CH3:25])[CH:27]([CH3:29])[CH3:28])=[C:18]([CH2:33][OH:34])[CH:17]=2)[N:9]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1CO)(C(C)C)C(C)C
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CO)(C(C)C)C(C)C
Yield: 57.3 %

Procedure:
A solution of Intermediate 61d (173 mg, 0.29 mmol), Intermediate B (100 mg, 0.27 mmol) and DIPEA (58 μL, 0.33 mmol) in 1,4-dioxane (2.9 mL) was stirred at 70° C. for 42 h. The mixture was evaporated in vacuo and the residue was partitioned between DCM and water. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-5% MeOH in DCM, to give the title compound as a cream colored glass (127 mg, 58%). LCMS (Method 3): Rt 4.97 min, m/z 821 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (10.1 g, 66.9 mmol) in N,N-dimethylformamide (200 mL) was added cesium carbonate (33.2 g, 102 mmol, 1.5 eq). The mixture was stirred for 30 min. A solution of methyl iodide (4.17 mL, 67.0 mmol, 1.0 eq) in N,N-dimethylformamide (50 mL) was added dropwise and the reaction mixture was maintained for 18 h at rt. The reaction mixture was partitioned between water (1 L) and ether (200 mL) and the water layer was extracted with an additional volume of ether (100 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous potassium carbonate, and concentrated to provide 10.2 g (92%) of methyl 2-amino-3-methylbenzoate. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82 (bs, 2H), 3.86 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:21]1(=[O:26])[CH2:25][CH2:24][CH:23]=[CH:22]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:22]2[C:21](=[O:26])[CH2:25][CH2:24][CH:23]=2)=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][N:9]=1
Reactant: O=C1C=CCC1
Reactant: O=Cc1cc(-c2ccccc2)cnc1Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: O=C1CCC=C1C(O)c1cc(-c2ccccc2)cnc1Cl
Yield: 95 %

Procedure:
The clear solution of 2-Chloro-5-phenylnicotinaldehyde (10 mmol, 2.17 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 95% yield (2.84 g).