Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:3]([NH:21][C:22]([C:24]1([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][CH2:14]3)=[CH:7][CH:6]=1)#[N:2].N>C(O)=O.O>[NH2:30][C:24]1([C:22]([NH:21][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[C:16](=[O:20])[NH:15][CH2:14]4)=[CH:9][CH:10]=2)=[O:23])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc4c(c3)CNC4=O)cc2)CCOCC1
Agent: N
Solvent: O
Solvent: O=CO
Product: N#C[C@H](Cc1ccc(-c2ccc3c(c2)CNC3=O)cc1)NC(=O)C1(N)CCOCC1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-(1-oxoisoindolin-5-yl)phenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 15, step (ii), 160 mg) was stirred in formic acid (0.5 mL) at 50° C. for 20 min. The reaction mixture was cooled to room temperature and the mixture diluted with water (20 mL). The solution was basified with 0.880 ammonia and extracted into ethyl acetate (100 mL). The extract was dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica using methanol/ethyl acetate (1/9) to afford the titled compound as a solid (70 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:27][NH2:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:27][NH:28][C:7]2[C:6]([C:4]([OH:3])=[O:5])=[CH:11][N:10]=[C:9]3[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:8]=23)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(CN)cc1Cl
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Product: CCn1ncc2c(NCc3ccc(OC)c(Cl)c3)c(C(=O)O)cnc21
Yield: 87 %

Procedure:
4-Chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester and (3-chloro-4-methoxyphenyl)methylamine was used to afford the title compound (87%) as a white solid: mp 250 ° C.(decomposed).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[O:6][CH2:7][C:8](=[O:14])[C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:2]1.C(OC)(=O)CC(OC)=O.ClCC(Cl)=O.C1(N)CC1.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][N:40]=2)[C:35]([CH:42]=O)=[CH:34]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:33]1[C:41]2=[N:40][CH:39]=[CH:38][CH:37]=[C:36]2[C:35]([CH:42]=[C:7]2[O:6][C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2=[O:14])=[CH:34]1
Reactant: COC(=O)C1=C(NC2CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: NC1CC1
Agent: O=C(Cl)CCl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Solvent: COC(=O)CC(=O)OC
Product: COC(=O)C1=C(NC2CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 1.5 %

Procedure:
To a solution of methyl 2-(cyclopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.5 mmol) which similarly prepared according to the procedure described in the Example 4, First step using dimethyl malonate, chloroacetyl chloride and cyclopropylamine, and 7-azaindole-3-carboxaldehyde (0.37 g, 2.5 mmol) in ethanol (6.0 mL), L-proline (0.029 g, 0.25 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.012 g, y. 30%).
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:22]=[C:21]([NH:23][C:24]3[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:8][C:7]=1[CH3:30])=[O:4].[OH-].[Na+].Cl>O.CCO>[C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:22]=[C:21]([NH:23][C:24]3[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:8][C:7]=1[CH3:30])([OH:4])=[O:2]
Reactant: COC(=O)Cc1ccc(Nc2nc(Nc3cc(C)n[nH]3)c3ccccc3n2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2nc(Nc3ccc(CC(=O)O)c(C)c3)nc3ccccc23)[nH]n1
Temperature: 70 °C
Yield: 95.3 %

Procedure:
A solution of [2-(4-methoxycarbonylmethyl-3-methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIc-64, 200 mg, 0.5 mmol) in a mixture of methanol/water (3/1, 8 mL) was treated with 1M NaOH (2 mL, 2 mmol). The mixture was heated at 70° C. for 2 hours and then neutralised with 1M HCl (2 mL, 2 mmol). The solid that formed was collected by filtration to afford the title compound (185 mg, 95%) as a pale yellow solid, mp 245° C. (dec.); 1H NMR (DMSO) δ 2.27 (6H, 2×s), 3.55 (2H, s), 6.49 (1H, s), 7.13 (1H, d), 7.26 (1H, t), 7.50 (1H, d), 7.62-7.78 (3H, m), 8.42 (1H, d), 9.34 (1H,d), 10.26 (1H, s), 12.36 (1H, s); IR (solid) 1660, 1590, 1562, 1504, 1427, 1385, 810, 776, 751, 693; MS 389.4 (M+H)+
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Si:12]([O:19][CH2:20][CH:21]=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(O)(C(F)(F)F)=O.[BH3-]C#N.[Na+]>CO>[C:15]([Si:12]([CH3:14])([CH3:13])[O:19][CH2:20][CH2:21][NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[I:1])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNc1ccc([N+](=O)[O-])cc1I
Reaction time: 2 h
Yield: 24.9 %

Procedure:
To a solution of 2-iodo-4-nitroaniline (2.0 g, 7.6 mmol) and 2-(tert-butyldimethylsilyloxy)-acetaldehyde (3.5 g, 75% purity, 15 mmol) in methanol (30 mL) was added TFA (1.5 mL) at 0° C. The reaction mixture was stirred at this temperature for 30 ml before NaCNBH3 (900 mg, 15 mmol) was added in portions. The mixture was stirred for 2 h and was then quenched with water. The resulting mixture was extracted with EtOAc (30 mL×3), the combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum, and the residue was purified by chromatography on silica gel (5% ethyl acetate/petroleum) to afford [2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-(2-iodo-4-nitro-phenyl)-amine (800 mg, 25%). 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J=2.7 Hz, 1H), 8.12 (dd, J=2.4, 9.0 Hz, 1H), 6.49 (d, J=9.3 Hz, 1H), 5.46 (br s, 1H), 3.89 (t, J=5.4 Hz, 2H), 3.35 (q, J=5.4 Hz, 2H), 0.93 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[C:12](=[O:19])[O:11][C:10]=2[CH:20]=1.[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:23])[CH3:22].C(N(CC)CC)C>O1CCCC1>[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=4[C:12](=[O:19])[O:11][C:10]=3[CH:20]=2)[CH2:27][CH2:26]1)(=[O:23])[CH3:22]
Reactant: CC(=O)NC1CCNCC1
Reactant: O=c1oc2cc(OCCCBr)ccc2c2c1CCCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCCC4)CC1

Procedure:
A mixture of 17.3 g. (0.051 mole) 3-(3-bromopropoxy)-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one, 7.3 g. (0.051 mole) 4-acetamidopiperidine, 5.2 g. triethylamine and 100 ml. tetrahydrofuran is heated under reflux for 14 hours and then cooled and filtered. The precipitate obtained is washed with tetrahydrofuran and water and dried in a vacuum. There are obtained 11.3 g. (55% of theory) of the desired compound (m.p. 167°-168° C.) which is identical to the compound of Example 23.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:7]1([CH3:17])[CH2:12][CH2:11][CH:10]([CH:13]([CH3:15])[CH3:14])[CH:9](O)[CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:6][CH:9]1[CH:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:12][CH:7]([CH3:17])[CH2:8]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1CC(C)CCC1C(C)C
Temperature: 150 °C

Procedure:
24 g of methacrylic acid, 31 g of menthol and 15 g of p-toluenesulfonic acid in 500 mL of toluene were heated under reflux at a oil temperature of 150° C. for 19 h. Subsequently, the reaction mixture was quenched by the addition of salt saturated sodium bicarbonate, solution. The mixture was extracted with ether, the organic layers were combined and washed with salt saturated sodium bicarbonate solution and then with an aqueous solution of sodium hydroxide, salt saturated ammonium chloride solution, then dried over salt saturated brine and sodium sulfate anhydrous. Finally, the resultant oily product was evaporated under reduced pressure to obtain menthyl methacrylate.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH:15]1([CH:18]=[O:19])[CH2:17][CH2:16]1>C1COCC1>[CH3:8][C:7]1[C:2]([CH:18]([CH:15]2[CH2:17][CH2:16]2)[OH:19])=[N:3][CH:4]=[CH:5][C:6]=1[Cl:9]
Reactant: Cc1c(Cl)ccnc1Br
Reactant: O=CC1CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(Cl)ccnc1C(O)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A solution of 2-bromo-3-methyl-4-chloro-pyridine (10.6 g, 57.1 mmol) in freshly distilled THF (120 mL) was cooled down to 0° C. and treated with isopropyl magnesium chloride (45.7 mL, 2.0 M in THF, 91.5 mmol). The resulting mixture was stirred at room temperature for 3 h then cooled to −5° C. Cyclopropane carboxaldehyde (6.83 mL, 91.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and quenched by adding water (100 mL), and extracted with ethyl acetate (2×150 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 3:1) to afford the title compound as a yellow oil (7.01 g, 62%).
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:20][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([CH:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:30][CH:31]=3)[N:21]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccccc1Nc1cccn2nc(Cl)nc12
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(Nc5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N(8)-(2-Methanesulfonyl-phenyl)-N(2)-[4-(1-methyl-piperidin-4-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine (75.0 mg, 0.232 mmol) and ]-4-(1-methyl-piperidin-4-yl)-phenylamine (53.0 mg, 0.279 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.063 g, 57%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (s, 1H), 8.13 (d, J=6.8 Hz, 1H), 7.98 (dd, J=7.8, 1.2 Hz, 1H), 7.58-7.48 (m, 4H), 7.29-7.25 (m, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.14-7.09 (m, 1H), 6.83-6.77 (m, 2H), 3.14 (s, 3H), 3.01-2.94 (m, 2H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 2.10-2.00 (m, 2H), 1.87-1.73 (m, 4H). MS=477 (MH)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([NH2:14])[C:7]=2[N:15]=1.Cl.[O:21]([NH2:23])[CH3:22].C(N(CC)CC)C.O>CN(C=O)C>[CH2:16]([N:5]1[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([NH2:14])[C:7]=2[N:15]=[C:4]1[CH2:3][NH:23][O:21][CH3:22])[CH:17]([CH3:19])[CH3:18]
Reactant: CON
Reactant: Cc1nc(N)c2nc(CCl)n(CC(C)C)c2c1C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONCc1nc2c(N)nc(C)c(C)c2n1CC(C)C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
2-(chloromethyl)-1-isobutyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine hydrochloride (1.53 g, 5.05 mmol) was dissolved in 10 mL of DMF in a pressure tube under a nitrogen atmosphere. Methoxylamine hydrochloride (1.27 g, 15.15 mmol) and triethylamine (4.22 mL, 30.3 mmol) were added, the tube was sealed and the contents heated to 50° C. for two hours, then to 60° C. for five hours. The mixture was then stored in the refrigerator over the weekend. The contents were poured into water (60 mL) and stirred for 20 minutes. The solution was extracted with chloroform (3×70 mL) and the organics were washed with water (4×40 mL) and brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by HPFC eluting with a gradient of 0-30% CMA (80/18/2 v/v/v chloroform/methanol/concentrated ammonium hydroxide) in chloroform and then recrystallized from acetonitrile to provide 1-isobutyl-2-[(methoxyamino)methyl]-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine as a white powder, mp 154.0-156.0° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@@H:52]([CH2:55][N:56]([CH3:70])[C:57]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=3)=[O:58])[CH2:51]2)=[O:49])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:54][CH2:53][C@@H:52]([CH2:55][N:56]([CH3:70])[C:57]([O:59][CH2:60][C:61]5[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=5)=[O:58])[CH2:51]4)=[O:49])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CN(C[C@@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)C1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@@H](CN(C)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 46.9 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.66 g) in anhydrous acetonitrile (5 ml), N,N-diisopropylethylamine (0.19 ml) and a solution of (2S,4S)-4-mercapto-1-methyl-2-[(3R)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (0.53 g) in anhydrous acetonitrile (5 ml) were added while stirring in an ice bath. The resulting mixture was allowed to react overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=6/4), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-[(3R)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.43 g) was obtained.
Reaction SMILES: C(OC(=O)[O:7][CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:26][C:25]3[C:20](=[N:21][CH:22]=[CH:23][C:24]=3[O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38](=[O:46])[CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[S:36])=[CH:30][C:29]=3[F:47])[CH:19]=2)=[CH:14][CH:13]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[F:47][C:29]1[CH:30]=[C:31]([NH:34][C:35]([NH:37][C:38](=[O:46])[CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[S:36])[CH:32]=[CH:33][C:28]=1[O:27][C:24]1[CH:23]=[CH:22][N:21]=[C:20]2[CH:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([CH2:11][NH:10][CH2:9][CH2:8][OH:7])=[CH:17][CH:16]=3)[S:26][C:25]=12
Reactant: CC(C)(C)OC(=O)OCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CNCCO)cc4)sc23)c(F)c1
Reaction time: 3 h

Procedure:
To a solution of 62 in DCM (190 mg, 0.24 mmol) was added TFA (excess) at room temperature and the reaction mixture was stirred for 3 hrs, evaporated under reduced pressure and the residual solid was triturated with Et2O to afford the title compound 63 as the di-TFA salt (100 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.49 (s, 1H), 11.84 (s, 1H), 8.89 (s, 1H), 8.53 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 8.01 (m, 1H), 7.62 (dd, J=2.5 and 7.7 Hz, 2H), 7.54 (d, J=2.7 Hz, 2H), 7.33 (m, 4H), 7.28 (m, 1H), 6.67 (d, J=5.5 Hz, 1H), 4.64 (m, 1H), 4.30 (m, 1H), 4.22 (t, J=5.3 Hz, 2H), 3.82 (s, 2H), 3.63 (t, J=5.3 Hz, 2H), 2.98 (m, 1H). MS (m/z) 587.0 (M+H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)=[O:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.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>[CH:1]([C:3]1[S:7][C:6]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=O)s1
Yield: 33.5 %

Procedure:
A solution of 5-formylthiophene-2-carboxylic acid (350 mg, 2.24 mmol), tert-butyl 2-aminophenylcarbamate (467 mg, 2.24 mmol) and triethylamine (470 μL, 340 mg, 3.36 mmol) and BOP (1.1 g, 2.68 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by flash chromatography using 25% EtOAc in hexanes as an eluent, yielding 260 mg (33%) of the title compound. 1H NMR (CDCl3) 9.95 (s, 1H), 9.7 (br. s, 1H), 7.84 (d, 1H, J=8.0 Hz), 7.74 (m, 2H), 7.15 (m, 2H), 6.72 (s, 1H), 1.56 (s, 9H). LRMS: (calc) 346.1; (found) 369.1 (M+Na)
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.C(O)(=O)C>CN(C)C=O>[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[N:13]([CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)N([C@H](C)c3ccccc3)[C@H]3COC(=O)[C@H]32)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
9.75 g (0.22 mol) of sodium hydride (55 percent in oil) was added in 10 portions in 2 hours at -10° C. under argon to a solution of 50.0 g (0.2 mol) of (3aS, 6aR)-1-[(R)-(1-phenylethyl)]-dihydro-1H-furo-[3,4-d] -imidazol-2,4-(3H, 3aH)-dione and 39.8 g (0.25 mol) of 4-methoxybenzyl chloride in 500 ml of dried N,N-dimethylformamide. The reaction mixture was stirred at 5° C. for 2 hours and then at room temperature for another 2 hours. Then 8 ml of acetic acid was added. Then the mixture was evaporated to dryness. Then the residue was taken up in 100 ml of water and 200 ml of dichloromethane, the phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane. The organic phases were dried over magnesium sulfate and concentrated. After suspension in ethanol with refluxing, cooling and filtering, 53.5 g (72 percent) of the title product was obtained in the form of white needles. Concerning the product: Melting point: 146.1°-146.4° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=CC=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CC>C1COCC1>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][CH2:48][CH2:49][CH3:50])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCN
Solvent: C1CCOC1
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in THF (2 mL) were added HBTU (30 mg, 0.079 mmol) and propylamine (0.031 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (16 mg, 37%). LC-MS m/z 563 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:11]([NH2:25])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:33][C:14]1[N:15]([CH2:18][CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:16]2[C:12]([N:13]=1)=[C:11]([NH2:25])[N:10]=[C:9]([NH:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[N:17]=2
Reactant: Nc1nc(NCC2CCCCC2)nc2c1ncn2CC1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1nc(NCC2CCCCC2)nc2c1nc(Br)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-(cyclohexylmethyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purine-2,6-diamine (90 mg) in dry chloroform (1 mL) at room temperature was added NBS (46 mg) in one go. The dark brown reaction was stirred at RT for 1 hour. The reaction was diluted with DCM (15 mL) and washed with water (5 mL). The organics were passed through a hydrophobic frit and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1.C(N(CC)CC)C.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[C:3]([C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[CH:4]=2)[C:9](=[O:12])[CH2:8][CH2:7]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc2c(cc1OS(=O)(=O)C(F)(F)F)C(C)(C)CCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C#C[Si](C)(C)C)C(C)(C)CCC2=O
Yield: 93.7 %

Procedure:
Following General Procedure D and using trifluoro-methanesulfonic acid 3,8,8-trimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (Intermediate 172, 5.04 g, 15 mmol), triethyl amine (20 mL), copper(I)iodide (0.6 g, 3 mmol), trimethylsilyl acetylene (5.3 mL, 37.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (2.2 g, 3 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 6% ethyl acetate in hexane as the eluent, the title compound (4 g, 93%) was obtained as a pale yellow solid.