Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:15][CH:16]([CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:17]N1C(=O)C2=CC=CC=C2C1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O.[NH2:46]N>C(O)C>[CH2:31]([O:30][CH:29]([NH2:46])[CH:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:17])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: NN
Reactant: CCCCCCCCCCCCCCOCC(CN1C(=O)c2ccccc2C1=O)OCCCCCCCCCCCCCC
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCOC(C)C(N)OCCCCCCCCCCCCCC
Yield: 86 %

Procedure:
Crude N-(2,3-dimyristyloxypropyl)phthalimide 4 (20.0 g, 25.0 mmol) was dissolved in ethanol (300 ml). Hydrazine monohydrate (20 ml, 412.3 mmol) was added and the reaction was left to reflux overnight. The ethanol was removed on the rotary evaporator and the residue was redissolved in chloroform (200 ml). The precipitate was filtered off and the chloroform was removed on the rotary evaporator. TLC (10% MeOH—CHCl3, developed in Molybdate) indicated that most of the starting material had reacted to form product. This resulting product was further purified by flash column chromatography (0-5% MeO—CHCl3) to yield 10.4 g (89.7% over three steps from 1,2-dimyristyloxypropan-3-ol 2) of 1,2-dimyristyloxypropylamin 5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([CH2:14][C@H:15]([N:19]2[C:23](=[O:24])[C@H:22]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[NH:21][C:20]2=[O:32])[C:16](O)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([CH2:14][C@H:15]([N:19]2[C:23](=[O:24])[C@H:22]([CH2:25][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[NH:21][C:20]2=[O:32])[C:16]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Nc1ccccn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Product: O=C(Nc1ccccn1)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O

Procedure:
By using the conditions described in Step (iv) of Example 17, 2-aminopyridine was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd for C24H34N4O3 (M+) 427.2709, found 427.2706.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[NH:20][N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.N12CCCN=C1CCCCC2.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1[N:45]=[CH:44][C:43]([CH2:46][CH:47]([C:52](=O)[CH2:53][CH2:54][CH2:55][CH3:56])[C:48](OC)=[O:49])=[CH:42][CH:41]=1)#[N:33].C(OCC)(=O)C>CCN(C1C=CC=CC=1)CC.O>[CH2:53]([C:52]1[N:20]2[N:19]=[CH:18][CH:17]=[C:16]2[N:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]2)[C:48](=[O:49])[C:47]=1[CH2:46][C:43]1[CH:42]=[CH:41][C:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:32]#[N:33])=[N:45][CH:44]=1)[CH2:54][CH2:55][CH3:56]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccn[nH]2)CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-5-amine (0.67 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL) and methyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxoheptanoate (0.8 g) in diethylaniline (5 mL) was stirred at 180° C. for 5 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was crudely purified by silica gel column chromatography. This was dissolved in tetrahydrofuran (4 mL). Tetrabutylammonium fluoride (2.5 mL) was added, and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool, ethyl acetate and saturated aqueous ammonium chloride solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. This was dissolved in acetonitrile (6 mL), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (1.0 g) was added, and the mixture was stirred for 3 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in ethanol (3 mL)-tetrahydrofuran (3 mL), and sodium borohydride (0.045 g) was added at 0° C. After stirring at 0° C. for 2 hr, ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.48 g, 44%).
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:9][C:10]1[N:11]=[C:12]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:13]2[S:18][C:17]([CH:19]=O)=[CH:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:13]2[S:18][C:17]([CH2:19][N:5]3[CH2:6][CH2:7][C:2]([CH3:1])([OH:8])[CH2:3][CH2:4]3)=[CH:16][C:14]=2[N:15]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(O)CCNCC1
Product: CC1(O)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction of 4-methyl-piperidin-4-ol with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 using standard reductive amination conditions yielded 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-methyl-piperidin-4-ol, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 382. 400 MHz 1H NMR CDCl3: 9.21 (s, 2H, 2×Ar): 7.19 (s, 1H, ArH); 5.17 (brs, NH2): 3.95 (t, 4H, 2×CH2, J=4.7 Hz); 3.80 (t, 4H, 2×CH2, J=4.7 Hz); 3.76 (s, 2H, CH2); 2.60-2.54 (m, 2H, CH2); 2.44 (t, 2H, CH2, J=10.9 Hz); 1.69-1.62 (m, 2H, CH2); 1.55 (d, 2H, CH2, J=16.1 Hz); 1.20 (s, 3H, Me); 1.12 (s, 1H, OH). LC-MS (m+1)=442.13
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]([CH2:10][OH:11])[CH:3]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:9])[O:11][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1sc(Br)cc1CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1OCc2cc(Br)sc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 50 mL round bottom flask, 5-bromo-3-(hydroxymethyl)thiophene-2-carboxylic acid (140 mg, 0.59 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol, 1.0 eq) were dissolved in DCM (5 mL) The solution was stirred at r.t. for 1 hr, concentrated and purified by flash column chromatography to give desired product. LC-MS (IE, m/z): 221.2 [M+1]+. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.1 (1H, aromatic), 5.2 (2H, s).
Reaction SMILES: C[CH:2]([N:6]([CH:14](C)[C:15]([O-:17])=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O-:5])=O.[NH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][NH2:25].CC(C)=O>C(O)C>[CH2:7]([N:6]1[CH2:2][C:3](=[O:5])[NH:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][NH:19][C:15](=[O:17])[CH2:14]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C(=O)[O-])N(Cc1ccccc1)C(C)C(=O)[O-]
Reactant: NCCNCCN
Solvent: CCO
Solvent: CC(C)=O
Product: O=C1CN(Cc2ccccc2)CC(=O)NCCNCCN1
Yield: 14.4 %

Procedure:
To a solution of 31.2 g dimethyl-N-benzyliminodiacetate in 2.5 l of dry ethanol at reflux under nitrogen was added dropwise 12.8 g of diethylenetriamine in 160 ml of dry ethanol. Reflux was carried out for a total of 137 hours. The solution was evaporated under reduced pressure leaving a yellow paste. Trituration with acetone left 5.2 g of the desired product as a colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1.[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)Cl.[OH-].[Na+]>CO.O>[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1ccnc(CCl)n1
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)NC(=O)C1CCN(Cc2nccc(N)n2)CC1
Yield: 94 %

Procedure:
A solution of 2-chloromethyl-pyrimidin-4-ylamine (Imperial Chemical Industries PLC Patent: U.S. Pat. No. 4,447,441 A1, 1984; 300 mg, 2.1 mmol) in methanol (25 mL) is treated with piperidine-4-carboxylic acid tert-butylamide (404 mg, 2.19 mmol) and TEA (0.872 mL, 6.27 mmol). The resulting mixture is heated at reflux overnight. DCM (25 mL) and water (25 mL) are added followed by NaOH 1M to adjust at pH 10. The organic phase is separated. The aqueous phase is extracted with DCM (25 mL). The combined organic phases are dried over MgSO4, filtered and evaporated. Evaporation of the solvent yields the crude product (0.57 g, 94%) as a brownish solid; LC-MS A: tR=0.40 min; [M+H]+=292.14.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(O)(=O)C.[Br:17]N1C(=O)CCC1=O>>[Br:17][C:4]1[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[F:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cc(Cl)c(F)cc1O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(F)c(Br)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a stirred solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (7.9 g, 42 mmol) in acetic acid (80 mL, 1.0 mol) was added N-bromosuccinimide (9.0 g, 50 mmol) and the resulting mixture was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to yield the desired product (93% yield). 1H NMR (300 MHz, CDCl3): δ 13.15 (s, 1H), 7.79 (m, 1H), 2.62 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:13]2[NH:14][C:15]([C:17]3[C:18](=[O:33])[NH:19][CH:20]=[CH:21][C:22]=3[NH:23][CH2:24][C@@H:25]([OH:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:36]>C1COCC1>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][C:35](=[O:36])[NH:7][C:8]2[C:13]3[NH:14][C:15]([C:17]4[C:18](=[O:33])[NH:19][CH:20]=[CH:21][C:22]=4[NH:23][CH2:24][C@@H:25]([OH:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: Nc1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(OC(=O)Nc2cccc3nc(-c4c(NC[C@@H](O)c5ccccc5)cc[nH]c4=O)[nH]c23)cc1
Temperature: 25 °C
Yield: 33 %

Procedure:
Pyridine (2.0 ml) was added to a solution of 3-(7-amino-1H-benzoimidazol-2-yl)-4-((S)-2-hydroxy-2-phenyl-ethylamino)-1H-pyridin-2-one (0.060 g, 0.166 mmol) (Prepared according to the general method for the intermediates of formula II and III above) and 4-methoxyphenyl chloroformate (0.062 g, 0.32 mmol) in THF (2 ml) and the reaction stirred at room temperature. After 20 hours the reaction was concentrated and the crude mixture was purified by column chromatography (1-2% methanol, dichloromethane) to give the desired product (0.028 g; 33%).
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[N:9]=[C:8]([N+:10]([O-])=O)[C:7]([O:13][CH2:14][C:15]([O:17]CC)=O)=[CH:6][CH:5]=1>O.CO.[Fe]>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:14][C:15](=[O:17])[NH:10][C:8]=2[N:9]=1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: O=C1COc2ccc(Br)nc2N1
Temperature: 95 °C
Yield: 79.9 %

Procedure:
Ammonium chloride (44 g, 0.823 mole) was dissolved in H2O (600 mL), and iron powder (−325 mesh, 27.4 g, 0.491 mole) was added. The mixture was mechanically stirred (vigorously), and a solution of ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (50 g, 0.164 mole) in MeOH (800 mL) was added slowly at RT over 3 hours. When the addition was done, the reaction was heated at reflux for 3 hr and then hot-filtered through a pad of Celite®. The filter pad was washed with hot MeOH (500 mL) and the filtrate was concentrated in vacuo. When most of the MeOH was removed, the mixture was filtered to collect the solid, which was washed with water (100 mL). The filtrate was extracted with CHCl3 (300 mL, 2 times) and the organic layer was washed sequentially with water and brine, dried (MgSO4), and concentrated in vacuo. The residue was combined with the solid from the filtration, suspended in glacial AcOH (150 mL), and the mixture was heated at 95° C. for 3 hr. The mixture was then concentrated in vacuo and the residue was triturated with Et2O (200 mL). The solid was collected, washed with ether, and dried to afford the title compound (30 g, 80%): MS (ES) m/e 229.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COCCN
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Product: COCCNC1CCC(C(=O)NCc2nccnc2Cl)CC1
Yield: 94.2 %

Procedure:
Using the procedure described in example 7 step 7a N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclo-hexanecarboxamide (1 g) and 2-methoxyethanamine (0.281 g) gave N-((3-chloropyrazin-2-yl)methyl)-4-(2-methoxyethylamino)cyclohexanecarboxamide (1.15 g, mixture of cis and trans).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:18])OCC)=[C:7]([CH2:21][CH2:22][CH3:23])[C:6]=1[OH:24])(=[O:4])[CH3:3].N[C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[NH2:37])[C:29]([O:31]CC)=[O:30].[OH-].[Na+]>C(O)C>[C:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[NH:18][C:26]3[CH:27]=[C:28]([C:29]([OH:31])=[O:30])[CH:34]=[CH:35][C:36]=3[N:37]=2)=[C:7]([CH2:21][CH2:22][CH3:23])[C:6]=1[OH:24])(=[O:4])[CH3:3]
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: CCCc1c(OCCCCC(=N)OCC)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(OCCCCc2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.7 %

Procedure:
A mixture of ethyl 5-(4-acetyl-3-hydroxy-2-propylphenoxy)-pentanimidate hydrochloride (3.0 g) and ethyl 3,4-diaminobenzoate (1.4 g) in ethanol (40 ml) was stirred at room temperature for 24 hours. To the mixture was added a solution of sodium hydroxide (1.6 g/30 ml of water) and the resulting mixture was refluxed for 40 minutes. After removal of the solvent under reduced pressure, the mixture was poured into ice-water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The extract was evaporated and the resulting residue was purified by silica gel column chromatography, eluting with dichloromethane-ethanol (9:1), to give the title compound (2.0 g, 58.1 %) as amorphous powder, mp 98-100 ° C.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][O:13][C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17].[CH3:21][O:22][C:23](=[O:33])[C:24]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:21][O:22][C:23](=[O:33])[C:24](=[O:25])[C:26]1[CH:27]=[CH:28][C:29]([O:1][CH2:2][C:3]#[C:4][C:5]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:12][O:13][C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])=[CH:30][CH:31]=1
Reactant: CCC(C)(C)C(=O)OCc1cccc(C)c1C#CCO
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)OCc1cccc(C)c1C#CCOc1ccc(C(=O)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A stirred solution of 2,2-dimethylbutanoic acid [2-(3-hydroxy-1-propynyl)-3-methylphenyl]methyl ester (1.05 g), 4-hydroxyphenylglyoxylic acid methyl ester (0.693 g) and triphenylphosphine (1.26 g) in tetrahydrofuran (30 mL) was cooled to 0° C., and a solution of diethyl azodicarboxylate (0.76 mL) in tetrahydrofuran (5 mL) was added over 5 minutes. The reaction mixture was stirred at 0° C. for 1 hour then at room temperature overnight. The solvent was evaporated and the residue triturated with diethyl ether to remove most of the triphenylphosphine oxide. The filtrate was concentrated in vacuo and the resulting oil was chromatographed over silica gel (10 g; diethyl ether-hexane; 1:19) to furnish 1.4 g of 4-[3-[2-[(2,2-dimethyl-1-oxobutoxy) methyl]-6-methylphenyl]-2-propynyloxy]-alpha-oxobenzeneacetic acid methyl ester as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:21])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH2:22](Br)[CH:23]=[CH2:24]>C1COCC1.[Cu]I>[CH2:24]([C:2]1[CH:3]=[C:4]([F:21])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2F)CC1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 0 °C
Yield: 68.9 %

Procedure:
In a dry 3-necked flask flushed with argon containing a solution of 11 (6.86 g, 19.05 mmol) in THF (40 mL) at 0° C. was added a 1.3 M THF solution of isopropyl magnesium chloride lithium chloride complex (19.1 mL, 24.8 mmol) over 10 min. After 10 additional minutes of stirring at 0° C., CuI (0.73 g, 3.81 mmol) was added, the mixture was stirred for 10 minutes at 0° C. and then a solution of allyl bromide (3.3 mL, 38.1 mmol) in THF (4.0 mL) was added at 0° C. over 10 min. After further stirring for 1 h at 0° C., the reaction was quenched with 10% citric acid and extracted with ethyl acetate (100 mL×2). The organic layers were combined which was washed with brine, dried over Na2SO4, and concentrated. The obtained residue was chromatographed on silica gel eluted with hexane and 10% ethyl acetate in hexanes to afford 4.22 g of 12 (69%) as a colorless oil which was used directly for the next step. LC/MS (M+1) 322.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][N:7]([C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)C.Cl>C(O)C>[Cl:22][C:15]1[N:16]=[CH:17][C:18]2[NH:19][C:4](=[O:3])[CH2:5][CH2:6][N:7]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:13]=2[N:14]=1
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: Cl
Solvent: CCO
Product: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Yield: 65.2 %

Procedure:
To a solution of 0.356 g (0.001 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-propanoic acid ethyl ester (IV-10) in 5 mL of ethanol was added 0.562 g (0.0025 mole) of stannous chloride dihydrate and 0.1 mL of hydrochloric acid. The mixture was heated to 60 degrees for 2 hrs. The solvent was evaporated under reduced pressure. The residue was taken up in 20 mL of water and extracted with three times with 20 mL of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5) gave 0.174 g of 2-chloro-9-cyclopentyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-10) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[C:12](=[O:16])[CH2:13][CH2:14][O:15][C:10]=2[C:9]=1[CH2:19][CH2:20][CH3:21].[CH2:22]([O:24][C:25](=[O:46])[CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]2[O:35][C:36](=[O:44])[C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[CH:39]=2)[CH:31]=[CH:30][C:29]=1[OH:45])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:22]([O:24][C:25](=[O:46])[CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]2[O:35][C:36](=[O:44])[C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[CH:39]=2)[CH:31]=[CH:30][C:29]=1[O:45][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[C:12](=[O:16])[CH2:13][CH2:14][O:15][C:10]=2[C:9]=1[CH2:19][CH2:20][CH3:21])[CH3:23]
Reactant: CCCc1c(OCCCCCBr)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(-c2cc3ccccc3c(=O)o2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(-c3cc4ccccc4c(=O)o3)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Yield: 58 %

Procedure:
A mixture of 0.352 g (0.99 mmol) of 7-[(5-bromopentyl)oxy]-2,3-dihydro-8-propyl-4H-1-benzopyran-4-one, 0.346 g (1.02 mmol) of 2-hydroxy-5-(1-oxo-1H-2-benzopyran-3-yl)benzenepropanoic acid ethyl ester, 0.574 g (4.15 mmol) of anhydrous granular potassium carbonate and 20.9 mL of 2-butanone was stirred and refluxed for 45 hrs. The resulting slurry was filtered with suction and the solids were washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the residue was purified by flash chromatography on 75 g of silica gel, eluting with 3:1 hexane-ethyl acetate, affording 0.352 g (58.1%) of the title compound as a white solid, mp 143.5°-144° C.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+].[CH3:24]I>C1COCC1>[CH3:24][N:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2c([nH]1)CN(C(=O)OC(C)(C)C)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(n1C)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-tert-butyl 2-ethyl 1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-2,6-dicarboxylate (1.0 eq) in dry THF was added NaH (1.2 eq) at 0° C. and reaction mixture was stirred at room temperature for 30 min. Methyl iodide (6.0 eq.) was added and stirred further at room temperature for 3 hrs. Reaction mixture was quenched with water and extracted with dichloromethane, over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired 6-tert-butyl 2-ethyl 1-methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridine-2,6-dicarboxylate.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:29])[C@H:18]([NH2:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:30]([O-])(O)=[O:31].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:29])[C@H:18]([N:28]=[C:30]=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(C[C@@H](N)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C[C@@H](N=C=O)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 98 %

Procedure:
1-[2-(R)-Amino-3-(4-methoxyphenyl)-propionyl]-pyrrolidin-2-(S)-carboxylic acid benzyl ester hydrochloride (2.8 g) was dissolved in 30 mL of dichloromethane followed by addition of 30 mL of NaHCO3 solution (1M) under vigorous stirring. Triphosgene (0.6 g) in 6 mL of dichloromethane was added at 0° C. and the mixture was kept stirring for 0.25 h. The organic layer was separated and the solvent removed in vacuo to yield 1.20 g (98%) of the title compound as a yellow oil. (+)-APCI-MS: 409 (MH+).