Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[CH:9]=[CH2:10].CCCCCC>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:10][CH:9]=[CH2:8])=[O:6]
Reactant: C=CCO
Reactant: O=C(O)CCCCl
Solvent: CCCCCC
Solvent: O
Product: C=CCOC(=O)CCCCl
Temperature: 25 °C
Yield: 79 %

Procedure:
To a mixture of 4-chlorobutyric acid (48 ml; 0.48 mole), allyl alcohol (200 ml) and hexane (1.2 l) p-toluenesulfonic acid (16.0 g; 0.08 mole) was added. The obtained mixture was heated for 5 hours at reflux temperature in such a way that water was simultaneously removed with Dean-Stark apparatus (Vogel's Textbook of Practical Organic Chemistry, Fourth Ed., Longman, London, 1978, p. 411). The mixture was then cooled to room temperature and shaken with 7% aqueous sodium hydrogencarbonate solution (2×500 ml). The obtained solution was dried with magnesium sulfate and after the filtration of the drying agent hexane was evaporated. The crude residue was distilled under reduced pressure 10 mbar at the temperature of 95° C. and the title compound (61.2 g; 79%) was obtained in the form of a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To the above ethyl (S)-4-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxybenzoate was added MeOH (100 mL) and 1 N NaOH (50 mL). The mixture was stirred for 15 hr at room temp. After removal of MeOH under a reduced pressure, water (50 mL) was added to the residual solution. The aqueous solution was washed with Et2O (×2) and then acidified by the addition of 1 N HCl. The mixture was extracted with EtOAc, washed with water, brine, dried over MgSO4 and evaporated in vacuo to afford 4.26 g (95%) (S)-4-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxybenzoic acid as a crystalline solid.
Reaction SMILES: CNC1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7](=[O:15])[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5](=[O:22])[C:4]=1[C:23]([NH:25]C(=O)OCC)=[S:24].[CH3:31][N:32]([CH3:35])[CH:33]=[O:34].C(N(CC)CC)C.Cl>O>[SH:24][C:23]1[C:4]2[C:5](=[O:22])[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7](=[O:15])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:31]=2[N:32]([CH3:35])[C:33](=[O:34])[N:25]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)NC(=S)c1c(NC)n(-c2ccccc2)c(=O)n(-c2ccccc2)c1=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(=O)nc(S)c2c(=O)n(-c3ccccc3)c(=O)n(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To crude ethyl (6-methylamino-2,4-dioxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrimidine-5-thiocarbonyl)-carbamate 23 (1.58 g) obtained in Step 4 was added N,N-dimethylformamide (8.4 ml), triethylamine (0.63 ml) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 min. Water (25 ml) was added, the mixture was stirred, 1N hydrochloric acid (5.0 ml) was added, and the mixture was stirred at room temperature for 1 hr. The crystals were collected by filtration, washed with water and dried to give crude 5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 24 (1.53 g, over weight) as yellow crystals, which were used for the next step without purification.
Reaction SMILES: Br.[CH3:2][C:3]12[CH2:17][CH:8]([CH:9](O)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=31)[CH2:7][N:6]([CH3:18])[CH2:5][CH2:4]2>O>[CH3:2][C:3]12[CH2:17][CH:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=31)[CH2:7][N:6]([CH3:18])[CH2:5][CH2:4]2
Reactant: CN1CCC2(C)CC(C1)C(O)c1ccccc12
Agent: Br
Solvent: O
Product: CN1CCC2(C)CC(Cc3ccccc32)C1
Yield: 50.6 %

Procedure:
70 g of 57% hydrobromic acid, 5.5 g of red phosphorus and 18 ml of water were added to 17 g of 1,4-dimethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonin-7-ol, and the mixture was heated and refluxed for 3 hours. The reaction mixture liquid was cooled and filtered, and the filtrate was subjected to distillation under reduced pressure. The residue was made alkaline with sodium hydroxide and extracted with ether. The ether extract was dried and filtered, and ether was distilled from the extract. The residue was subjected to vacuum distillation to obtain 8 g of 1,4-dimethyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine boiling at 160° to 170° C. (bath temperature) under 3 mmHg in the form of a colorless oily product. When the hydrochloride was recrystallized from isopropyl alcohol, the melting point of the recrystallized product was 225° to 230° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=O)[C:5]([OH:10])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][CH:2]1[N:7]([CH3:8])[CH:6]=[C:5]([O:10][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:4]=[N:3]1
Reactant: COc1ccc(CCl)cc1
Reactant: Cn1c(Cl)ncc(O)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COC2=CN(C)C(Cl)N=C2)cc1
Temperature: 60 °C
Yield: 62.7 %

Procedure:
To a solution of 9.60 g (59.8 mmol) 2-chloro-5-hydroxy-3-methylpyrimidin-4(3H)-one in 300 ml DMF was added 20.4 ml (149 mmol) PMBCl, and 48.7 g (149 mmol) Cs2CO3. The reaction mixture was heated to 60° C. for 3 h, cooled to rt, quenched with 200 ml water, extracted with 500 ml EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (330 g silica gel, 3-80% EtOAc:hexane) gave 10 g (60% yield) of 2-chloro-5-[(4-methoxybenzyl)oxy]-3-methylpyrimidin -4(31-1)-one. LCMS [M+H]+=281.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[N:6][CH:7]=1.[CH3:12][N:13](C(OC(C)(C)C)=O)[C@H:14]([CH2:16][CH:17]=[CH2:18])[CH3:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][NH:13][C@H:14]([CH2:16]/[CH:17]=[CH:18]/[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=1)[CH3:15]
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: C=CC[C@H](C)N(C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN[C@@H](C)C/C=C/c1cncc(OC(C)C)c1
Temperature: 80 °C

Procedure:
The halo-substituted pyridine, (e.g., 5-bromo-3-isopropoxypyridine) can be synthesized by two different routes. In one preparation, 3,5-dibromopyridine is heated at 140° C. for 14 hours with 2 molar equivalents of potassium isopropoxide in dry isopropanol in the presence of copper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glass tube to yield 5-bromo-3-isopropoxypyridine. A second preparation of 5-bromo-3-isopropoxypyridine from 5-bromonicotinic acid can be performed as follows: (i) 5-Bromonicotinic acid is converted to 5-bromonicotinamide by treatment with thionyl chloride, followed by reaction of the intermediate acid chloride with aqueous ammonia. (ii) The resulting 5-bromonicotinamide, previously described by C. V. Greco et al., J. Heteocyclic Chem. 7(4): 761 (1970), is subjected to Hofmann degradation by treatment with sodium hydroxide and a 70% solution of calcium hypochlorite. (iii) The resulting 3-amino-5-bromopyridine, previously described by C. V. Greco et al., J. Heteocyclic Chem. 7(4): 761 (1970), can be converted to 5-bromo-3-isopropoxypyridine by diazotization with isoamyl nitrite under acidic conditions, followed by treatment of the intermediate diazonium salt with isopropanol to yield 5-bromo-3-isopropoxypyridine. The palladium-catalyzed coupling of 5-bromo-3-isopropoxypyridine and (2S)—N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine is carried out in acetonitrile-triethylamine (2:1, v,v) using a catalyst consisting of 1 mole % palladium(II) acetate and 4 mole % tri-o-tolylphosphine. The reaction can be carried out by heating the components at 80° C. for 20 hours to yield (2S)-(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine Removal of the tert-butoxycarbonyl protecting group can be accomplished by treatment with 30 molar equivalents of trifluoroacetic acid in anisole at 0° C. to afford (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:20]=[C:17]3[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][N:18]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2cn3cc(C)ccc3n2)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To a magnetically stirred solution of 2-bromo-1-(4-methoxy-phenyl)-ethanone (3.0 g, 13.09 mmol) and 5-methyl-pyridin-2-ylamine (1.42 g, 13.09 mmol) in EtOH (30 mL) under Ar atmosphere was added sodium carbonate (2.77 g, 26.18 mmol). The reaction mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated in vacuo. Water (60 mL) was added, and the aqueous phase was extracted with dichloromethane (100 mL). The combined organic layers were washed with water (100 mL), dried (MgSO4), and concentrated in vacuo to provide the title compound (2.8 g, 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.27 (s, 3H), 3.82 (s, 3H), 6.95 (m, 3H), 7.48 (d, J=8.8 Hz, 1H), 7.65 (s, 1H), 7.85 (m, 3H).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].N1(C2C=C3C(=CC=2)NC(=O)CC3)CCNCC1.[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46]>CN(C=O)C.O.C(N(CC)CC)C>[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:3][CH2:4]1)=[O:46]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(N3CCN(C(=O)c4cccc(Cl)c4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril monohydrobromide (1 g) was suspended in 15 ml of DMF. After adding 296 mg of sodium hydrogencarbonate, the suspension was stirred at room temperature for 30 minutes to convert the starting compound to 6-(1-piperazinyl)-3,4-dihydrocarbostyril. Then, to the mixture was added 0.62 ml of triethylamine and the mixture was stirred at room temperature while slowly adding dropwise 5 ml of DMF solution containing 532 mg of m-chlorobenzoyl chloride. After completion of addition the reaction mixture was stirred for at room temperature 1 hour. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 0.4 g of 6-[4-(3-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 197°-197.5° C., colorless scales.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33](=[O:47])[N:34]([CH:44]2[CH2:46][CH2:45]2)[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:37]=2[CH3:43])[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH:44]1([N:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:37]=2[CH3:43])[C:33]([C@@H:10]2[C@@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]4[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[Cl:32])=[CH:18][CH:19]=3)[CH2:12][CH2:13][NH:8][CH2:9]2)=[O:47])[CH2:45][CH2:46]1
Reactant: Cc1cc(Cl)c(OCCOc2ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)N(Cc3cccc(C)c3C)C3CC3)cc2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(Cl)c(OCCOc2ccc([C@H]3CCNC[C@@H]3C(=O)N(Cc3cccc(C)c3C)C3CC3)cc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
Compound D3 (0.068 g, 0.10 mmol) was dissolved in CH2Cl2 (1 mL) and the sol. was cooled to 0° C. 4M HCl in dioxane (1 mL) was added and the reaction mixture was stirred for 1 h at rt. The solvents were evaporated under reduced pressure. Purification of the residue by HPLC yielded the title compound (37 mg, 63%). LC-MS: tR=0.95 min, ES+=581.44.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.Cl.[NH2:7][C:8]1[N:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:33])[N:12]2[CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CN1C(=O)CCC1>[NH2:7][C:8]1[N:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:33])[N:12]2[CH2:22][CH2:23][CH2:24][N:25]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:1](=[O:3])[CH3:2]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccccc3)c2n1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3ccccc3)C(C)=O)c2n1
Reaction time: 2 h

Procedure:
Acetylchloride (0.08 ml) was added to a mixture of the product from step (viii) (250 mg) and triethylamine (0.6 ml) in NMP (5 ml) and stirred for 2 h. The mixture was purified by to RPHPLC, yield 85 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:21])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[CH3:20])[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])[CH3:29]>C1(C)C=CC=CC=1.O.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:21][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:28](=[O:30])[CH3:29])=[CH:32][CH:33]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH3:20]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc(-c3nc(CCN4CCC[C@H]4C)c(C)o3)cc2)cc1
Yield: 55.7 %

Procedure:
To a stirred solution of 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 munol), sodium carbonate (91 mg, 0.860 mmol) and 4-acetylphenyl boronic acid (235 mg, 1.43 mmol) in toluene (5 mL), water (1 mL) and ethanol (1.5 mL) under nitrogen is added Tetrakis (triphenylphosphine) palladium (0) (33.1 mg, 0.029 mmol). The reaction is heated at reflux for 48 h. The reaction is allowed to cool and bound to a SCX-2 cartridge (10 g). The cartridge is washed with one cartridge volumes of dimethylformamide and two volume of methanol. The product is eluted using 2M ammonia in methanol. The ammonia/methanol solution is evaporated on a Genevac® HT4. The sample is further purified by prep-LCMS. The resulting acetonitrile/water fractions are combined and evaporated using a Genevac® HT4 to give 62 mg of a colourless oil (56%). MS (m/e) 389.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4](I)[CH:3]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([NH2:19])[CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([NH:19][C:14]2[CH:13]=[C:12]([CH3:11])[CH:17]=[C:16]([CH3:18])[N:15]=2)[CH:3]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: N#Cc1cnc(Cl)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(C)nc(Nc2cc(Cl)ncc2C#N)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 6-chloro-4-iodopyridine-3-carbonitrile (CAS: 1061357-83-2) (5.0 g, 19 mmol), 4,6-dimethylpyridin-2-amine (2.31 g, 18.9 mmol), Xantphos (2.2 g, 3.8 mmol), Pd2(dba)3 (1.73 g, 1.89 mmol), and cesium carbonate (8.62 g, 26.5 mmol) was purged with nitrogen. Dioxane (45 mL) was added, and the reaction mixture was heated to 50° C. After 1 hour, the mixture was allowed to cool to room temperature, filtered through a pad of CELITE, and washed with dichloromethane. The mixture was concentrated under reduced pressure, diluted with water, and extracted with dichloromethane (2×20 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to provide 6-chloro-4-[(4,6-dimethylpyridin-2-yl)amino]pyridine-3-carbonitrile. MS ESI calc'd. for C13H12ClN4 [M+H]+ 259. found 259. 1H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 2.37 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [CH2:1]1[O:5][CH2:4][O:3][CH:2]1[CH2:6][OH:7].N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>CCOCC>[C:15](=[O:16])([O:7][CH:6]1[CH2:2][O:3][CH2:4][O:5][CH2:1]1)[O:17][CH2:18][Cl:19]
Reactant: O=C(Cl)OCCl
Reactant: OCC1COCO1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCCl)OC1COCOC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 6.4 %

Procedure:
Glycerol formal (14 g) was dissolved in anhydrous ether (400 ml) and, after adding pyridine (15 g) at −10° C., a solution of chloromethyl chloroformate (25 g) in anhydrous ether (50 ml) was added dropwise over the period of 10 minutes. After the reaction solution was stirred at room temperature for 20 hours, the deposited pyridine hydrochloride was removed by filtration. The filtrate was washed with a saturated sodium chloride aqueous solution (400 ml×2), and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by subjecting it to silica gel chromatography (eluent: ethyl acetate/hexane=1/5→ethyl acetate/hexane=1/3) to obtain chloromethyl (1,3-dioxan-5-yl) carbonate (1.7 g) as a colorless oily product.
Reaction SMILES: C([O:8][C:9](=[O:38])[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:37])[C@@H:15]([NH:29]C(OC(C)(C)C)=O)[CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])C1C=CC=CC=1.[ClH:39]>O1CCOCC1>[ClH:39].[CH2:22]([N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:37])[C@@H:15]([NH2:29])[CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C:9](=[O:38])[OH:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)NCCN(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 270 mg (0.511 mmol) of benzyl-[2-({(2S)-4-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]butanoyl}amino)ethyl]carbamate (Example 110A) and 9 ml of a 4M solution of hydrogen chloride in dioxane is stirred at RT for 2 h. The reaction solution is concentrated, coevaporated with dichloromethane several times and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[CH:6][N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2>CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH:5]([C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)[CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2
Reactant: COC(=O)CC(=Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Yield: 49.8 %

Procedure:
4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-but-3-enoicacid methyl ester (100 mg, 0.266 mmol) was dissolved in MeOH (10 mL) and 10% dry Pd/C (50 mg) was added and hydrogen gas was purged in to the reaction mixture at RT for 12 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was filtered through Celite. The filtrate was concentrated to obtain the crude product, which was recrystallized in ether-hexane to obtained 50 mg of 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyric acid methyl ester. 1H NMR (CDCl3, freebase) δ (ppm): 8.47 (d, 2H), 7.18 (s, 1H), 7.16 (d, 1H), 6.98 (d, 3H), 4.22 (dd, 1H), 4.05 (dd, 1H), 3.7 (m, 2H), 3.57 (s, 3H), 3.5 (dd, 1H), 2.74 (m, 3H), 2.71 (m, 2H), 2.49 (s, 3H), 2.43 (s, 3H), 2.2 (m, 1H). Separation by chiral HPLC provides enantiomers II-223a-b.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)[CH:5]=1)([O-:3])=[O:2].Cl.[CH3:22][O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH2:28][S:29][CH3:30])[NH2:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.COC(=O)[C@H](CCSC)N(C(=O)C1C=CC(N)=CC=1)C(OC(C)(C)C)=O>ClCl.CCN(CC)CC>[CH3:22][O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH2:28][S:29][CH3:30])[NH:26][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: Cc1cc(C)cc(-c2cc([N+](=O)[O-])ccc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1cc(C)cc(C)c1
Yield: 56.8 %

Procedure:
4-nitro-2-(3,5-dimethylphenyl)benzoic acid (0.15 g, 0.55 mmol), methionine methyl ester hydrochloride salt (0.11 g, 0.55 mmol), EDCI (0.11 g, 0.55 mmol), HOBT (0.07 g, 0.55 mmol) and Et3N (0.08 ml) in dry CH2 Cl2 (2.2 ml) were reacted and worked up according to the procedure for N-BOC-4-aminobenzoyl methionine methyl ester in Example 1. After recrystallization from ethyl acetate and hexanes, 0.13 g (58.4%) of pure product was isolated. mp 122-124° C.; 1H NMR (CDCl3) 1.2-1.84 (1 H, m), 1.85-1.97 (1 H, m), 2.01 (3 H, s), 2.05 (3 H, t, J=7.7 Hz), 2.38 (6 H, s), 3.70 (3 H, s), 4.67-4.74 (1 H, m), 6.03 (1 H, d, J=7.9 Hz), 7.05 (2 H, s), 7.09 (1 H, s), 7.84-7.87 (1 H, m), 7.84-7.87 (1 H, m), 8.23-8.26 (2 H, m); 13C NMR (CDCl3), 15.20, 21.26, 29.22, 31.15, 51.79, 52.57, 122.07, 25.11, 126.27, 130.03, 130.53, 137.77, 138.82, 140.29, 141.56, 148.41, 167.14, 171.53.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.OS(O)(=O)=O.[CH3:16]O>C(Cl)Cl>[CH3:16][O:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)cn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A mixture of 5-bromo-2-pyridine carboxylic acid (26.2 g, 0.124 mol) and conc. H2SO4 (12.5 mL) in MeOH (250 mL) was heated to 60° C. and diluted with additional MeOH (250 mL). After 18 h at 60° C., the mixture was cooled to rt, diluted with DCM, and washed with a solution consisting of 21 g KOH in 200 mL water, sat. K2CO3, and water. The organic layer was dried and concentrated to give the title compound (21.4 g, 76%) as a white solid. This material was used in the next step without further purification.