Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: N#Cc1ccc(Br)cc1
Product: Cc1c(C)c(N2CCN(c3ccc(C#N)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 18.6 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (2.74 g, 10.0 mmol) synthesized in Reference example 61 and 4-bromobenzonitrile (2.73 g, 15 mmol), the reaction was carried out in the same manner as Example 23 to synthesis the title compound 700 mg (yield 19%). Melting point was 255 to 257° C. (ethanol).
Reaction SMILES: [I:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.C(O)(=O)C>[OH-].[Na+].C(OCC)(=O)C>[I:1][C:2]1[N:3]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Yield: 86.9 %

Procedure:
A suspension of 2-iodo-4-(methoxycarbonyl)-1-triphenylmethylimidazole (1.978 g, 4 mmol) in 6N sodium hydroxide (15 mL) was heated at reflux for 4 hours. The resulting suspension was diluted with ethyl acetate (20 mL) and then slightly acidified with acetic acid. The resulting clear solution was extracted three times with ethyl acetate (20 mL) and the combined extracts were dried (magnesium sulfate) and concentrated in vacuo. Residual acetic acid was removed under high vacuum to give 2-iodo-1-triphenylmethylimidazole-4-carboxylic acid (1.67 g, 87%) as a white solid, mp 203-205° C.: 1H NMR (CDCl3) δ 7.60 (s, 1H), 7.38-7.20 (m, 9H), 7.18-7.09 (m, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[I-].[K+].[CH3:26][CH:27]=[CH:28][CH2:29][NH2:30]>O1CCCC1>[CH2:28]([CH2:29][NH:30][CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1)[CH:27]=[CH2:26]
Reactant: CC=CCN
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 32, 1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cu][C:12]#[N:13].CN1CCCC1=O.Cl>[Fe](Cl)(Cl)Cl.O>[C:12]([C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1)#[N:13]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cc(F)c(N)c(F)c1
Yield: 57.2 %

Procedure:
21 g of 4-bromo-2,6-difluoroaniline, 11 g of copper (I) cyanide, and 70 ml of N-methyl-2-pyrrolidone were placed in a flask for three hours to form a reaction mixture. The reaction mixture was poured into a solution of 41 g of iron (III) chloride mixed with 13 ml of concentrated hydrochloric acid and 50 ml of water. The mixture was extracted with chloroform and washed with water and 10% potassium hydroxide and the chloroform was removed by distillation. The residue was distilled under reduced pressure (bp 90° to 110° C. at 4 mmHg) and recrystallized with a mixture of hexane and chloroform to yield 8.9 g of 4-cyano-2,6-difluoroaniline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([N+:19]([O-])=O)[CH3:18])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.O.[C].[Pd]>[CH3:13][O:12][C:10](=[O:11])[C@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([CH3:18])[NH2:19])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CCCC(C)(C)[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CCCC(C)(C)N)NC(=O)OC(C)(C)C
Yield: 77.3 %

Procedure:
Methyl (S)-2-t-butoxycarbonylamino-6-methyl-6-nitroheptanoate (500 mg, 1.57 mmol) was dissolved in methanol (8 ml) and water (0.5 ml), and 5% palladium-carbon (219 mg, 50% wet) and ferrous sulfate 7 hydrate (1.32 g, 4.75 mmol) were added. The mixture was stirred at a hydrogen pressure of 3 atm and room temperature for 3 h. Palladium-carbon was removed by filtration and methanol was evaporated by concentration under reduced pressure. Ethyl acetate (50 ml), water (50 ml) and sodium carbonate were added for pH adjustment to 10 and extraction. After layer partitioning, the aqueous layer was extracted again with toluene-isopropyl alcohol (1:1, 100 ml). The organic layers were combined and the solvent was evaporated by concentration under reduced pressure to give the objective compound (350 mg, yield 77.3%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH2:11])[C:8]([NH2:12])=[CH:7][CH:6]=1.[CH:13](O)=O>>[CH3:3][O:4][C:5]1[N:10]=[C:9]2[N:11]=[CH:13][NH:12][C:8]2=[CH:7][CH:6]=1
Reactant: COc1ccc(N)c(N)n1
Reactant: O=CO
Agent: Cl
Product: COc1ccc2[nH]cnc2n1

Procedure:
10.19 g of 6-methoxypyridine-2,3-diamine dihydrochloride were dissolved in 100 ml formic acid and stirred under reflux for 72 h. The formic acid was evaporated under vacuum and the residue was dried under vacuum at 95° C. to give crude 5-methoxy-1H-imidazo[4,5-b]pyridine (as hydrochloride and/or as formic acid salt and/or as free base) that was used for the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]34[CH2:19][CH2:18][C:17]([CH2:22][C:23]([O:25][CH2:26][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:24])([CH2:20][CH2:21]3)[O:16][CH2:15]4)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cn4)cc3)(CC1)CO2
Reactant: OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: Nc1ccc(-c2ccc(C34CCC(CC(=O)OCc5ccccc5)(CC3)OC4)cc2)nc1
Temperature: 130 °C
Yield: 43 %

Procedure:
To a mixture of methyl 2-(4-(4-(5-aminopyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (286 mg, 0.812 mmol) in neat benzyl alcohol (6 mL, 57.9 mmol) was added titanium(IV) isopropoxide (1.5 mL, 5.12 mmol) and 4 A molecular sieves (5 g, 0.812 mmol). The reaction mixture was heated at 130° C. overnight. The reaction was quenched by saturated NaHCO3 and was extracted with EtOAc. The combined organic layer was filtered and washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC (15 to 90% ACN-water (0.1% NH4OH) with X-bridge C18 column) to give the title compound after drying (150 mg, 43% yield). LC/MS, ESI-MS(+): 429.1, RT: 1.41 (Condition E).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CS(C)=O>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:18])=[O:17]
Reactant: Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
A solution of 4-chlorophenol (5.54 g, 43 mmol) in DMSO (75 mL) was treated sequentially with potassium t-butoxide (5.15 g, 46 mmol) then with a solution of 4-fluorophenyl methyl sulfone (5.00 g, 29 mmol) in DMSO (25 mL), heated at 120° C. for 2 hours, cooled to rt, then partitioned between dichloromethane and 1 N sodium hydroxide, dried (Mg2SO4), filtered, and concentrated to give crude product as a white solid. Recrystallization from ethyl acetate and hexane afforded 5.44 g (66%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([F:12])[F:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[N:14]([O-])=O.[Na+].[OH-].[Na+].C(Cl)(Cl)Cl>O.Cl>[Cl:1][C:2]1[C:8]([O:9][CH:10]([F:11])[F:12])=[CH:7][C:5]([NH:6][NH2:14])=[C:4]([F:13])[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(OC(F)F)c(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: NNc1cc(OC(F)F)c(Cl)cc1F
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A mixture of 13.3 g of 4-chloro-2-fluoro-5-difluoromethoxyaniline XIII-1 and 106 ml of hydrochloric acid was stirred at 0° C. A solution of 4.76 g of sodium nitrite in 35.4 ml of water was dropwise added in 10 minutes to the mixture, which was stirred at 0° to 5° C. for an hour. A solution of 35.4 g of stannous chloride dihydrate in 35.4 ml of hydrochloric acid was dropwise added in 15 minutes to the mixture, which was stirred at 0° to 5° C. for 2 hours. The reaction mixture was basified with 10% aqueous sodium hydroxide and shaken with chloroform. The chloroform layer was dried and concentrated, and 12.7 g of the titled compound XIV-1 thus obtained was used for the subsequent reaction without purification.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[CH:9]=[CH:8]2)=[O:4].[NH2:24][CH2:25][C:26]([O-:28])=[O:27].[Na+]>COCCO>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:23])[C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])=[N:14][CH:13]=2)[CH:8]=[CH:9][C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(ccc(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1ncc2c(ccc(=O)n2Cc2ccccc2)c1O
Yield: 74.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.32 mmol) and sodium glycinate (626 mg, 6.45 mmol) in 2-methoxyethanol (10 mL) was refluxed for 2 h. The solvent was evaporated in vacuo, and the residue was dissolved in saturated NaHCO3. The aqueous phase was washed with ether, and then acidified to pH about 2 with 4M HCl. The resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 84 mg of the title compound as a pale yellow solid. MS: (+) m/z 354.02 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](F)[CH:6]=1)[CH:2]=[CH2:3].[CH3:15][NH2:16]>C1COCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([CH:6]=1)[NH:16][CH3:15])[CH:2]=[CH2:3]
Reactant: CN
Reactant: C=CCOc1ccc([N+](=O)[O-])c(F)c1
Solvent: C1CCOC1
Product: C=CCOc1ccc([N+](=O)[O-])c(NC)c1

Procedure:
The title compound of Example 11 Step A (15.2 mmol, 3.01 g) was stirred in 15 mL of 2 M methylamine in THF at 0° C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was partitioned into DCM/brine. The organic phase was concentrated under reduced pressure affording the product as a bright yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.03 (d, 1H), 6.30-6.36 (overlapping m, 2H), 6.06 (m, 1H), 5.44 (m, 1H), 5.31 (m, 1H), 2.96 (d, 3H). MS (ESI): m/z 209 (M+H). HPLC A: 2.20 min.
Reaction SMILES: C(O)C.[CH:4]1([CH2:10][C@@H:11]2[NH:15][C:14](=[O:16])[C:13](C(OCC)=O)=[C:12]2[OH:22])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(=O)=O>O>[CH:4]1([CH2:10][C@@H:11]2[NH:15][C:14](=[O:16])[CH2:13][C:12]2=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)C1=C(O)[C@H](CC2CCCCC2)NC1=O
Agent: O=C=O
Solvent: CCO
Solvent: O
Product: O=C1CC(=O)[C@H](CC2CCCCC2)N1
Yield: 97.4 %

Procedure:
A solution of 1 L of 50% ethanol in water is brought to the boiling point in a large beaker and 68.2 g (0.255 mol) of (S)-5-(cyclohexylmethyl)-2,5-dihydro-4-hydroxy-2-oxo-1H-pyrrole-3-carboxylic acid, ethyl ester is added over about 5 minutes (pot temperature is 82°-84° C.). The solid goes into solution as carbon dioxide evolves. The ethanol is allowed to boil-off over a period of one-half hour (pot temperature is 87° C.). The volume is about 750 ml, a slight turbidity develops and crystals separate on cooling to afford 48.5 g of (S)-5-(cyclohexylmethyl)-2,4-pyrrolidinedione after recrystallization from ethyl acetate; mp 165°-167° C.; [α]D23 =-75° (c=1.1% chloroform).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][OH:13])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([OH:27])(=[O:9])=[O:26].[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][OH:13])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Agent: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a stirred mixture of 31.2 parts of 3-[(2-amino-4,5-dichlorophenyl)amino]-1-propanol hydrochloride in 200 parts of water is added dropwise, during a 15 minutes-period, a solution of 10.6 parts of potassium cyanate in 50 parts of water at a temperature between 15° and 20° C. Upon completion, stirring is continued first for 20 minutes at room temperature and further for 20 hours at reflux. The reaction mixture is allowed to cool over week-end to room temperature. The precipitated product is filtered off and boiled in trichloromethane. The undissolved part is filtered off and boiled in 4-methyl-2-pentanone. After cooling, the product is filtered off and dried, yielding 14.5 parts (48%) of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one; mp. 174.7° C. To a stirred mixture of 13.3 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, 8 parts of N,N-diethylethanamine and 260 parts of dichloromethane are added dropwise 7.4 parts of methanesulfonyl chloride. Upon completion, stirring is continued for one hour at reflux temperature. The reaction mixture is washed with water, dried, filtered and evaporated. The solid residue is shaken with acidified water and 4-methyl-2-pentanone. The whole is filtered (the filtrate is set aside) and the filter-cake is dried, yielding a first fraction of 6.2 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate. The 4-methyl-2-pentanone-phase is separated from the filtrate, dried, filtered and evaporated, yielding a second fraction of 8 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate as an oily residue.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25](O)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH2:22][C:23]#[N:24])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][C:34]=2[N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:36]2)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH2:22][C:23]#[N:24])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2c1
Reactant: Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OCc4ccccc4)C3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(cyanomethyl)quinoline-2-carboxylic acid (46.2 mg, 0.128 mmol), benzyl [(3S)-1-(3-aminopyridin-4-yl)piperidin-3-yl]carbamate (46.6 mg, 0.143 mmol) and HATU (153.3 mg, 0.4032 mmol), DMF (2.00 mL) was added, followed by DIPEA (181.8 mg, 1.406 mmol). The reaction mixture was stirred at room temperature for 15 h, and was then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to give the sub-title compound as a brown solid (65.8 mg, 77%). LCMS calc. for C38H36N7O5 (M+H)+: m/z=670.3. found 670.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][NH2:11]>C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:11][CH3:10])[CH:7]=1
Reactant: CN
Reactant: Cc1cc(Cl)cc(Cl)n1
Solvent: CCO
Product: CNc1cc(Cl)cc(C)n1
Temperature: 100 °C
Yield: 12 %

Procedure:
A mixture of 2,4-dichloro-6-methylpyridine (7.0 g) (West German Patent DE 2162238) and 33% w/v methylamine in ethanol (25 ml) was heated in a sealed tube at 100° C. for 8 hours. The solvent was removed by evaporation and the residual solid was purified by flash chromatography (Merck 9385 Silica, 100 g), using as eluant first an increasing gradient [20%-100% v/v] of diethyl ether in petrol (b.p. 60°-80° C.) and then an increasing gradient of up to 5% v/v methanol in dichloromethane. There was thus obtained 4-chloro-6-methyl-2-methylaminopyridine (0.8 g, 12% yield), m.p. 69°-70° C.; NMR: 2.2-2.3(3H,s, CH3), 2.7-2.8(3H,s,NHCH3), 6.25(1H,s, pyridine-3H), 6.4(1H,s, pyridine-5H), 6.55-6.7(1H,br,NH).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O1CCOCC1.[F-:36].[K+]>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([F:36])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: [F-]
Reactant: Nc1c(Oc2ccc(S(=O)(=O)Cl)cc2)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(Oc2ccc(S(=O)(=O)F)cc2)cc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
To a mixture of 1-amino-4-hydroxy-2-(4-chlorosulphonylphenoxy)anthraquinone (2 parts) and 1,4-dioxane (25 parts), stirring at ambient temperature, was added a solution of potassium fluoride (0.6 parts) in water (5 parts). The mixture was heated to 60° C. and stirred at this temperature for 20 minutes. After cooling to 0°-5° C., the product was isolated by filtration, washed with water and dried at 50° C. to yield: 1-amino-4-hydroxy-2-(4-fluorosulphonylphenoxy)anthraquinone (1.6 parts). λmax=515.0 nm (CH2Cl2).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]3)[CH2:23][CH2:22]2)[CH:18]=[C:17]([CH:36]2[CH2:39][CH2:38][CH2:37]2)[N:16]=1)([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([NH:35][C:8]([C@H:5]4[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]4)=[O:10])[CH2:33][CH2:34]3)[CH2:25][CH2:26]2)[CH:18]=[C:17]([CH:36]2[CH2:39][CH2:38][CH2:37]2)[N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CC[C@H]3CC[C@H](NC(=O)[C@H]4CC[C@H](O)CC4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Trans-4-hydroxycyclohexanecarboxylic acid (1,991 g, 13.81 mmol) was added to a solution of trans-4-(2-(4-(2-(tert-butyl)-6-cyclobutylpyrimidin-4-yl)piperazin-1-yl)ethyl)cyclohexanamine (4.6 g, 11.51 mmol) in dichloromethane. HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate, 5.25 g, 13.8 mmol) and diisopropylethylamine (6.03 mL, 34.5 mmol) were added and the mixture stirred at room temperature for 14 h. The solvent was evaporated and the residue partitioned between dichloromethane and water. The aqueous phase was extracted several times with dichloromethane. The combined organic layers were washed twice with 5% aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. Purification via silica gel chromatography (330 g Reveleris NP cartridge) with di-chloromethane/methanol (0-80%) as eluent yielded 6.05 g of the title compound.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10](OCC)=[O:11])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>C1COCC1>[CH:1]([C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(C(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)c1cccc(CO)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
Ethyl 6-isopropylpicolinate (prepared as in Preparation C; 75 g, 0.39 mol) was dissolved in 1.5 liters of dry THF, chilled to 0° C. and lithium aluminum hydride (0.39 L, 0.39 mol, 1M in THF) was added slowly over a 20 minute period. The resulting dark solution was stirred at 0° C. for 30 minutes, then allowed to warm to ambient temperature. TLC showed complete consumption of starting material. The reaction mixture was chilled to 0° C. and quenched carefully by the addition of sodium sulfate decahydrate until no gas evolution was observed. A thick mixture resulted. Celite and ether (about 200 mL) were added and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 32 g of brown oil. The filter cake was slurried in IPA/EtOAc overnight and filtered to give an additional 8 g of product (68%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[CH3:12][C:11]([NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1)=[O:13]
Reactant: NC[C@@H]1CC[C@H](C(=O)O)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC[C@@H]1CC[C@H](C(=O)O)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a mixture of cis-3-aminomethylcyclopentancarboxylic acid (0.2 g, 1.4 mmol) in pyridine (about 5 mL) was added acetic anhydride (about 1 mL) and the mixture stirred at about 70° C. for about 2 h. The solvent was removed under reduced pressure, water was added several times and evaporated in vacuo. A light, viscous oil was obtained and dried in vacuo over acetone reflux to give 0.25 g (97%) of cis-3-[(methylcarbonylamino)methyl]cyclopentancarboxylic acid.