Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.[H][H]>C(O)(=O)C.Cl(O)(=O)(=O)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: O=C(O)/C=C/C(=O)c1ccc(-c2ccccc2F)cc1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(-c2ccccc2F)cc1

Procedure:
13.7 gm (0.05 mol) of 4-(2'-fluoro-4-biphenylyl)-4-oxo-crotonic acid in 100 ml of glacial acetic acid and 2 ml of perchloric acid were hydrogenated in the presence of 4 gm of 5% palladium/barium sulfate at room temperature and at atmospheric pressure; the reaction was finished after absorption of 3 mols of hydrogen. After filtering, the mixture was evaporated in vacuo, the residue distributed between water and ethyl acetate and the ethyl acetate phase was evaporated. The residue was crystallized from cyclohexane. Yield: 11.1 gm (61.4% of theory); m.p. 65°-66° C. Melting point of the cyclohexylamine salt: 130°-132° C. Melting point of the sodium salt: 139°-141° C. Melting point of the isobutylamine salt: 92°-93° C. (from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([C:14]#[N:15])[CH3:13])[CH:6]=2.[Br:30]N1C(=O)CCC1=O>C(#N)C.O>[Br:30][C:6]1[N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)([C:14]#[N:15])[CH3:13])[N:8]=[C:9]2[C:5]=1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10]2
Reactant: CC(C#N)(Cn1cc2ccc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CC(C#N)(Cn1nc2cc(Cl)ccc2c1Br)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 44.3 %

Procedure:
A mixture of N-[2-(6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (25 mg, described in Example 132), and N-bromosuccinimide (10 mg) in acetonitrile (1 mL) was heated to 60° C. for 3.5 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound (12.5 mg, 42%). MS (ES): M/Z [M+H]=501. 1H NMR: (400 MHz, CHLOROFORM-d): 1.90 (s, 3H), 4.82 (d, J=14.3 Hz, 1H), 5.05 (d, J=14.3 Hz, 1H), 7.14 (dd, J=9.0, 1.6 Hz, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.9 Hz, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.93 (d, J=8.8 Hz, 2H) and 8.71 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O.Cl>C(O)C>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[CH:19][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(c1ccccc1)c1ccc(-c2ccccc2)cc1

Procedure:
38.8 g (0.15 mol) of 4-phenylbenzophenone are dissolved in 200 ml of ethanol and 3 g (0.075 mol) of sodium borohydride are added. After heating for 15 hours under reflux, and allowing to cool, the reaction mixture is hydrolyzed with water containing a little hydrochloric acid. The solid thereby produced is purified by recrystallization from ethanol. 36 g (89% of theory) of (biphenyl-4-yl)-phenyl-carbinol [alternatively named as diphenyl-phenyl carbinol or α-(biphenyl-4-yl)benzylalcohol] of melting point 72°-73° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:21])=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1)([O-])=O>CO.[Pd]>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH2:21])[C:4]=2[NH2:1])=[N:12][CH:13]=1
Reactant: Nc1nccc(Nc2ccc(C(F)(F)F)cn2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1nccc(Nc2ccc(C(F)(F)F)cn2)c1N
Reaction time: 17 h

Procedure:
Hydrogenate a mixture of 3-nitro-N4-(5-(trifluoromethyl)pyridin-2-yl)pyridine-2,4-diamine (1.1 g, 0.00368 moles) and 10% Pd/C (150 mg) in 50 mL of MeOH at room temperature under 50 psi of H2 (g). After 17 hours, filter the mixture through Celite, and wash the Celite well with MeOH. Concentrate the filtrate under vacuum to give the title compound as a brown solid. 1H NMR (400 MHz, DMSO-D6) δ 8.81 (s, 1H), 8.41 (s, 1H), 7.819 (d, 1H, J=2.2 Hz), 7.273 (d, 1H, J=1.9 Hz), 6.885 (d, 2H, J=1.9 Hz), 5.685 (bs, 2H), 4.575 (bs, 2H). Mass spec. (270.04, M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:10][C:5]1[C:6]([NH:8][CH3:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CNc1nc(Cl)ncc1N
Temperature: 80 °C
Yield: 54 %

Procedure:
A mixture of 2-chloro-4-(methylamino)-5-nitropyrimidine (3.76 g, 20 mmol, synthesized from the above procedure), tin(II) chloride dihydrate (18.0 g, 80 mmol) in ethanol (200 mL) is heated at 80° C. After heating for 2 hours, the reaction mixture is cooled to room temperature and concentrated. Ethyl acetate and celite is added to the residue and the mixture is basified with saturated sodium carbonate solution to a pH of 9-10. The mixture is filtered through a pad of celite and washed with ethyl acetate. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. Further purification by column chromatography (silica gel, eluting with ethyl acetate) affords the title compound (1.72 g, 54%).
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]([CH:10]=[CH:11][N:12]=[N:13]2)=[C:8]([Cl:23])[CH:7]=1)[CH3:5])=[N+]=[N-].O.CP(C)C>O1CCCC1>[Cl:23][C:8]1[CH:7]=[C:6]([CH:4]([NH2:1])[CH3:5])[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[N:13]2
Reactant: CC(N=[N+]=[N-])c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of peak 1 of 7-(1-azidoethyl)-5-chloro-8-(3-fluorophenyl)cinnoline (0.57 g, 1.7 mmol), from step A, in tetrahydrofuran (9.3 mL) and water (1.8 mL) was treated with 1 M of trimethylphosphine in tetrahydrofuran (2.1 mL, 2.1 mmol) and stirred at 20° C. for 30 minutes.
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][CH2:14][N:15]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:16](=[O:28])[NH:17][C:18]2[S:19][C:20]([S:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][N:22]=2)=[CH:7][CH:6]=1)(=O)=O.BrC1C=CC=CC=1>>[CH3:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:15]([CH2:14][CH2:13][C:12]#[C:11][C:8]2[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=2)[C:16](=[O:28])[NH:17][C:18]2[S:19][C:20]([S:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][N:22]=2)[CH2:30][CH2:31]1
Reactant: CS(=O)(=O)c1ccc(C#CCCN(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1
Solvent: Brc1ccccc1
Product: C[C@H]1CC[C@H](N(CCC#Cc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[3-[4-(4-Methanesulfonyl-phenyl)-but-3-ynyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using bromobenzene.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[C:6]([CH3:27])[C:7]([NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:8][C:9]=2[C:10]([CH3:14])([CH3:13])[CH2:11][CH:12]=1)[CH3:2].[CH:28](=O)[CH3:29]>>[CH2:28]([N:15]([C:7]1[C:6]([CH3:27])=[CH:5][C:4]2[C:3]([CH2:1][CH3:2])=[CH:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=2[CH:8]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(CC)=CCC3(C)C)cc1
Reactant: CC=O
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(CC)=CCC3(C)C)cc1
Yield: 63 %

Procedure:
Following General Procedure D, ethyl 4-(5-ethyl-3,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 55, 0.37 g, 1.0 mmol) was reacted with acetaldehyde (0.56 mL, 10.0 mmol) to give 0.25 g (63%) of the title compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.O.C([O-])(O)=[O:13].[Na+]>OS(O)(=O)=O.C(OC(=O)C)(=O)C>[OH:13][CH2:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C)c(C#N)n1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1ccc(CO)nc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 3,6-dimethylpyridine-2-carbonitrile (4.44 g, 30.0 mmol) and conc. H2SO4 (2 drops) in acetic anhydride (30 mL) was stirred at 100° C. for 16 h, cooled to room temperature, poured into water (100 mL) and basified to pH 8 with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (3×25 mL) and the combined organic phase dried (MgSO4) and concentrated in vacuo. The residue was treated with MeOH (100 mL), water (40 mL) and K2CO3 (8.8 g), stirred at room temperature for 1 h, concentrated in vacuo and partitioned between EtOAc and water. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (2.4 g, 51%) as a yellow oil; NMR δH (400 MHz, CDCl3) 2.57 (3H, s), 4.78 (2H, s), 7.42 (1H, d, J 8.5 Hz) and 7.67 (1H, d, J 8.5 Hz); M/Z 149 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[Br:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:3]=1[O:13][CH2:16][CH2:15][Br:14]
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(Br)cc(Br)c1OCCBr

Procedure:
To a solution of 2,4-dibromo-6-tert-butylphenol (5.00 g, 16.2 mmol) in acetone (70 mL) is added 1,2-dibromoethane (2.80 mL, 32.5 mmol) and K2CO3 (6.70 g, 48.7 mmol). The mixture is heated at reflux for 14 h, and then is filtered and evaporated. The residue is purified by chromatography over SiO2 eluting with hexanes. The resulting oil is distilled to give 1,5-dibromo-(2-bromoethoxy)-3-tert-butylbenzene as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:18][CH2:19][CH3:20])=[O:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][C:26]1[C:35]([O:36][CH3:37])=[CH:34][C:29]2[NH:30][C:31](=[O:33])[S:32][C:28]=2[CH:27]=1>>[CH3:24][O:23][CH2:22][CH2:21][N:17]([CH2:18][CH2:19][CH3:20])[C:15]([CH:13]1[CH2:12][CH2:11][C:10]2[C:3]3[C:2]([NH:25][C:26]4[C:35]([O:36][CH3:37])=[CH:34][C:29]5[NH:30][C:31](=[O:33])[S:32][C:28]=5[CH:27]=4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH2:14]1)=[O:16]
Reactant: CCCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Product: CCCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1

Procedure:
100 mg (272 μmol) (RS)-4-chloro-N-(2-methoxyethyl)-N-propyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 87a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 11.7 mg (8%) of the title compound.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:41])[NH2:40])[CH:35]=2)[CH:30]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:8][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:40])[NH2:41])[CH:35]=2)[CH:30]=1)(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6]
Reactant: C/C=C/C=C/C(=O)O
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: C/C=C/C=C/C(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h

Procedure:
To a solution of 2.0 g of sorbic acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was collected by filtration, washed with ethyl ether, then with acetone, dissolved in methanol, and filtered to remove the insolubles. The filtrate was concentrated under reduced pressure and recrystallized from an ethanol-methanol mixture to yeild 2.4 g of colorless granular crystals 6-amidino-2-naphthyl sorbate methanesulfonate.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([I:14])[CH:10]=[C:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([I:14])[CH:10]=[C:9]1[C:15]([NH2:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(I)cc(C(=O)O)n1Cc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(I)cc(C(N)=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 129A (450 mg) in tetrahydrofuran (12 mL) at 0° C. was added carbonyldiimidazole (642 mg). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C. and ammonium hydroxide (3 mL) was added. The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate, washed with brine and concentrated to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.C[Si](C)(C)[C:18]([F:21])([F:20])[F:19]>C1COCC1.[Cl-].[NH4+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:18]([F:21])([F:20])[F:19])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(Br)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(c1ccc(Br)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled (−20° C.) solution of 2-methyl-propane-2-sulfinic acid 1-(6-bromo-pyridin-3-yl)-meth-(E)-ylideneamide (1.25 g, 4.32 mmol) and tetrabutylammonium triphenyldifluorosilicate (2.6 g, 4.82 mmol) in THF (20 mL) was added a solution of trimethyl(trifluoromethyl)silane (1 g, 7.0 mmol) in THF (10 mL) in several portions. After 30 minutes, the mixture was warmed to room temperature. The reaction was monitored by TLC (ethyl acetate-hexanes 2:8). The mixture was diluted with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography eluting with a gradient of 0-20% ethyl acetate in hexanes. The material from the column was triturated with ether-hexanes to afford 2-methyl-propane-2-sulfinic acid [1-(6-bromo-pyridin-3-yl)-2,2,2-trifluoro-ethyl]-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[C:13]([Cl:19])=[N:14][CH:15]=[N:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[N:16][C:17]=2[Cl:18])=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(Nc1c(Cl)ncnc1Cl)c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 5-amino-4,6-dichloropyrimidine as a white solid as described in Example 1. 1H NMR (CDCl3): 8.95 (d, J=2.4, 1H), 8.78 (s, 1H), 8.25-8.22 (m, 1H), 7.57 (s, 1H), 7.54 (d, J=8.4, 1H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:18]1([NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: Ic1cccc2ccccc12
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(CNc2cccc3ccccc23)cc1
Yield: 69.9 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), 1-iodonaphthlene (146 μl, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rf=0.4) afforded N-(1-naphthyl)benzylamine (163 mg, 70% isolated yield) as light yellow solid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Janin, Y. L.; Bisagni, E. Synthesis 1993, 57–59.
Reaction SMILES: C([Li])CCC.[CH2:6]=[CH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12].C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:33]1CCCC1>>[CH2:8]([C@@H:9]([OH:13])[CH2:10][C@@H:11]1[CH2:12][O:33]1)[CH:7]=[CH2:6]
Reactant: C1CCOC1
Reactant: C=CCC(O)CC=C
Agent: [Li]CCCC
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: C=CC[C@@H](O)C[C@@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium, 129 mL (200 mmol), is added dropwise to a 0° C. solution of 1,6-heptadien-4-ol, 22.4 g (0.2 mol), in 200 mL of anhydrous tetrahydrofuran until the triphenylmethane indicator turned red. Carbon dioxide is then bubbled in for 30 minutes (lecture bottle carbon dioxide passed through drierite) and the light yellow solution is stirred for 30 minutes under a balloon of carbon dioxide. To this solution is added iodine, 101.4 g (04 mol), dissolved in ~200 mL of anhydrous tetrahydrofuran over 60 minutes. The mixture is allowed to warm to room temperature overnight, diluted with ethyl acetate, washed with 10% sodium bisulfite solution, saturated solution of sodium bicarbonate, brine, and dried (magnesium sulfate). The crude product is dissolved in 200 mL of methanol and 20 mL of water, cooled to 0° C. and 0.5 g of solid potassium carbonate is added. The mixture is vigorously stirred for six hours, filtered, concentrated, and partitioned between ethyl acetate and brine. After extracting the aqueous layer 2× with ethyl acetate, the combined organics are washed with brine and dried (magnesium sulfate). Flash chromatography (4:1 hexane-ethyl acetate) provides, after concentration in vacuo, 18 g of (R*,R*)-α-2-propenyloxiraneethanol.
Reaction SMILES: C(O)(C)C.[OH:5][CH:6]([CH2:16][OH:17])[CH2:7][NH:8][C:9]([CH3:15])=[CH:10][C:11]([O:13][CH3:14])=[O:12].[Cl:18][C:19]1[N:20]=[C:21]([N+:27]([O-:29])=[O:28])[C:22]([NH2:26])=[N:23][C:24]=1Cl>C(N(CC)CC)C>[NH2:26][C:22]1[N:23]=[C:24]([C:10](=[C:9]([NH:8][CH2:7][CH:6]([OH:5])[CH2:16][OH:17])[CH3:15])[C:11]([O:13][CH3:14])=[O:12])[C:19]([Cl:18])=[N:20][C:21]=1[N+:27]([O-:29])=[O:28]
Reactant: COC(=O)C=C(C)NCC(O)CO
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)NCC(O)CO)c1nc(N)c([N+](=O)[O-])nc1Cl

Procedure:
To 75 ml of isopropanol is added 3.3 g (0.017 m) methyl 3-(2,3-dihydroxypropyl)amino-2-butenoate (3), 4.18 g (0.02 m) 5,6-dichloro-3-nitropyrazinamine (5), and 2.0 g (0.02 m) triethylamine. This solution is heated at 60°-65° for two days. The reaction mixture is then stripped on the rotary evaporator and the residue chromatographed on silica gel eluted with 12% methanol/chloroform. Material with Rf =0.5 is collected and after crystallization from acetonitrile the desired product is an orange solid, m.p. 184°-186° (dec).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:24][CH:23]2[OH:40])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:24][C:23]2=[O:40])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CCOC(=O)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-[N-(ethoxycarbonyl)amino]phenyl]piperidin-3-ol (600 mg, 1.1 mmol) in 10 ml of dimethylsulfoxide (DMSOI), was added 0.46 ml of triethylamine (3.3 mmol). The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.51 g, 3.3 mmol) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 20 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 320 mg of the titled compound as white color.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]3)[CH:23]=2)[CH:18]=1)[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][C@H:28]3[CH2:29][CH2:30][C@H:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:32][CH2:33]3)[CH:23]=2)[CH:18]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CCN(Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCC(=O)O)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 0 °C

Procedure:
To a solution of ethyl 3-(tert-butoxycarbonyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoate (485 mg, 0.94 mmol) in EtOH (10 mL) was added aqueous NaOH (2 mL, 20%, 5.0 equiv) and refluxed for 2 h. Then the reaction was cooled to 0° C., the pH of the solution was adjusted to 6 using 1M HCl, concentrated and the residue was dissolved in DCM, washed with water, dried and concentrated to give 3-(tert-butoxycarbonyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoic acid as a gray oil (392 mg, 75%). ESI-MS (M+H+): 484.3. 1H NMR (400 MHz, DMSO-d6) δ: 7.79˜7.72 (m, 2H), 7.62˜7.57 (m, 1H), 7.35˜7.26 (m, 2H), 7.14˜7.08 (m, 1H), 4.49 (s, 2H), 4.41˜4.30 (m, 1H), 3.38˜3.26 (m, 2H), 2.33˜2.26 (t, 2H), 2.23˜2.15 (m, 2H), 1.95˜1.84 (m, 2H), 1.47˜1.28 (m, 11H), 1.27˜1.15 (m, 2H), 1.11˜1.02 (m, 1H), 0.87 (s, 9H).