Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:42])[NH:32][C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]2[C:39]([OH:41])=O)([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[NH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:42])[NH:32][C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]2[C:39]([NH:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[O:41])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Reactant: COC(=O)CCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCNC(=O)[C@H]1CCCC[C@H]1NC(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
To a solution of (1S,2R)-2-(3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)cyclohexanecarboxylic acid (11.6 mg, 0.019 mmol) and methyl 4-aminobutanoate (3.2 mg, 0.027 mmol) in CH2Cl2 (185 μL), was added EDCI (4.6 mg, 0.024 mmol) followed by DMAP (2.9 mg, 0.024 mmol) at room temperature. The reaction mixture was stirred at room temperature until starting material was consumed as indicated by HPLC analysis. The reaction mixture was concentrated to dryness and the resulting residue was taken up in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18; mobile phase: MeCN/H2O/TFA) to provide methyl 4-((1S,2R)-2-(3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)cyclohexanecarboxamido)butanoate as white solid (7.1 mg, 53% yield). LC/MS RT=3.200 min; [M+H] 711.1 (LCMS Method 4), NMR: 500 MHz 1H (CDCl3) 8.19 ppm, 1 H, d, J=2.20 Hz; 7.57 ppm, 1 H, dd, J=8.25, 2.20 Hz; 7.04 ppm, 6 H, m; 6.99 ppm, 2 H, t, J=7.42 Hz; 6.79 ppm, 1 H, d, J=8.25 Hz; 6.52 ppm, 2 H, d, J=7.15 Hz; 6.18 ppm, 1 H, s; 5.78 ppm, 1 H, m; 4.28 ppm, 1 H, d, J=12.65 Hz; 3.87 ppm, 1 H, s; 3.61 ppm, 3 H, m; 3.47 ppm, 2 H, m; 3.40 ppm, 1 H, m; 2.40 ppm, 5 H, m; 1.58 ppm, 9 H, m.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[C:10]([S:16]([CH3:18])=[O:17])[CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C(N(CC)CC)C.O1CCCC1.[P:31](=[O:51])(Cl)([S:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)[O:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[P:31](=[O:51])([S:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)([O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[C:10]([S:16]([CH3:18])=[O:17])[CH:9]=[CH:8][CH:7]=3)[CH:3]=1)[O:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1
Reactant: O=[N+]([O-])c1ccc(SP(=O)(Cl)Oc2ccc(F)cc2)cc1
Reactant: CS(=O)c1cccc2cc3cc(O)ccc3nc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CS(=O)c1cccc2cc3cc(OP(=O)(Oc4ccc(F)cc4)Sc4ccc([N+](=O)[O-])cc4)ccc3nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-5-methylsulfinylacridine (0.01 mole), triethylamine (0.01 mole), tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-(4-fluorophenyl) S-(4-nitrophenyl) phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-(4-fluorophenyl) O-(5-methylsulfinylacridin-2-yl) S-(4-nitrophenyl) phosphorothioate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)C.Br[CH2:18][CH2:19][CH2:20][OH:21].[OH-].[Na+]>O>[OH:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCCOc1ccc(-c2ccccc2)cc1
Yield: 42.6 %

Procedure:
Into a 200 ml flask, 7.82 g (41.1 mmol) of 4-hydroxybiphenyl, 83 ml of ethanol, 6 g (43.2 mmol) of 3-bromo-1-propanol and a NaOH aqueous solution (1.73 g (43.2 mmol) of NaOH/6 ml of water) were sequentially added, and the mixture was heated and refluxed for 6.5 hours. To the reaction solution, 50 ml of water was added, whereupon precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 4.0 g (yield: 43%) of 4-(3-hydroxypropoxy)biphenyl (1) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Yield: 69.2 %

Procedure:
Using 6-chloropyridazine-3-carboxylic acid (1 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.2 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (1.44 g) was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:12]=3[S:11](=[O:23])(=[O:22])[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]=3[N:8]=2)[CH2:3][CH2:2]1.[OH-].[K+].O.C(O)C>O1CCOCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:12]=3[S:11](=[O:23])(=[O:22])[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]=3[N:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2N1CCOCC1

Procedure:
Stir 386 mg (1 mmole) of the ester of Example 19 in a solution of 131.8 mg (2 mmole) of 85% aqueous potassium hydroxide, 1.3 ml of water, 6.5 ml of ethanol and 0.65 ml of dioxane at room temperature under argon for 1 hour. Evaporate to dryness and dissolve the residue in 5 ml of water. Acidify with acetic acid, separate the precipitate by filtration, wash with water and dry. Recrystallize from methanol to obtain the title product (m.p. 200-295 dec).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>O1CCCC1>[C:13]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N+:3]([O-:5])=[O:4])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
1.89 g of sodium hydride (60% content) was suspended in 23.76 g of tetrahydrofuran and cooled with ice. To the obtained suspension, 23.79 g of a tetrahydrofuran solution containing 3.00 g of 2nitroaniline was dropwise added over 1 hour, stirred for 10 minutes, allowed to stand at room temperature and stirred for 30 minutes. To the obtained mixture, 2.41 g of acetic anhydride was added dropwise over 1 hr at room temperature and stirred for 2 hours. Then, water was added to the reaction mixture, and extraction and separation were conducted. The obtained organic layer was analyzed by high performance liquid chromatography to find the yield of the desired product was 84%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[N:9]2)[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)[CH2:6][CH2:7]1
Reactant: CN1CCC(n2cc([N+](=O)[O-])cn2)CC1
Solvent: CO
Product: CN1CCC(n2cc(N)cn2)CC1
Reaction time: 3 h

Procedure:
1-Methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine (132 mg, 0.628 mmol) was dissolved in methanol (6 mL) and the flask was purged with N2. Pd/C (15 mg) was added and the flask was flushed with H2 and stirred under 1 atm H2 (balloon) for 3 hours. The reaction mixture was purged with N2, and filtered through a pad of Celite. The filtrate was concentrated to dryness, yielding 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:24])[NH:11][CH2:12][C@@H:13]([OH:23])[C@@H:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:25]([NH:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH:36]=1)[C:31](O)=[O:32])[CH3:26]>>[CH2:2]([O:9][C:10](=[O:24])[NH:11][CH2:12][C@@H:13]([OH:23])[C@@H:14]([NH:22][C:31]([C:30]1[CH:34]=[C:35]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[CH:36]=[C:28]([NH:27][CH2:25][CH3:26])[CH:29]=1)=[O:32])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Reactant: CCNc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: Cl
Product: CCNc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNC(=O)OCc2ccccc2)cc(N2CCCC2=O)c1

Procedure:
Description 106 was prepared in an analogous manner to Description 105 from 3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzoic acid hydrochloride (D104) and 3-ethylamino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (A31).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][C:22]3[N:26]=[CH:25][NH:24][N:23]=3)[CH:13]=2)=[O:9])=[N:5][C:4]2[S:27][CH:28]=[C:29]([CH2:30][O:31][CH2:32][C:33]3[CH:43]=[CH:42][C:36]([C:37]([O:39]CC)=[O:38])=[CH:35][CH:34]=3)[C:3]1=2.[OH-].[Na+].C1COCC1.CO>O>[O:1]=[C:2]1[NH:7][C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][C:22]3[N:26]=[CH:25][NH:24][N:23]=3)[CH:13]=2)=[O:9])=[N:5][C:4]2[S:27][CH:28]=[C:29]([CH2:30][O:31][CH2:32][C:33]3[CH:43]=[CH:42][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)[C:3]1=2
Reactant: CCOC(=O)c1ccc(COCc2csc3nc(C(=O)NCc4ccnc(OCCCc5nc[nH]n5)c4)[nH]c(=O)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(COCc2csc3nc(C(=O)NCc4ccnc(OCCCc5nc[nH]n5)c4)[nH]c(=O)c23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of ethyl 4-[({[4-oxo-2-({[(2-{[3-(1H-1,2,4-triazol-3-yl)propyl]oxy}pyridin-4-yl)methyl]amino}carbonyl)-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl]methyl}oxy)methyl]benzoate obtained in Example 41 (309 mg, 0.512 mmol), 4N aqueous sodium hydroxide solution (0.64 mL, 2.6 mmol), THF (6 mL), methanol (6 mL) and water (6 mL) was stirred at 100° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid and methanol were added to the residue. The resulting crystals were recrystallized from ethyl acetate to give the title compound as a white powder (221 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[NH4+].[OH-].[CH2:18](O)[CH3:19]>>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:18][CH3:19])=[O:9]
Reactant: Nc1cnccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)c1ccncc1N
Yield: 87 %

Procedure:
To a solution of 1 g (7.25 mmol) of 3-amino-4-pyridinecarboxylic acid in 5 mL of ethyl alcohol was added 2 mL of sulfuric acid. The mixture was warmed under reflux for 2 h. It was cooled and basified with conc. NH4OH solution to pH=8. The resulting solution was extracted with ethyl acetate and the organic layer was washed with brine and water, dried (MgSO4) and concentrated in vacuo to give 1.04 g of the title compound as a white solid (87%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH2:12][C@H:13]1[C:43](=[O:44])[CH2:42][C@H:41]([OH:45])[C@@H:40]([CH3:46])[C@@H:39](/[C:47](/[CH3:58])=[CH:48]/[C@H:49]2[CH2:54][C@@H:53]([O:55][CH3:56])[C@H:52]([OH:57])[CH2:51][CH2:50]2)[O:38][C:36](=[O:37])[C@H:35]2[N:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[C:28](=[O:29])[C:26](=[O:27])[C@:24]2([OH:59])[O:25][C@@H:20]([C@@H:21]([O:61][CH3:62])[CH2:22][C@H:23]2[CH3:60])[C@@H:19]([O:63][CH3:64])[CH2:18][C@@H:17]([CH3:65])[CH2:16][C:15]([CH3:66])=[CH:14]1.C(N(CC)CC)C>C(Cl)Cl.CCOCC>[CH2:12]([C@@H:13]1[CH:14]=[C:15]([CH3:66])[CH2:16][C@H:17]([CH3:65])[CH2:18][C@H:19]([O:63][CH3:64])[C@H:20]2[O:25][C@:24]([OH:59])([C@H:23]([CH3:60])[CH2:22][C@@H:21]2[O:61][CH3:62])[C:26](=[O:27])[C:28](=[O:29])[N:30]2[C@@H:35]([CH2:34][CH2:33][CH2:32][CH2:31]2)[C:36](=[O:37])[O:38][C@H:39](/[C:47](/[CH3:58])=[CH:48]/[C@@H:49]2[CH2:50][CH2:51][C:52](=[O:57])[C@H:53]([O:55][CH3:56])[CH2:54]2)[C@H:40]([CH3:46])[C@@H:41]([OH:45])[CH2:42][C:43]1=[O:44])[CH3:11]
Reactant: CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CCC(=O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Methylsulfide-chlorine complex was prepared by adding oxalyl chloride (0.32 g) into a solution of dimethylsulfoxide (0.44 g) in 4 mL of methylene chloride and stirred at -70° C. for 30 minutes. The solution of the complex was slowly added to a stirred solution of ascomycin (1.6 g) in 5 mL of methylene chloride at -70° C. After stirring for 30 minutes, triethylamine (1.4 g) was added and the mixture was allowed to stir for an additional 30 minutes at -70° C. The reaction mixture was then allowed to warm to room temperature followed by additional stirring for 1 hour. The reaction mixture was diluted with 100 mL of ether, washed with 1N-HCl aq. solution (30 mL×2), brine (30 mL), dried over magnesium sulfate anhydrous, and the solvent removed in vacuo. The crude product was purified on 70 gram of silica gel, eluting with ether to obtain 0.95 g of the title compound.
Reaction SMILES: I.C([O:4][C:5](=[O:19])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[NH:18])[NH2:17])=[CH:12][CH:11]=1)C>Cl.C(O)(=O)C>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][C:5]([OH:19])=[O:4])=[CH:11][CH:12]=1)(=[NH:17])[NH2:18]
Reactant: CCOC(=O)CCCOc1ccc(C(=N)N)cc1
Agent: Cl
Agent: I
Solvent: CC(=O)O
Product: N=C(N)c1ccc(OCCCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The compound (500 mg) obtained in the above (2) is dissolved in a mixture of 1N hydrochloric acid (5 ml) and acetic acid (5 ml), and the mixture is stirred at 50° C. for 8 hours. The reaction mixture is concentrated under reduced pressure, and the residue is dried to give the title compound (388 mg) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=5)[CH:31]=4)[CH:26]=3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:56]OC(=O)NC(C(N1CCCC1C1NC(C2C=CC3C(=CC=C(Br)C=3)C=2)=CN=1)=O)C(C)C.C(OC(N1C(C2NC(C3C=CC(B4OC(C)(C)C(C)(C)O4)=CC=3)=CN=2)C2CC1CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH:9]([C:14]2[NH:15][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:35]6[NH:36][C:37]([CH:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:48])[CH3:49])=[N:38][CH:39]=6)[CH:31]=5)[CH:26]=4)=[CH:23][CH:24]=3)=[CH:17][N:18]=2)[CH:10]2[CH2:56][CH:12]1[CH2:13][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 46 %

Procedure:
This compound was synthesized using the procedure used to make 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester using (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.161 g, 0.322 mmol) and 3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.195 g, 0.419 mmol) to give 3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.133 g, 46% yield). LCMS-ESI+: calc'd for C44H51N7O5: 757.40 (M+); Found: 758.26 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:19])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18])=[O:4].[OH-].[K+]>CO>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:9]1[C:8]([CH3:19])=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1scc(C)c1Nc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1csc(C(=O)O)c1Nc1c(Cl)cccc1Cl

Procedure:
3.16 g (0.1 mole) of 3-(2,6-dichloroanilino)-4-methyl-2-thiophencarboxylic acid methyl ester are boiled in 300 ml of methanol and 100 ml of 6 N potassium hydroxide solution for six hours. Methanol is then distilled off, and the mixture is taken up in water and washed with toluene. The aqueous phase is acidified and extracted with ether. The organic phase is dried, clarified with bleaching earth (for example Tonsil®) and concentrated. Recrystallization of the residue from toluene gives 3-(2,6-dichloroanilino)-4-methyl-2-thiophencarboxylic acid (m. 157° to 158°).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[SH:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.CN(C)C=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Sc2ncccn2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 3.5 g. of 2-amino-4-chloro-1-nitrobenzene, 5.5 g. of potassium carbonate, and 4.5 g. of 2-mercaptopyrimidine in 25 ml. dimethylformamide is heated overnight under nitrogen at 105°-110° C. The mixture is cooled, diluted with water and the product filtered off. Recrystallization from methanol yields 2-amino-1-nitro-4-(pyrimidin-2-ylthio)benzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:4]2[C:22]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].C(N(CC)CC)C.[O:38]1CC[CH2:40][CH2:39]1.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[C:39]([N:19]1[CH2:20][CH2:21][C:22]2[C:4]3[C:5]([S:16][C:17]=2[CH2:18]1)=[N:6][C:7]([CH2:8][N:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]1=[O:14])=[C:2]([Cl:1])[C:3]=3[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:38])[CH3:40]
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCNC4)cc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCN(C(C)=O)C4)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution mixture containing the compound obtained in Example 1 (1 g), triethylamine (343 mg) and tetrahydrofuran (50 ml) was added acetic anhydride (254 mg) while cooling with ice. After stirring for 2 hours at room temperature, the reaction solution was concentrated under reduced pressure. The residue thus obtained was dissolved in ethyl acetate (50 ml), washed with water, dried (MgSO4) and then the solvent was distilled off to obtain the title compound (582 mg, 53%). The product was recrystallized from tetrahydrofuran. A colorless prism crystal. M.p. 266 to 267° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.CC1(C)C(C)(C)OB(/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ncc(/C=C/c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stiffed at 100° C. for 2 hours, then 80° C. for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Br:15]Br.O.[OH-].[Na+]>CO>[Br:15][C:4]1[CH:3]=[C:2]([CH3:1])[S:6][C:5]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)s1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Br)c(NC(=O)OC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
To a solution of tert-butyl 5-methylthiophen-2-ylcarbamate (5.1 g, 23.91 mmol) in MeOH (478 mL) at 0° C. was added drop wise a solution of bromine (1.232 mL, 23.91 mmol) in MeOH (478 mL) during 1.5 h. The reaction mixture was then stirred at 0° C. for 0.5 h and at ambient temperature for 45 min. The reaction was poured into water (400 mL) and the solution was neutralized with 2 M NaOH (aq). MeOH was removed under reduced pressure and the cloudy aqueous phase was extracted with DCM (3×200 mL). The combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure to give (5.3 g, 76%) of the title compound that was used in the next step without further purification: LC/MS (Table 1, Method a) Rt=2.48 min; m/z: 292.1 (M−H)−.