Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:40]([NH:42][C@H:43]([C:48]([O:50]C(C)(C)C)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[CH2:19][S:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]C(C)(C)C)=[CH:6][CH:5]=1.O>FC(F)(F)C(O)=O.C(S)C>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:40]([NH:42][C@H:43]([C:48]([OH:50])=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[CH2:19][SH:20])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCS
Product: NC(=O)C[C@H](NC(=O)[C@H](CS)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Reaction time: 4 h

Procedure:
2.2 g (2.9 mmol) of H-Tyr(tBu)-Cys(Trt)-Asn-OtBu are dissolved in a mixture of 25 ml of trifluoroacetic acid and 25 ml of ethyl mercaptan. After 4 hours, the mixture is tipped into 250 ml of water. The aqueous solution is extracted 3 times with ether and freeze-dried. Yield 1.05 g (91%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10]([NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)=[O:11].[S].[NH2:25][C:26]1[CH:44]=[CH:43][C:29]([C:30]([N:32]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])=[CH:28][C:27]=1[NH:45][CH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>C(O)C>[ClH:8].[CH3:36][CH:35]([CH3:37])[CH2:34][CH2:33][N:32]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[C:30]([C:29]1[CH:43]=[CH:44][C:26]2[N:25]=[C:9]([C:10]([NH:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=3)=[O:11])[N:45]([CH2:46][CH2:47][CH2:48][N:49]3[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]3)[C:27]=2[CH:28]=1)=[O:31]
Reactant: CCOC(=O)c1ccc(NC(=O)CCl)cc1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCCN2CCCCC2)c1
Agent: [S]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(=O)c2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCN2CCCCC2)cc1
Product: Cl
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (100 μL), ethyl 4-[(chloroacetyl)amino]benzoate (173 mg) and sulphur (12 mg) are successively added to a solution of 4-amino-N,N-bis(3-methylbutyl)-3-[(3-piperidin-1-ylpropyl)amino]benzamide (100 mg) in ethanol (3 ml), placed in a “Personal Chemistry®” reaction tube. The tube is sealed with a cap, placed in the “Personal Chemistry®” microwave and heated under magnetic stirring at 130° C. for 20 minutes. The ethanol is then evaporated off and water and dichloromethane are added to the residue. After decantation and extraction, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the compound by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/ethanol 85:15) produces the expected compound in the form of the free base. The corresponding hydrochloride salt is formed by the addition of a solution of 1N hydrochloric acid in diethyl ether. The precipitate obtained is filtered and dried in order to produce the expected monohydrochloride compound (80 mg, 51% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[O:5][C:4](=O)[CH:3]=1.Cl.[NH2:18][OH:19].NC1C=CC=CN=1.NO>>[OH:19][N:18]1[C:6]([CH2:8][CH:9]([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: Cc1cc(CC(C)CC(C)(C)C)oc(=O)c1
Reactant: NO
Agent: Cl
Agent: Nc1ccccn1
Product: Cc1cc(CC(C)CC(C)(C)C)n(O)c(=O)c1
Yield: 66.5 %

Procedure:
10 g of 4-methyl-6-(2,4,4-trimethylpentyl)-2-pyrone, 5 g of hydroxylamine hydrochloride and 20 g of 2-aminopyridine were heated for 26 hours to 70°C, whereupon after 17 hours a further 2 g of hydroxylamine were added. Working up was effected as usual and there were obtained 7.1 g (67 %) of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone melting at 108° C (Calc.: 5.9 % N, found 5.9 % N).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:24])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2cccc(OC)c2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.5 g of m-methoxyphenyl isocyanate and 40 ml of dimethylformamide, as yellow crystals having the following physical properties.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[N:5]1.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>C(Cl)Cl>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:9]([C:6]3[CH:7]=[CH:8][N:4]([CH:3]=[C:2]([CH3:1])[CH3:12])[N:5]=3)=[O:11])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: CC(C)=Cn1ccc(C(=O)O)n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: ClCCl
Product: CC(C)=Cn1ccc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)n1
Yield: 77.8 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1-(2-methyl-prop-1-en-1-yl)-1H-pyrazole-3-carboxylic acid (1.076 mmol, 179 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (0.897 mmol, 250 mg) using DCM (5 ml) as the solvent. The mixture was diluted with DCM, washed with 1M Na2CO3 and water. The organic phase was dried, filtered and evaporated. The product was purified by flash chromatography. 298 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.12 (d, 3H), 1.80 (d, 3H), 1.84 (d, 3H), 4.27-4.50 (m, 3H), 6.66 (d, 1H), 6.77-6.80 (m, 1H), 7.01 (d, 1H), 7.83 (d, 1H), 7.85-7.89 (m, 2H), 7.95-7.98 (m, 1H), 8.15 (d, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(ON1[C:29](=[O:30])[CH:28]2[C:31](=C=O)[CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:37])C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C(#N)C>[CH:19]1([CH2:18][O:17][C:9]2[CH:8]=[C:7]([CH:2]([N:1]3[C:29](=[O:30])[C:28]4[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]3=[O:37])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=2[O:13][CH:14]([F:16])[F:15])[CH2:21][CH2:20]1
Reactant: NC(CC(=O)O)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CCON1C(=O)C2=CC=CC(=C=O)C2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (0.78 g, 2.9 mmol) and N-ethoxy-carbonyl-phthalimide (0.64 g, 2.9 mmol) in 30 ml of water and acetonitrile (1:1) was added sodium carbonate (0.33 g, 31 mmol). The mixture was stirred at room temperature for 5 hours. 1N HCl was added dropwise until pH=2. The mixture was extracted with ether (2×25 ml). The organic layer was washed with water (2×20 ml), brine (20 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a colorless oil (1.1 g, 91%). 1H NMR (CDCl3): δ 0.32-0.38 (m, 2H), 0.60-0.67 (m, 2H), 1.17-1.28 (m, 1H), 3.33 (dd, J=6, 17 Hz, 1H), 3.79 (dd, J=10, 17 Hz, 1H), 3.86 (d, J=8 Hz, 2H), 4.92 (broad, 1H), 5.74 (dd, J=6, 10 Hz, 1H), 6.58 (t, JH-F=75 Hz, 1H), 7.10 (s, 2H), 7.16 (s, 1H), 7.69-7.74 (m, 2H), 7.78-7.83 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH3:24])[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH3:3].[C:25]([C@:27]1([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)[CH2:29][C@@H:28]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])#[N:26].N1C=CC=CC=1.CCOCC>ClCCl>[CH2:1]([O:4][C@@H:5]([CH3:24])[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:42][C:39]3[CH:38]=[CH:37][C:36]([C@@:27]4([C:25]#[N:26])[CH2:29][C@@H:28]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:41][CH:40]=3)=[O:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH3:3]
Reactant: CCCCCC[C@H]1C[C@]1(C#N)c1ccc(O)cc1
Reactant: CCCO[C@@H](C)C(=O)Oc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCC[C@H]1C[C@]1(C#N)c1ccc(OC(=O)c2ccc(-c3ccc(OC(=O)[C@H](C)OCCC)cc3)cc2)cc1
Reaction time: 3 h
Yield: 46 %

Procedure:
In 10 ml of dichloromethane were dissolved 83 mg of (S)-4-[4-(2-propoxypropanoyloxy)phenyl]benzoyl chloride and 65 mg of (1R,2S)-1-cyano-2-hexyl-1-(4-hydroxyphenyl)cyclopropane. To this solution was added 0.5 ml of pyridine. The resulting mixture was stirred for 3 hours under reflux. The reaction mixture was cooled, and then ether was added thereto. The ethanol phase was separated, washed with diluted hydrochloric acid, water, and then saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate=5/1). Recrystallization from ethanol afforded, thereby obtaining 61 mg of the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([Li])CCC.[CH3:15][Si:16]([CH3:19])([CH3:18])Cl.C(N(CC)CC)C>COCCOCCOC>[CH3:15][Si:16]([CH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])([CH3:19])[CH3:18]
Reactant: Cc1cccc(CO)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: C[Si](C)(C)Cc1cccc(CO)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylbenzylalcohol (6.10 g, 50 mmol) in anhydrous diglyme (200 ml) at -78° C. was added 1.5M butyllithium (100 ml) over 20 min. The resulting mixture was allowed to warm to -20° C. and stirred for 30 min. Then a mixture of trimethylchlorosilane (19.0 g, 175.0 mmol) and triethylamine (5.05 g, 50 mmol) was added and the final solution was stirred at room temperature for 3 hours. The reaction mixture was treated with ice water (200 ml), extracted three times with diethyl ether (100 ml) and the extracts washed twice with water, brine, dried over MgSO4 and concentrated. The crude product was dissolved in 90% aqueous methanol (200 ml) and refluxed for 1 hour. Then the solvents were removed and 3-trimethylsilylmethylbenzylalcohol was purified by fractional distillation.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]1[C:11]([CH3:12])=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:9]([F:19])=[CH:8][N:7]=1.CCOCC.[CH:25](Cl)(Cl)[Cl:26]>>[ClH:3].[Cl:26][CH2:25][C:6]1[C:11]([CH3:12])=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:9]([F:19])=[CH:8][N:7]=1
Reactant: Cc1c(O)ncc(F)c1N1CCOCC1
Reactant: ClC(Cl)Cl
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: Cc1c(CCl)ncc(F)c1N1CCOCC1
Product: Cl

Procedure:
Thionyl chloride (0.73 ml) in chloroform (5 ml, alumina dried) was added dropwise to a stirred and cooled solution of 2-hydroxy-3-methyl-4-morpholino-5-fluoro pyridine (0.75 g) in chloroform (15 ml). After 2 hours at room temperature the solution was reduced in volume and ether added. The precipitate was filtered off, washed and dried to give 2-chloromethyl-3-methyl-4-morpholino-5-fluoropyridine hydrochloride (0.6 g) m.p.148°-156°.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([C:7]1[CH:23]=[CH:22][C:10]2[N:11]=[C:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:13][C:9]=2[CH:8]=1)[CH3:6])C.[OH-].[Na+].C(O)(=O)C>C1COCC1.O>[C:18]([O:17][C:15]([NH:14][C:12]1[S:13][C:9]2[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([OH:24])=[O:3])[CH:23]=[CH:22][C:10]=2[N:11]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(C)c1ccc2nc(NC(=O)OC(C)(C)C)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc2nc(NC(=O)OC(C)(C)C)sc2c1
Temperature: 25 °C

Procedure:
A mixture of 5 (239 mg, 1 mmol) in THF (10 ml) and H2O (10 ml) is stirred at room temperature. Sodium hydroxide (68.2 mg, 2.5 mmol) is added to the mixture. The reaction mixture is stirred for 15 h at room temperature. The reaction mixture is acidified to pH 3-4 with acetic acid. Water is added to the mixture and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Yield: quantitative.
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])C.[C:25]([CH2:27][C:28]([NH2:30])=[O:29])#[N:26].N1CCCCC1>CO>[C:25]([C:27]1[C:28]([OH:29])=[N:30][C:4]([OH:24])=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])#[N:26]
Reactant: N#CCC(N)=O
Reactant: CCCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CO
Product: CCCCCCCCCCCCCCCCc1cc(O)nc(O)c1C#N
Yield: 40 %

Procedure:
3-Oxo-nonadecanoic acid ethyl ester (11.3 mmol), cyanoacetamide (0.95 g, 11.3 mmol) and piperidine (0.95 g, 11.3 mmol) in MeOH (3 mL) were heated under reflux for 24 h. The solvent was evaporated, and the residue was dissolved in hot water. The product was precipitated by addition of concentrated HCl, filtered, washed with ice water and CHCl3 and dried in vaccum to give 3-cyano-2,6-dihydroxy-4-hexadecyl-pyridine as a white powder. Yield: 40%. Anal. C22H36N2O2: Calcd: C, 73.29; H, 10.06; N, 7.77; O, 8.88. Found: C, 73.35; H, 10.12; N, 7.85; O, 8.97. MS (ESIMS): m/z: 360.3.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCOC.[Na].[O:15]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[O:25][C:26](F)=[C:27]([F:32])[C:28]([F:31])([F:30])[F:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[O:15]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[O:25][C:26]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[C:27]([F:32])[C:28]([F:29])([F:30])[F:31])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(Oc1cccc(Oc2ccccc2)c1)=C(F)C(F)(F)F
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: COCCOC
Solvent: O
Product: FC(=C(Oc1cccc(Oc2ccccc2)c1)Sc1ccccc1)C(F)(F)F
Temperature: 75 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
Eleven g (0.1 mole) of thiophenol and 150 ml 1,2-dimethoxy ethane are placed into a flask and stirred under nitrogen while 2.3 g of metal sodium are added in portions. When this reaction is complete, 32 g of 1-(3-phenoxyphenoxy)perfluoropropene are added dropwise causing a slight exotherm. The mixture is stirred at 75° C. for six hours following this addition. After cooling, 150 ml of dilute base water solution is added and the mixture is stirred. The product layer is separated and washed with 150 ml water, separated, dried over sodium sulfate, filtered and distilled to produce the title compound as an oil in a yield of 38 percent. The oil has a pour point of -26° C. and a boiling range of 150° to 190° C. at 0.5 mm Hg.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.Cl.[CH2:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])[CH:11]([CH3:13])[CH3:12]>>[CH2:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH3:8])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: CCC(C)CC(=O)O
Agent: Cl
Product: CCC(C)CC(=O)N[C@@H](C)C(=O)OCC(C)C

Procedure:
Following General Procedure B′ and using 3-methylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>C(O)(=O)C.O.C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:31]([C:30]3[CH:32]=[CH:33][C:27]([C:26]([F:25])([F:34])[F:35])=[CH:28][CH:29]=3)[C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccc(-c3ccc([N+](=O)[O-])cc3)n2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 170 °C
Reaction time: 0.25 h
Yield: 8 %

Procedure:
To a slurry of the product from Example 1A (1.00 g, 3.05 mmol) in acetic acid (30 mL) was added 4-(trifluoromethyl)aniline (1.9 mL, 15 mmol). The mixture was heated to 170° C. for 15 minutes under microwave irradiation. The cooled mixture was diluted with water and diethyl ether and stirred vigorously for 15 minutes and then filtered. The crude product was purified by chromatography on silica gel eluting with a solvent gradient of 0-30% ethyl acetate in hexane. Product containing fractions were combined and concentrated under reduced pressure and then triturated with diethyl ether to give the title compound (110 mg, 8% yield).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].[C:14]([O:18][C:19]([O:21]C(OC(C)(C)C)=O)=O)([CH3:17])([CH3:16])[CH3:15].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCOCC1.O.C(N(CC)CC)C>[C:14]([O:18][C:19]([N:6]1[CH2:7][CH2:8][N:3]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:4]([C:9]([OH:11])=[O:10])[CH2:5]1)=[O:21])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(O)C1CNCCN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C(C(=O)O)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Amine preparation: To a suspension of piperazine-2-carboxylic acid dihydrochloride (10.0 g) in 1,4-dioxane (100 mL) and water (50 mL), cooled down to 0° C., was slowly added 17M sodium hydroxide solution (8.6 mL) followed by di-tert-butyldicarbonate (11.8 g). The reaction mixture was warmed to room temperature and stirred for 5 h. Triethylamine (13.7 mL) followed by methanesulfonyl chloride (3.8 mL) was then added. After stirring for 24 h the reaction mixture was concentrated down, the residue diluted with ethyl acetate, washed with 2M hydrochloric acid, brine, dried (MgSO4) and the solvent removed in vacuo to yield crude 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (8.46 g). This was subsequently dissolved in DMF (50 mL), and was treated with added potassium carbonate (7.5 g) and iodomethane (8.5 mL). After stirring for 24 h the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.27 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[Br:16]Br.[OH-].[Na+]>C(O)(=O)C>[Br:16][C:4]1[C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:12]=[C:13]([O:14][CH3:15])[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1cc2c(cc1OC)CCNCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc2c(c(Br)c1OC)CCNCC2
Temperature: 70 °C

Procedure:
To a solution of 12.8 g. (0.052 mole) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (prepared as in Example 1) in 50 ml. of glacial acetic acid at 55° C. was added 3.0 ml. of bromine (8.8 g., 0.055 mole) dropwise over 1 hour with stirring. After addition was completed, the temperature was raised to 70° C. for 2 hours. The reaction mixture was poured into ice/water and made basic with 40% sodium hydroxide solution. The basic solution was extracted with ethyl acetate and the extract dried over sodium sulfate. Removal of the solvent gave 6-bromo-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine as an oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][NH2:15].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:49](O)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C.C(OCC)(=O)C.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][NH:15][C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To a solution of N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (166 mg, 0.50 mmol) in DMF (3 mL) was added 1-hydroxybenzotriazole hydrate (100 mg, 0.74 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (142 mg, 0.74 mmol), and benzoic acid (73 mg, 0.59 mmol). The reaction mixture was stirred overnight at room temperature. Then it was diluted with ethyl acetate (40 mL) and water (25 mL). The organic layer was washed with saturated NaHCO3 (30 mL) and brine (30 mL), dried (Na2SO4), filtered, concentrated, and dried in vacuo to afford a yellow oil. Purification by radial chromatography on silica gel (1 mm plate; using NH4OH/CH3OH/CH2Cl2; 1:1:100→1:3:100) afforded the product as a yellow foam (80 mg, 37%). 1H NMR (CDCl3) δ 1.68-1.74 (m, 4H), 2.02-2.04 (m, 1H), 2.22 (m, 1H), 2.62-2.69 (m, 2H), 2.81 (t, 1H, J=4.8 Hz), 2.84-2.90 (m, 2H), 3.34-3.38 (m, 1H), 3.55-3.59 (m, 1H), 4.01-4.05 (m, 2H), 7.10-7.18 (m, 4H), 7.32 (t, 2H, J=7.8 Hz), 7.42-7.48 (m, 2H), 7.59 (dd, 2H, J=8.0, 1.5 Hz), 7.65 (br s, 1H), 8.43 (dd, 1H, J=3.9, 1.2 Hz).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[CH:3]=1.[Li][C:14]1[CH:15]=[CH:16]C=[CH:18][CH:19]=1.O.[CH3:21]COCC>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]3[CH:16]=[CH:15][CH:14]=[CH:19][CH:18]=3)=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Cc1ccc2ccc(Br)cc2c1
Reactant: CCOCC
Reactant: [Li]c1ccccc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Product: Cc1ccc2ccc(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Solution of 2-bromo-7-methylnaphthalene (10 g, 45 mmole) in ether (100 ml) was cooled to −0° C., and Ni(dppp)Cl2 and solution of PhLi (obtained from 1.3 g of Mg and 5.6 ml of PhBr in 55 ml of ether) were added subsequently. Reaction mixture was allowed to warm to room temperature, stirred for additional 4 h with heating, cooled room temperature, stirred for additional 16 h, and treated by water (100 ml). Organic layer was separated, water layer was extracted by ether (3×50 ml). Combined organic fraction was evaporated, giving practically pure solid product. The yield 9.23 g (94%).