Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[C:13](=O)[CH:5]3[C:6]4[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=4[CH:8]1[CH:2]2[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=13.[CH3:19][NH2:20].[BH4-].[Na+]>CO.C(O)C>[CH3:19][NH:20][CH:1]1[CH:8]2[C:2]3[C:3]([CH2:18][CH:17]=[CH:16][CH:15]=3)=[C:4]3[CH:13]1[CH:5]3[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=12
Reactant: O=C1C2c3ccccc3C3C1C3c1ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CNC1C2C3=CC=CCC3=C3C(c4ccccc42)C31

Procedure:
An amount of 11.6 g (0.05 mole) of 1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cyclohepten-11-one [V. Ioan, M. Popovici et al.: Tetrahedron Letters 38, 3383 (1965)] is dissolved in 200 ml of methanol, and 50 ml of a 33% solution of methylamine in ethanol added; the whole is heated, with stirring, to 35°, and subsequently stirred for a further hour at ca. 20°, whereby a thick precipitate is formed. There is then introduced into the reaction mixture with stirring, 3.8 g (0.1 mole) of sodium borohydride, with the temperature being maintained at 20° by cooling. The reaction mixture is subsequently stirred for one hour at 20° and then briefly refluxed. After cooling, the reaction mixture is completely concentrated in a waterjet vacuum. The residue is distributed between water and ether, and the ethereal phase extracted with 2N hydrochloric acid. The combined acidified extracts are rendered alkaline with concentrated ammonia and extracted with ether; the combined ether extracts are washed with water, dried over sodium sulphate and concentrated in a waterjet vacuum to obtain N-methyl-1,1a,6,10-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cycloheptene-11-amine; M.P. 142°-143°.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1.[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:29]=2)[C:24](F)=[N:25][CH:26]=1.Cl>C1COCC1.CO>[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[CH2:45][C:46]3[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=3)[N:29]=2)[C:24]([NH:11][C:12]2[CH:17]=[N:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:25][CH:26]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 2 h
Yield: 47.6 %

Procedure:
LiHMDS (1 M in THF, 1250 μL, 1.250 mmol) was added to a solution of 5-amino-2-methoxypyridine (123 mg, 0.990 mmol) and 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (190 mg, 0.396 mmol) in THF (5 mL) under nitrogen at rt. A dark orange mixture formed. After 2 h, HCl (5N, 0.3 mL) was added. The mixture was partitioned between EtOAc-water (10 mL each). The aqueous layer was extracted 3× with EtOAc. The combined organic layers were washed with water 3×, NaHCO3 (satd), dried over MgSO4, and concentrated. The residue was purified on silica (10-80% EtOAc in hexane) to give a yellow oil which, upon trituration with MeOH, resulted in a yellow solid (110 mg). LCMS (ES, pos.): calcd for C31H30ClN7O3: 583.2. found: 584.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.64 (s, 1H); 8.73 (d, J=2.74 Hz, 1H); 8.25 (d, J=2.54 Hz, 1H); 8.19 (d, J=2.74 Hz, 1H); 7.83 (dd, J=9.00, 2.74 Hz, 1H); 7.19 (dd, J=16.43, 8.61 Hz, 4H); 6.78-6.92 (m, 4H); 6.70 (d, J=8.80 Hz, 1H); 4.86 (s, 2H); 4.81 (s, 2H); 3.92 (s, 3H); 3.80 (d, J=9.19 Hz, 6H); 2.57 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[F:30][C:31]1[C:32]([C:44]([F:47])([F:46])[F:45])=[CH:33][C:34]([C:38]2[CH:43]=[CH:42][N:41]=[N:40][CH:39]=2)=[C:35]([OH:37])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O.[Cl-].[NH4+]>[Cl:1][C:2]1[C:3]([O:37][C:35]2[CH:36]=[C:31]([F:30])[C:32]([C:44]([F:47])([F:45])[F:46])=[CH:33][C:34]=2[C:38]2[CH:43]=[CH:42][N:41]=[N:40][CH:39]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1cc(F)c(C(F)(F)F)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(F)c(C(F)(F)F)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Yield: 23 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 247, 63 mg, 0.14 mmol) was added to a mixture of 5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 884, mg, 0.14 mmol) and potassium carbonate (22 mg, 0.16 mmol) in dimethyl sulfoxide (2 mL, 30 mmol). The reaction mixture was stirred at ambient temperature. After 3 hours the reaction mixture was diluted with water and saturated aqueous ammonium chloride and extracted with ethyl acetate (3×). The combined organic layers were washed with water then brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in methylene chloride, concentrated onto diatomaceous earth, and purified by automated flash chromatography (12 g SiO2, hexanes to ethyl acetate) to afford the intermediate 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-[5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide as a glass (22 mg, 23%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([NH:13]C(OC(C)(C)C)=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[ClH:30]>ClCCl.C(OCC)(=O)C>[ClH:30].[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[NH:5][C:6]([C:8]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(N)CCCC1

Procedure:
To a solution of N-[[1-[[(1,1-dimethylethoxy)carbonyl]amino]-1-cyclopentyl]carbonyl]-L-tyrosine methyl ester (3.50 g, 8.6 mmol) in dichloromethane (60 mL) and ethyl acetate (10 mL) is bubbled dry HCl gas for 15 minutes. The solvent is then removed under reduced pressure to give, as a foam, [[1-amino(1-cyclopentyl)]carbonyl]-L-tyrosine methyl ester hydrochloride, the compound of formula III wherein R1 is 4-hydroxyphenyl, R2 is methyl, R3 is acetyl and R4 is isopropyl.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:21](=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:25][CH:24]=2)[CH2:52][CH2:53]1)=[O:69]
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
DIPEA (133 mg, 0.18 mL, 0.56 mmol) was added drop wise to 4-phenylamino-benzoic acid (preparation as described above) (75 mg, 0.35 mmol) in DMF (5 mL). EDCI (167 mg, 0.87 mmol) and HOBT (56 mg, 0.42 mmol) were added. After 10 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its TFA salt form (187 mg, 0.42 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added, filtered the solid precipitated to afford 87 mg (47% yield) of N-{2-[4-(5-Fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LC-MS purity: 88.27%. 1H-NMR (DMSO-D6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.9 (m, 1H), 7.8 (d, 2H), 7.6 (m, 2H), 7.3 (t, 2H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.2 (d, 2H), 3.8 (m, 4H), 3.6 (m, 2H), 3.2 (m, 2H), 3.1 (m, 1H).
Reaction SMILES: Cl.[CH:2]1[C:15]2[C:14](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:25])[CH2:23][NH2:24])[CH2:18][CH2:17]3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[O:25]=[C:22]([N:19]1[CH2:20][CH2:21][C:16](=[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:7][C:6]3[C:15]2=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:17][CH2:18]1)[CH2:23][NH:24][C:34](=[O:35])[O:36][CH2:37][CH3:38]
Reactant: NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Reaction time: 0.25 h

Procedure:
50 mg (0.134 mmol) of 2-[4-(9H-thioxanthen-9-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was dissolved in dichloromethane. 41 mg (0.405 mmol) of triethylamine was added to the obtained solution. A solution of 17.5 mg (0.161 mmol) of ethyl chloroformate in 0.5 ml of dichloromethane was added to the resultant mixture. After stirring for 15 minutes, the product was purified by the thin-layer silica gel chromatography (hexane: ethyl acetate=85:100) to obtain the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:11][O:10][CH2:9]1)(=O)=O.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24].CCN(CC)CC>CC#N>[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][N:24]1[CH2:6][CH2:7][C:8]2([CH2:9][O:10][CH2:11]2)[CH2:12][CH2:13]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)COC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(CN2CCC3(CC2)COC3)c(OC)c1
Yield: 65.2 %

Procedure:
To a solution of (124) (2.0 g, 6.6 mmol) in MeCN (20 mL) were added 2,4-dimethoxy-benzylamine (1.2 g, 7.3 mmol) and Et3N (2.0 g, 19.8 mmol). The solution was allowed to heat at reflux for 12 h. The reaction mixture was then filtered through a pad of silica (washing with 30 percent EtOAc:Petrol ether), and the solvent removed under reduced pressure to give the product (125) (1.2 g, 4.3 mmol, yield: 65%). ESI-MS (M+1): 278 calc. for C16H23NO3 277.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([NH:27][C@@H:28]([CH3:41])[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][C:35]([F:40])=[C:36](I)[CH:37]=2)[CH2:32][CH2:31]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C[Sn](C)(C)C.[F-].[K+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([O:24][C:25]([NH:27][C@@H:28]([CH3:41])[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][C:35]([F:40])=[C:36]([CH3:1])[CH:37]=2)[CH2:32][CH2:31]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: C[C@@H](CN1CCc2cc(F)c(I)cc21)NC(=O)OC(C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Sn](C)(C)C
Solvent: C1CCOC1
Product: Cc1cc2c(cc1F)CCN2C[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 275.6 %

Procedure:
Triphenylphosphine (66 mg, 0.2 mmol) was added in one portion to a stirred solution of palladium(II) acetate (18 mg, 0.06 mmol) in tetrahydrofuran (2.5 mL) under Ar. The mixture was stirred for 5 min then a solution of (S)-1-[2-(tert-butoxycarbonylamino)propyl)-5-fluoro-6-iodoindoline (0.45 g, 1.1 mmol) in tetrahydrofuran (7.5 mL) was added in one portion. The mixture was stirred for 10 min then tetramethyltin (2.0 g, 11 mmol) was added in one portion. The mixture was heated to reflux and stirred for 168 h. After cooling to room temperature, the mixture was poured into an aqueous solution of potassium fluoride (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo to leave a crude oil. The oil was purified by column chromatography [SiO2; ethyl acetate-heptane (1:19)] to give the product (0.17 g, 50%) as a yellow solid; NMR δH (400 MHz, CDCl3) 6.74 (1H, d, J 9 Hz), 6.22 (1H, d, J 5.9 Hz), 4.57 (1H, br. s), 3.82-3.91 (1H, m), 3.31-3.40 (2H, m), 2.89-2.99 (4H, m), 2.05 (3H, s), 1.44 (9H, s), 1.22 (3H, d, J 6.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]([NH:15][C:16]1[CH:21]=[CH:20][C:19](/[C:22](=[N:25]/[H])/[NH:23]O)=[CH:18][CH:17]=1)[C:12]([OH:14])=[O:13].O>C(O)(=O)C.[Ni]>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH:11]([C:4]2[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:12]([OH:14])=[O:13])=[CH:21][CH:20]=1)(=[NH:23])[NH2:25]
Reactant: [H]/N=C(\NO)c1ccc(NC(C(=O)O)c2cc(OC)ccc2OC)cc1
Agent: [Ni]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(OC)c(C(Nc2ccc(C(=N)N)cc2)C(=O)O)c1
Yield: 76.3 %

Procedure:
555 mg of (Z)-(RS)-(2,5-dimethoxy-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid were stirred under hydrogen in 8 ml of acetic acid and 16 ml of water in the presence of Raney-nickel. After the addition 13 ml of acetic acid the solution was filtered clear and evaporated in a vacuum. The residue was triturated in water and then in methanol, filtered off under suction and dried. There were obtained 404 mg of (RS)-(4-carbamimidoyl-phenylamino)-(2,5-dimethoxy-phenyl)-acetic acid, m.p. 310° C., MS: 330 (M+H)+.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:17]1[C:21]([C:22]2[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=2)=[N:20][N:19]=[N:18]1>>[NH:20]1[C:21]([C:22]2[CH:23]=[C:24]([NH:28][S:7]([C:4]3[CH:5]=[CH:6][C:1]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH:25]=[CH:26][CH:27]=2)=[N:17][N:18]=[N:19]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccccc2)cc1
Yield: 58.3 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from biphenyl-4-sulfonyl chloride (14 mg, 0.055 mmol) and [3-(1H-tetrazol-5-yl)phenyl]amine (8 mg, 0.05 mmol) giving 11 mg (60%) of the title product. MS (ESI+) calcd for C19H15N5O2S 377.094645, found 377.094375.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:29][C:10]1([CH3:30])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCN(C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
To a stirred mixture solution of 3,3-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0 g, 2.5 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (840 mg, 90%) as a white solid: LC/MS m/e calcd for C23H29N3O2 (M+H)+: 380.51, observed: 380.0.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][CH2:8]O)[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BrH:20].S(Cl)(Cl)=O>C(Cl)(Cl)Cl.C(O)(C)C>[C:14]1([N:3]2[C:4]3[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=3[N:6]3[CH2:7][CH2:8][N:1]=[C:2]23)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BrH:20]
Reactant: N=c1n(CCO)c2ccccc2n1-c1ccccc1
Agent: Br
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: c1ccc(N2C3=NCCN3c3ccccc32)cc1

Procedure:
A solution of 2,3-dihydro-2-imino-3-phenyl-1H-benzimidazole-1-ethanol [prepared by basification of the hydrobromide (2.23 g.)]and thionyl chloride (1.5 ml.) in chloroform (20 ml.) was heated under reflux for 2 hours. After removal of the solvent the oily residue was dissolved in ethanol (50 ml.), 10N aqueous sodium hydroxide solution (2ml.) added and the solution heated under reflux for 5 hours. After removal of the ethanol the residue was taken up in chloroform, washed twice with water and dried over magnesium sulphate. Removal of the chloroform gave an oil which was taken up in isopropanol and acidified with conc. hydrobromic acid. The isopropanol was evaporated and the residue crystallised from acetone. The product (0.862 g., m.p. 223°-225°C.) was recrystallised from ethanol/ether to give the title compound as its hydrobromide (0.765 g., m.p. 225°-228° C).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH3:9])C.[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH:33]=2)=[N:29][C:28]=1[CH2:43][CH2:44][O:45]S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH:33]=2)=[N:29][C:28]=1[CH2:43][CH2:44][O:45][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:25])=[O:3])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Reactant: CCCCC(Cc1ccc(O)cc1)(Oc1ccccc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCCCC(Cc1ccc(OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
A mixture of 2-(4-hydroxybenzyl)-2-phenoxyhexanoic acid ethyl ester (0.030 mmol) (see Ex 61, Part C), toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester (0.030 mmol) (see Ex. 5, Part B) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-2-phenoxy-hexanoic acid. 1H NMR (400 MHz, CDCl3) δ 8.15–8.12 (m, 1H), 7.79 (d, 1H, J=7.43 Hz), 7.57 (d, 1H, J=7.82 Hz), 7.37–7.32 (m, 2H), 7.24–7.18 (m, 3H), 7.01 (dd, 1H, J=5.08 Hz, J=3.52 Hz), 6.99–6.87 (m, 5H), 6.68 (d, 2H, J=8.99 Hz), 4.10 (t, 2H, J=6.65 Hz), 3.21 (s, 2H), 2.91 (t, 2H, J=6.65 Hz), 2.31 (s, 3H), 2.02–1.88 (m, 2H), 1.34–1.08 (m, 4H), 0.71 (t, 3H, J=7.04 Hz); MS (ES+) calcd for C35H36NO5S: Found m/e 582.2 (M+1, 100%).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][CH:4]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[CH2:3]1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([CH:4]2[CH2:3][CH:2]=[CH:7][CH2:6][O:5]2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(C2CC(Br)CCO2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Brc1ccc(C2CC=CCO2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
To a solution of 4-bromo-2-(4-bromophenyl)tetrahydro-2H-pyran (320 mg, 1.00 mmol) in toluene (5 mL) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (304 mg, 2.00 mmol). The mixture was stirred at 100° C. for 16 hours. The mixture was then diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (150 mg) which contained some impurity of 4-bromobenzaldehyde. 1H NMR (400 MHz, CDCl3) δ ppm 7.48 (d, 2H) 7.30 (d, 2H) 5.92 (m, 1H) 5.82 (m, 1H) 4.52 (dd, 1H) 4.36 (m, 2H) 2.27 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][P:9](=O)([O:18]CC2C=CC=CC=2)[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:33]1([CH2:39][O:40][C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH2:47][C@H:48]([OH:66])[C:49]([N:51]2[CH2:65][CH2:64][CH2:63][C@H:52]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[O:54])=[O:50])=[O:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][P:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([O:66][C@@H:48]([CH2:47][CH2:46][CH2:45][CH2:44][NH:43][C:41]([O:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:42])[C:49]([N:51]2[CH2:65][CH2:64][CH2:63][C@H:52]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[O:54])=[O:50])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NCCCC[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=P(CCc1ccccc1)(OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCCCC[C@H](OP(=O)(CCc1ccccc1)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A mixture of (2-phenylethyl)phosphonic acid, dibenzyl ester (1.48 g., 4.04 mmole, 1.5 eq.) in dry benzene (15 ml.) is treated with phosphorus pentachloride (952 mg., 4.57 mmole, 1.7 eq.) and the solution is heated at 75° (oil bath) for 2.5 hours under argon. The mixture is evaporated to dryness (0.5 mm of Hg.), taken up in benzene (10 ml.), and evaporated. This procedure is repeated twice. The clear residue is taken up in dry methylene chloride (15 ml.), 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-hydroxy-1-oxohexyl]-L-proline, phenylmethyl ester (1.26 g., 2.69 mmole, 1.0 eq.) is added, the mixture is cooled to 0° (ice-bath), then treated with triethylamine (0.56 ml., 4.04 mmole, 1.5 eq.) and dimethylaminopyridine (49 mg., 0.40 mmole, 0.15 eq.), stirred at 0° for 15 minutes, and then at room temperature for one hour. The mixture is partitioned between 5% potassium bisulfate and methylene chloride. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and evaporated to a yellow oil. The crude oil is purified by flash chromatography (LPS-1 silica gel) eluting with hexane:acetone (7:3). Product containing fractions are pooled and evaporated to give 916 mg. of 1-[(S)-2-[[(2-phenylethyl)(phenylmethoxy)phosphinyl]oxy]-6-[[((phenylmethoxy)carbonyl]amino]-1-oxohexyl]-L-proline, phenylmethyl ester as a clear, colorless oil.