Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([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][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[O:7].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH3:44])[CH:37]=[C:38]([O:42]C)[C:39]=1[O:40][CH3:41].Cl>[N+](C1C=CC=CC=1)([O-])=O.O>[OH:42][C:38]1[C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=[C:36]([CH3:44])[C:37]=1[C:6]([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][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: COc1cc(C)c(C(=O)CCCCCCCCCCCCCCCCCCCCC(=O)O)c(O)c1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Aluminum chloride (2.5 g) is added portionwise in a nitrogen atmosphere to a solution of 1 g of methyl 21-chloroformylheneicosanoate and 1.7 g of 3,4,5-trimethoxytoluene in 50 ml of nitrobenzene, and the resulting mixture is stirred at room temperature for 48 hours. To the reaction mixture are added water and diluted hydrochloric acid, and the whole mixture is extracted with ether. After distilling of the solvent, the residue is dissolved in methanol, 4.6 ml of a 30% sodium hydroxide solution is added, and the mixture is stirred at 60° C. for an hour. The reaction mixture is washed with ether, then made acidic with diluted hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and dried, the solvent distilled off, and the residue chromatographed on silica gel. The crystals recovered from the chloroform-ethanol (17:1) eluate are recrystallized from ether-hexane to give colorless crystals of 21-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)heneicosanoic acid. m.p. 103°-150° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>C(Cl)Cl.CCOCC.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:23]=[N+:24]=[N-:25])=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CSc1ccc(CO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CSc1ccc(CN=[N+]=[N-])cc1
Reaction time: 1 h
Yield: 80 %

Procedure:
A cold (5° C.) solution of 4-methylthiobenzyl alcohol (3.0 g, 19.45 mmol) in CH2Cl2 (60 mL) was treated with triethylamine (2.17 g, 21.4 mmol) and methanesulfonyl chloride (2.45 g, 21.4 mmol). The mixture was stirred for 1 h, then diluted with Et2O and filtered. The filtrate was evaporated to dryness, redissolved in CH3CN and treated with NaN3 (1.52 g, 23.34 mmol) and (Bu)4NCl (0.150 g). The mixture was stirred at room temperature for 18 h, then diluted with ethyl acetate and washed successively with water, dilute NaHCO3 and brine, dried (MgSO4), and finally evaporated. The crude compound was purified by silica gel chromatography (eluted with petroleum ether and CH2Cl2) to afford 2.79 g (80.0%) of the title product as a mobile oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:32])=[O:31])=[CH:22][N:21]=1>>[O:18]=[C:9]1[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]1[CH:5]1[CH2:4][CH2:3][N:2]([C:20]2[N:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[C:23]([C:30]([OH:32])=[O:31])=[CH:22][N:21]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1cnc(Cl)nc1C(F)(F)F
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)nc1C(F)(F)F

Procedure:
The title compound was prepared from 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.70 g) and 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (1.8 g) using the method of example 115 step (ii). Yield 1.1 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].Cl.[O:30]1[CH2:35][CH2:34][CH:33]([NH:36][NH2:37])[CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:36]([CH:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[N:37]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: NNC1CCOCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCOCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with (tetrahydropyran-4-yl)hydrazine hydrochloride (CAS Reg. No. 194543-22-1) to give the title compound as orange oil. MS (ESI): m/z=502.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][C:34]=1[NH:41][C:42]1[N:46]([CH3:47])[C:45]2[CH:48]=[C:49]([N:53]3[CH2:58][CH2:57][CH:56]([C:59]([F:62])([F:61])[F:60])[CH2:55][CH2:54]3)[C:50]([Cl:52])=[CH:51][C:44]=2[N:43]=1>CN(C=O)C.[Cl-].[Na+].O>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:3](=[O:4])[C:2]([F:7])([F:1])[CH3:6])=[CH:35][C:34]=1[NH:41][C:42]1[N:46]([CH3:47])[C:45]2[CH:48]=[C:49]([N:53]3[CH2:54][CH2:55][CH:56]([C:59]([F:61])([F:60])[F:62])[CH2:57][CH2:58]3)[C:50]([Cl:52])=[CH:51][C:44]=2[N:43]=1
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Nc2cc(CNC(=O)C(C)(F)F)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,2-difluoropropanoic acid (37 mg; 0.34 mmol), HBTU (129 mg; 0.34 mmol) and TEA (69 mg; 0.68 mmol) in DMF (1.5 mL) was stirred for 30 min at rt and added to a solution of 4-chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzylamine (161 mg; 0.34 mmol) in DMF (1.5 mL). The resulting mixture was stirred overnight at rt, poured into brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated and the residue was purified by column chromatography.
Reaction SMILES: ClC1(NCC)C=CN(C2C=NC=CC=2)N1.[Cl:16][C:17]1[C:21]([NH:22][C:23](=O)[CH3:24])=[CH:20][N:19]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:18]=1.CC(C)([O-])C.[Na+].C(Br)C.Cl>O1CCCC1>[Cl:16][C:17]1[C:21]([NH:22][CH2:23][CH3:24])=[CH:20][N:19]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:18]=1
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Agent: CC(C)(C)[O-]
Agent: CCNC1(Cl)C=CN(c2cccnc2)N1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCBr
Product: CCNc1cn(-c2cccnc2)nc1Cl
Temperature: 35 °C
Reaction time: 144 h
Yield: 110.1 %

Procedure:
Alternate synthetic route to 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (2-10): To a 3-neck, 100-mL round bottom flask was charged N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (5 g, 21.13 mmol) and tetrahydrofuran (50 mL). Sodium tert-butoxide (4.06 g, 42.3 mmol) was added (causing a temperature rise from 22° C. to 27.6° C.), followed by ethyl bromide (6.26 mL, 85 mmol). The reaction was stirred at 35° C. for 144 h at which point only 3.2% (AUC) starting material remained. The reaction mixture was concentrated to give a brown residue, which was dissolved in 1 N hydrochloric acid (106 mL, 106 mmol) and heated at 80° C. for 24 hours, at which point HPLC analysis indicated that the starting material had been consumed. The reaction was cooled to 20° C. and basified with sodium hydroxide (50 wt % in water) to pH>9. The resulting suspension was stirred at 20° C. for 1 hour and filtered. The filter cake was rinsed with water (25 mL) to afford a brown solid (5.18 g). The resulting crude product was dissolved in ethyl acetate and passed through a silica gel plug (50 g) using ethyl acetate (500 mL) as eluent. The filtrate was concentrated to dryness to afford a white solid (3.8 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27]([OH:29])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic acid (Example 41) (500 mg, 1.156 mmol) in 10% MeOH in DCM (10 mL) was added (trimethylsilyl)diazomethane (2.0 M in diethyl ether) (1 mL). The yellow colored reaction mixture was stirred at room temperature for 30 min. The reaction was concentrated under reduced pressure and was purified by flash chromatography on silica gel (eluent: 0 to 50% EtOAc in hexanes) to give the title compound as a clear oil.
Reaction SMILES: [C:1](OC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C2CC(COC)OC=2C=1)=O)(C)(C)C.[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:61])[N:58]([CH3:60])[CH3:59])=[C:53]([F:62])[CH:52]=2)[C:41]2[CH2:42][C:43]([CH2:46][OH:47])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CI>>[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:61])[N:58]([CH3:59])[CH3:60])=[C:53]([F:62])[CH:52]=2)[C:41]2[CH2:42][C:43]([CH2:46][O:47][CH3:1])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:32])([CH3:34])[CH3:33]
Reactant: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)OC(C)(C)C)cc3c2CC(C)(CO)O3)cc1F
Solvent: CI
Product: COCC1(C)Cc2c(Oc3ccc(C(=O)N(C)C)c(F)c3)cc(C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 201a, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (229a) and methyl iodide. 1H NMR (400 MHz, CDCl3) δ 7.36 (t, J=8.21 Hz, 1H) 7.26 (s, 1H) 7.20 (s, 1 H) 6.78 (dd, J=8.46, 1.89 Hz, 1 H) 6.66 (dd, J=10.74, 1.89 Hz, 1 H) 3.40-3.49 (m, 2 H) 3.39 (s, 3 H) 3.07-3.14 (m, 4 H) 2.97 (s, 3 H) 2.76 (d, J=16.67 Hz, 1 H) 1.56 (s, 9 H) 1.45 (s, 3 H); LCMS for C25H30FNO6 m/z 482.00 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CSCCN1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCSCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, thiomorpholine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.45 minutes; C21H20Cl2N4O2S (463.39); mass spectrum: (M−H)−=462/464/466 (chlorine isotope).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=1)=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)[O:11][CH2:10]2)=[O:6].[N+:37]([CH3:40])([O-:39])=[O:38].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:36][C:2]([F:1])([F:35])[C:3]([CH2:40][N+:37]([O-:39])=[O:38])([C:26]1[CH:27]=[C:28]([Cl:34])[C:29]([Cl:33])=[C:30]([Cl:32])[CH:31]=1)[CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1([CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]1)[O:11][CH2:10]2)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Reactant: C[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.4 %

Procedure:
To the stirred solution of tert-butyl 5′-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 2, 8.6 g, 15.33mmol) in DMF (215 mL) was added nitro methane (8.20 mL, 153.29mmol) and DBU (2.22 mL, 14.87 mmol) at room temperature. Reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, the reaction mixture was quenched with addition of water (250 mL) and extracted with ethyl acetate (2×300 mL). Combined organic layer was washed with LiCl Solution (2×400 mL) and brine (500 mL). Organic layer was dried over sodium sulfate and concentrated to get crude compound sticky solid (11.23 g). Purification was done by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 10% ethyl acetate in n-hexane to afford light yellow sticky liquid (5.10 g, impure-used as such in next step). 1H NMR (400 MHz, CDCl3) δ: 1.48 (s, 9H), 3.95 (d, J=18.72 Hz, 1H), 4.13-4.18 (m, 3H), 4.33-4.36 (m, 2H), 5.17-5.18 (m, 2H), 5.42 (d, J=12.2 Hz, 1H), 5.58 (d, J=12.16 Hz, 1H), 7.20 (s, 1H), 7.31 (s, 1H), 7.60-7.65 (m 1H), 7.78 (d, J=16.92 Hz, 1H), 7.98-8.00 (m, 1H). LC-MS (m/z): 622.9 (M−H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:35]([CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[S:36]([C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=1)(=[O:38])=[O:37])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[C:7]=1[NH:13][C:14](=[O:34])[C@H:15]([CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:16][C:17]([O:19][CH3:20])=[O:18].[Cl-].[NH4+]>C(O)C.C1COCC1.O.[Fe]>[NH2:45][C:42]1[CH:41]=[CH:40][C:39]([S:36]([N:35]([CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[C@H:3]([CH2:2][OH:1])[CH2:4][S:5][C:6]2[CH:11]=[CH:10][NH:9][C:8](=[O:12])[C:7]=2[NH:13][C:14](=[O:34])[C@H:15]([CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:16][C:17]([O:19][CH3:20])=[O:18])(=[O:38])=[O:37])=[CH:44][CH:43]=1
Reactant: COC(=O)N[C@H](C(=O)Nc1c(SC[C@@H](CO)N(CCC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc[nH]c1=O)C(c1ccccc1)c1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)Nc1c(SC[C@@H](CO)N(CCC(C)C)S(=O)(=O)c2ccc(N)cc2)cc[nH]c1=O)C(c1ccccc1)c1ccccc1
Temperature: 74 °C
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
A solution of N-(4-{[(2R)-3-hydroxy-2-{(3-methylbutyl)[(4-nitrophenyl)sulfonyl]amino}propyl]sulfanyl}-2-oxo-1,2-dihydropyridin-3-yl)-Nα-(methoxycarbonyl)-β-phenyl-L-phenylalaninamide (50, 61.3 mg, 0.082 mmol) in ethanol (3 ml), THF (1.5 ml) and water (0.8 mL) was treated with saturated solution of ammonium chloride (298 mg, 5.57 mmol) in water (0.8 mL) followed by addition of powdered iron (80 mg, 1.433 mmol). The mixture was degassed and stirred under N2 at external temperature of 74° C. for 90 min. Diluted with DCM, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated. Purification performed in a column of silicagel eluted with 5% to 35% MeOH in DCM to afford the title compound (27 mg, 45% yield) as pale yellow foam. MS: m/z=722.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:22])[CH2:10][CH:11]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)Br.C(#N)C.[C:27]([O-:30])(=[S:29])[CH3:28].[K+]>CCOCC>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:22])[CH2:10][CH:11]([S:29][C:27](=[O:30])[CH3:28])[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1
Reactant: CC([O-])=S
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CC(Br)C(=O)c1ccc(Br)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)[C@@H]1CCCN1C(=O)CC(SC(C)=O)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.28 g. of 1-[3-(4-bromobenzoyl)-3-bromopropionyl)-L-proline methyl ester (Example 30) in 35 ml. of acetonitrile is added 1.48 g. of potassium thioacetate. The mixture is stirred at room temperature for 2 hours, filtered and the filtrate is evaporated to dryness in vacuo leaving an amber gum. This is dissolved in ether and chromatographed on a 1"×16" silica gel column, eluting with ether and taking 100 ml. cuts. Cut number 3 gives the desired product (1.64 g.) as a glass.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([N+:10]([O-])=O)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Cl.[OH-].[Na+]>[Fe].C(O)C>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1cccc(N)c1

Procedure:
2 G. (0.127 mole) of 3-isopropylnitrobenzene is dissolved in 300 ml. of 50% aqueous ethanol and 23 g. of iron powder is added with good stirring. The reaction mixture is brought to reflux and 13.5 ml. of a solution of 5.2 ml. of concentrated hydrochloric acid in 25 ml. of 50% aqueous ethanol is added while maintaining reflux and stirring. After 1/2 hour of stirring, the reaction mixture is made basic with 2.5 N sodium hydroxide and steam distilled. The distillate is extracted with chloroform and the chloroform layer dried and concentrated by distillation through a short vigreau column under atmospheric pressure. The residue is vacuum distilled. One fraction with boiling point of 117°-118° C. at 18 mm. Hg. contains 15.14 g. of 3-isopropylaniline which is suitable for use in the next step without further purification.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][I:8].[OH:9][C:10]1[C:11](=[O:21])[C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>C1C=CC=CC=1.[Ag]>[I:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:20][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:21])[C:10](=[O:9])[CH:19]=1
Reactant: ICCCCCCI
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag]
Solvent: c1ccccc1
Product: O=C1C=C(OCCCCCCI)c2ccccc2C1=O
Yield: 57 %

Procedure:
A mixture of 1,6-diiodohexane (10.14 g, 30 mmol) and the silver salt of 2-hydroxy-1,4-naphthoquinone (2.81 g, 10 mmol) in benzene (60 mL) was stirred for 12 h at room temperature. The reacton mixture was filtered through Celite, concentrated in vacuo, and purified by flash chromatography (hexane/ EtOAc 4:1) to give a yellow solid (2,19 g, 57%); mp 85-87° C.; 1H NMR (CDCl3) 8.12 (dd, J=6.5, 1.0 Hz, 1H), 7.86 (dd, J=6.9, 0.9 Hz, 1H), 7.70 (dt, J=7.6, 1.5 Hz, 1H), 7.58 (dt, J=7.5, 1.3 Hz, 1H), 5.95 (s, 1H), 4.15 (t, J=6.3, 2H), 3.22 (t, J=6.9 Hz, 2H), 1.80-2.05 (m, 4H), 1.45-2.10 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]3[O:23][CH3:24])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.[ClH:27]>O1CCOCC1>[ClH:27].[ClH:27].[F:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]3[O:23][CH3:24])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC1n1c(C)nc2cc(F)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: COC1CNCCC1n1c(C)nc2cc(F)ccc21
Reaction time: 1.5 h

Procedure:
4-(5-fluoro-2-methylbenzimidazol-1-yl)-3-methoxy-Boc-piperidine (185 mg, 0.23 mmol) was dissolved in 4M HCl in dioxane and stirred for 90 minutes after which all volatiles were removed under reduced pressure. The resulting gummy solid was triturated with diethyl ether to yield 4-(5-fluoro-2-methylbenzimidazol-1-yl)-3-methoxy-piperidine dihydrochloride as an off-white solid (76 mg, quant.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:6][CH2:7][C:8]#[C:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O.[CH3:29][NH:30][NH2:31].C([O-])(=O)C.[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:6][CH2:7][C:8]1[N:30]([CH3:29])[N:31]=[C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=1
Reactant: CNN
Reactant: COc1ccc(OCC#CC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(OCc2cc([C@@H]3CCCN3C(=O)OC(C)(C)C)nn2C)cc1OC

Procedure:
To an EtOH (5.0 mL) solution of the compound (390 mg) obtained in Example 13-(1), methylhydrazine (106 μL) and sodium acetate (246 mg) were added and the mixture was heated under reflux for 20 hours. The reaction mixture was concentrated and a saturated aqueous solution of NH4Cl (50 mL) was added to separate the organic layer, which was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by neutral silica gel chromatography (AcOEt/hexane) to give the titled compound (378 mg, pale brown oil.)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Cl.[CH2:14]([NH:17][C:18](=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[CH2:15][CH3:16].C(N(C(C)C)C(C)C)C>O1CCOCC1.C(OCC)(=O)C>[CH3:27][O:26][C:21]1[CH:20]=[C:19]([C:18](=[O:28])[NH:17][CH2:14][CH2:15][CH3:16])[CH:24]=[CH:23][C:22]=1[NH:25][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: CCCNC(=O)c1ccc(N)c(OC)c1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5 g (21.9 mmol) 2,4-dichloro-5-trifluoromethyl-pyrimidine are dissolved in 50 ml 1,4-dioxane and combined with 5.50 g (21.9 mmol) 4-amino-3-methoxybenzoic acid-propylamide hydrochloride (Journal of Pharmaceutical Sciences 1989, 78(10), 829-32). 7.50 ml (43.8 mmol) ethyldiisopropylamine are added to this reaction mixture and it is stirred for 2 days at ambient temperature. Then the reaction mixture is diluted with 250 ml of ethyl acetate and washed first of all with 300 ml aqueous 10% KHSO4 solution, then with 300 ml saturated, aqueous NaCl solution. The organic phase is dried with MgSO4 and the solvent is eliminated in vacuo.