Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24](=[O:25])[N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=2[CH3:44])=[CH:15][CH:14]=1>CN(C)C=O.C(OCC)(=O)C>[CH:5]1([CH2:4][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:24](=[O:25])[N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]5[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:28]=4)[C:22]([CH2:41][CH2:42][CH3:43])=[N:21][C:20]=3[CH3:44])=[CH:17][CH:18]=2)[CH2:3][CH2:2]1
Reactant: CCCc1nc(C)c(-c2ccc(O)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(C)c(-c2ccc(OCC3CC3)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of (bromomethyl)cyclopropane (0.17 mL), cesium carbonate (1.7 g) and 4′-{[5-(4-hydroxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g) in N,N-dimethylformamide (5 mL) was stirred for 2 hr at 80° C. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (0.56 g, 100%).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]1=[O:57])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCCCN(CCc2ccccc2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(CCc4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-1-phenethylazepan-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and (S)-3-amino-1-phenethylazepan-2-one (2.9 mg, 0.012 mmol) to give a white solid (2.0 mg, 20% yield). Anal. Calcd. for C45H56N4O6S m/z 780.7. found: 781.7 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.31-7.27 (m, 2H), 7.24-7.19 (m, 6H), 7.18-7.10 (m, 7H), 6.91 (d, J=6.60 Hz, 1H), 6.86 (d, J=6.60 Hz, 1H), 5.32 (t, J=4.95 Hz, 1H), 5.19-5.09 (m, 1H), 5.04-4.92 (m, 1H), 4.50 (dd, J=9.89, 6.60 Hz, 1H), 3.73-3.69 (m, 1H), 3.68 (s, 3H), 3.53-3.39 (m, 2H), 3.24-3.03 (m, 2H), 2.86-2.77 (m, 5H), 2.76-2.67 (m, 2H), 2.43-2.32 (m, 3H), 2.06-1.97 (m, 2H), 1.91-1.83 (m, 2H), 1.79-1.47 (m, 13H).
Reaction SMILES: C(OC([NH:8][CH:9]1[C:39](=[O:40])[N:11]2[C:12]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[NH2:22])[CH2:14][S:15][C@H:10]12)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC>C(#N)C.O>[NH2:8][CH:9]1[C:39](=[O:40])[N:11]2[C:12]([C:23]([O:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[NH2:22])[CH2:14][S:15][C@H:10]12
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(N)c(=O)c3=O)CS[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCCC
Solvent: CC#N
Product: Nc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)c(=O)c1=O
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
Diphenylmethyl 7-(t-butoxycarbonylamino)-3-(2-amino-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate (400 mg, 0.712 mmol) was added to a stirred solution of p-toluenesulfonic acid monohydrate (272 mg, 1.43 mmols) in acetonitrile (1.6 mL). Stirring was continued for 0.5 hr at 22° C., at which time additional acetonitrile (1 mL) and H2O (2 drops) were added. Stirring was continued for an additional 0.5 hr at 22° C. and then for 0.33 hr at a water bath temperature of 35°-40° C. The solution was applied to a Michel-Miller HPLPLC column (22×300 mm, purchased from Ace Glass) containing Partisil Prep 40 ODS-3 (purchased from Whatman Chemical Separation Inc., Clifton, N.J.). The column was eluted with a mixture of 80% acetonitrile-20% H2O (50%) and 0.05M (pH 6.5) ammonium phosphate (50%). The appropriate fractions were combined and acetonitrile was removed on a rotary evaporator. The resulting mixture was extracted with ethyl acetate (3×). The combined extracts were washed (saturated aqueous NaCl), dried (MgSO4), and partially concentrated. Dilution with n-heptane precipitated the title compound as a yellow powder (93.6 mg, 28% yield). Analytical HPLC indicated a purity of 97 area percent.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH:12]2[C:21]([OH:23])=[O:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[C@H](N)C1C=CC=CC=1>CC(O)C>[C:1]1([CH2:7][O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][C@H:12]2[C:21]([OH:23])=[O:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CCc2ccccc2N1C(=O)OCc1ccccc1
Agent: C[C@H](N)c1ccccc1
Solvent: CC(C)O
Product: O=C(O)[C@@H]1CCc2ccccc2N1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
(±)-1,2,3,4-Tetrahydro-1-phenylmethoxycarbonyl-2-quinolinecarboxylic acid (243 g) was dissolved with warming in 2-propanol (1170 ml) and this solution was treated with (S)(-)-α-methylbenzylamine (100 ml). After stirring overnight, the solid product was filtered and dried to constant weight at 60°; yield 160 g, m.p. 135°-148°, [α]D20 -25.6° (c 1, methanol). This crystalline salt was recrystallized from 2-propanol (1400 ml) and washed with ether (400 ml); yield 108 g, m.p. 155°-159°, [α]D20 -50.0° (c 1, methanol). This product was again recrystallized from 2-propanol (1100 ml) and washed with ether (500 ml); yield 84 g, m.p. 159°-160°, [α]D20 -54.9° (c 1, methanol). This salt was added to a mixture of ethyl acetate (500 ml) and 5% aqueous potassium hydrogen sulfate (1000 ml) and stirred for one hour. The layers were separated and the aqueous layer extracted with additional ethyl acetate (250 ml). The organic phase and extract were combined and washed with water (500 ml), dried over magnesium sulfate and activated charcoal, and concentrated to an oily residue which rapidly crystallized to yield (S)(-)-1,2,3,4-tetrahydro-1-phenylmethoxycarbonyl-2-quinolinecarboxylic acid, 57 g, m.p. 75°-79°, [α]D20-82.9° (c 1, methanol). This product was dissolved in methanol (400 ml) and hydrogenated over 5% Pd on carbon (2.0 g) at 40 psi for three hours. The catalyst was filtered and the filtrate concentrated under reduced pressure to an oily residue. Addition of concentrated hydrochloric acid (30 ml) to the residue gave (S)(-)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid hydrochloride; yield 23.6 g, m.p. 172°-176°, [α]D20 -17° (c 1, 0.5 N HCl).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][NH:25][C:24]1=[O:29].N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:23]4[CH2:28][CH2:27][CH2:26][NH:25][C:24]4=[O:29])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C1NCCCN1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C(NCc1cn(-c2ccc(N3CCCNC3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 110 °C
Yield: 5.3 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 prepared in Example 1 (80 mg, 0.18 mmol), tetrahydro-2-pyrimidinone (54 mg, 0.54 mmol), 1,2-trans-diaminocyclohexane (13 μL, 0.11 mmol) and K3PO4 (100 mg, 0.47 mmol) in dioxane (1 mL) was degassed with Ar before being charged with CuI (20 mg, 0.11 mmol). The mixture in a sealed tube was heated at 110° C. overnight. It was then purified by HPLC to give the title compound (4 mg). MS 416.1 and 418.1 (M+H, Cl pattern).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH:11]([C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])[CH2:12][O:13][CH2:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[F:22])=O)(C)(C)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[ClH:1].[F:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1[CH2:14][O:13][CH2:12][CH:11]([C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])[CH2:10][NH2:9]
Reactant: Cc1cccc(C)c1C(CNC(=O)OC(C)(C)C)COCc1c(F)cccc1F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1C(CN)COCc1c(F)cccc1F

Procedure:
A strong current of HCl gas is piped into a solution of 23 g (57 mmol) of N-tert.-butoxycarbonyl-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine in 23 ml of ethyl acetate for 3 min. The mixture is left to react for 30 min, the solvent is eliminated in vacuo and the residue taken up in 30 ml of toluene. The solvent is again eliminated in vacuo and the residue crystallised from ether. Yield: 18.5 g (95%), melting point: 123° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([C:19]1[CH:20]=[C:21]([NH:25][C:26]([CH:28]2[CH2:32][S:31][CH:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[N:29]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:27])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CI.[C:48](=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:11]([C:19]1[CH:20]=[C:21]([N:25]([CH3:48])[C:26]([CH:28]2[CH2:32][S:31][CH:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[N:29]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:27])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1C(C(=O)Nc2cccc(C(=O)c3ccccc3)c2)CSC1c1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)C1CSC(c2cccnc2)N1C(=O)OC(C)(C)C)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.33 h
Yield: 45 %

Procedure:
Lithium hexamethyl disilazide (0.6 mL, 1.0M in hexanes) was added at 0° C. under nitrogen to a solution of N-(3-benzoylphenyl) 2-(3-pyridinyl)-3-tert-butoxycarbonyl-4-thiazolidinecarboxamide prepared as described in example 2 (202 mg, 0.41 mmol), in dry THF (4 mL, 0.1 mL). The mixture was stirred for 20 min then methyl iodide (25 μL) was added and the mixture stirred for an additional 8 hours. The reaction mixture was partioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfated and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with hexanes:ethyl acetate (12:3) to yield the desired product (0.53 g, 45%).
Reaction SMILES: [Na].[CH3:2][C:3]([SH:6])([CH3:5])[CH3:4].Br[CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[Cl-].[Na+]>C(O)C.O>[CH3:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[CH2:8][S:6][C:3]([CH3:5])([CH3:4])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(C)(C)S
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)(C)SCC(=O)C(C)(C)C
Temperature: 0 °C

Procedure:
To a solution of 5.8 g (0.25 mol) of sodium metal in 175 ml of absolute ethanol is added, dropwise, 24.4 g (0.27 mol) of 2-methyl-2-propanethiol. The stirred solution is heated for 20 minutes, cooled, and treated in a dropwise manner with 44.8 g (0.25 mol) of 1-bromopinacolone, prepared according to the procedure of J. Am Chem Soc., 74, 4507 (1952). This reaction mixture is heated at reflux for 20 minutes, cooled, and poured onto 200 g of ice and water. After being saturated with sodium chloride, the mixture is extracted with four portions of ether. The combined ether extracts are dried over anhydrous magnesium sulfate, filtered, and stripped of solvent. Distillation of the residue through a short Vigreaux column gives the desired product. Properties of this, and similar compounds prepared by substantially the same procedure using the appropriate mercaptans and haloketones, are given in Table 1.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.CC(C)([O-])C.[K+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:1][S:2][C:3]1[C:4]2[C:5](=[CH:9][N:10]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[N:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CSc1ncnc2cn[nH]c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncnc2cn(-c3ccc([N+](=O)[O-])cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (500 mg) in N,N-dimethylformamide (10 mL) was added potassium tert-butoxide (405 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Subsequently, 1-fluoro-4-nitrobenzene (465 mg) was added, and the mixture was stirred at 70° C. for 30 min. After the completion of the reaction, water was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant solid was collected by filtration, washed with diisopropyl ether and dried to give the title compound (860 mg) as brown crystals.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4](O)[CH2:3]1.CS([Cl:23])(=O)=O>N1C=CC=CC=1>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([Cl:23])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1C[C@H](O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: c1ccncc1
Product: CN1C[C@H](Cl)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 80 °C

Procedure:
To a solution of 5 g of 6-methyl-8β-hydroxyergoline in 80 ml of pyridine, 3.2 ml of methanesulfonyl chloride were slowly added at room temperature. The mixture obtained was heated at 80° C. for about 3 hours and then evaporated. The residue was taken up with chloroform and washed with saturated aqueous sodium bicarbonate solution and then water. Evaporation of the organic solvent yielded a residue which was chromatographed over a silica gel column using cyclohexane:acetone 8:2 by volume as eluant. Fractions containing the product were combined and crystallized from methanol to give 3.8 g of 6-methyl-8β-chloro-ergoline, m.p. 195°-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].[OH-].[Na+].Cl>C(Cl)Cl.C(OCC)(=O)C>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30]
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 2.14 g (9.63 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 40 ml of dry methylene chloride, add 1.83 g (16.87 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.24 g (12.33 mmol) of triethylamine and a suspension of 1.53 g (8.22 mmol) of 4-nitrobenzoyl chloride in 10 ml of dry ethyl acetate. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization in dioxane/H2O . This yields 1.33 g (43%) of 4-[2-(4-nitrobenzoylamino) benzoylamino] butanoic acid as a cream-coloured solid.
Reaction SMILES: C1COCC1.C1(C)C=CC=CC=1.[Br:13][C:14]1[CH:15]=[C:16]([Mg]Br)[CH:17]=[C:18]([CH3:20])[CH:19]=1.[CH2:23]([N:30]1[CH2:35][CH:34]=[C:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[CH2:23]([N:30]1[CH2:31][CH2:32][CH:33]([C:36]([O:38][CH3:39])=[O:37])[CH:34]([C:16]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([Br:13])[CH:15]=2)[CH2:35]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1=CCN(Cc2ccccc2)CC1
Reactant: Cc1cc(Br)cc([Mg]Br)c1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1CCN(Cc2ccccc2)CC1c1cc(C)cc(Br)c1
Temperature: -15 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A 2.5 M THF/toluene solution of (3-bromo-5-methylphenyl)magnesium bromide (40 mL, 99 mmol) was cooled to −15° C., and methyl 1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (9.85 g, 42.6 mmol) in benzene (17.5 mL) was slowly added for 3 h at −15° C. The reaction mixture was stirred additional 2 h at −15° C. and warmed to 20° C. The reaction was quenched by addition of saturated NH4Cl aqueous solution followed by extraction with EtOAc. The combined organic solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to give methyl 1-benzyl-3-(3-bromo5-methyl-phenyl)piperidine-4-carboxylate (12.2 g, 30.3 mmol).
Reaction SMILES: Cl.[CH2:2]([P:4]1(=[O:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:3].[C:11]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:2]([P:4]1(=[O:10])[CH2:9][CH2:8][N:7]([C:25](=[O:26])[CH2:24][C:21]2[CH:20]=[CH:19][C:18]([C:16]([O:15][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:17])=[CH:23][CH:22]=2)[CH2:6][CH2:5]1)[CH3:3]
Reactant: CCP1(=O)CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCP1(=O)CCN(C(=O)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Ethyl-1,4-azaphosphinane 4-oxide hydrochloride (233 mg, 1.27 mmol), [4-(tert-butoxycarbonyl)phenyl]acetic acid (200 mg, 0.847 mmol), EDC (325 mg, 1.69 mmol), HOBT (259 mg, 1.69 mmol), and DIEA (296 μl, 1.69 mmol) were combined in DMF (4 mL) and stirred at room temperature overnight. The solution was diluted with saturated NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) afforded the title compound as a colorless oil. MS: cal'd 366 (MH+), exp 366 (MH+).
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].[C:13]([OH:16])(=[S:15])[CH3:14]>>[C:13]([S:15][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([OH:7])=[O:6])(=[O:16])[CH3:14]
Reactant: C=CCCCC(CCC)C(=O)O
Reactant: CC(O)=S
Product: CCCC(CCCCCSC(C)=O)C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A mixture of 2-propyl-6-heptenoic acid (1 g) and thioacetic acid (450 mg) was heated for 4 hours at 60° C. and allowed to stand overnight at ambient temperature in an air-tight container. Excess thioacetic acid was evaporated under reduced pressure to give oil of 7-acetylthio-2-propylheptanoic acid (0.9 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[NH:27]1[CH:31]=[N:30][N:29]=[N:28]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:5]([CH2:4][CH2:3][CH2:2][N:28]3[N:29]=[N:30][CH:31]=[N:27]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: c1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3ncnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=430.5 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[N:10][C:9]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:15][C:9]1[N:10]=[N:11][C:12]([Cl:14])=[CH:13][C:8]=1[N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1
Reactant: C1=CCNCC1
Reactant: Clc1cc(Br)c(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(N2CC=CCC2)c(Cl)nn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
1,2,3,6-Tetrahydropyridine, (1.04 ml) was added to a stirred solution/suspension of 4-bromo-3,6-dichloropyridazine (2.0 g, 8.8 mmol) and potassium carbonate (2.4 g) in dry DMF (10 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 5 hours. The reaction was poured into water (100 ml) and extracted with ethyl acetate (×3). The combined extracts were washed with water (200 ml), brine, dried (MgSO4), filtered and evaporated. The residue was triturated with ether/petroleum ether to afford a white powder (1.96 g, 97%). 1H NMR (250 MHz, CDCl3) 6.82 (1H, s), 5.97 (1H, m), 5.80 (1H, m), 3.77 (2H, m), 3.59 (2H, m), 2.38 (2H, m). MS (ES+) 232 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].Br[CH2:14][C:15]([O:17]C)=[O:16].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O>[C:10]([C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[O:1][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])[CH3:11]
Reactant: COC(=O)CBr
Reactant: COc1ccc(O)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(OCC(=O)O)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-hydroxy-5-methoxyphenyl)ethanone (25.0 g), methyl bromoacetate (15.5 mL) and N,N-dimethylformamide (250 mL) was added potassium carbonate (31.1 g), and the mixture was stirred overnight at room temperature. The insoluble material was filtered off, 1N hydrochloric acid was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a brown solid. To a mixture of the obtained solid, tetrahydrofuran (300 mL) and ethanol (300 mL) was added 1N aqueous sodium hydroxide solution (300 mL), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. 1N Hydrochloric acid (300 mL) was added to the residue at 0° C., and the resulting precipitate was collected by filtration to give the title object compound (34.2 g, quantitative) as a white solid.