Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[S:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.Cl>C(Cl)Cl>[O:11]=[C:5]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: c1ccsc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1cccs1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
Anhydrous aluminium chloride (15.8 g, 0.12 mol) was added to a solution of succinic anhydride (11.9 g, 0.12 mol) in dry CH2Cl2 (50 MI) and the reaction mixture was cooled to 0° C. A solution of thiophene (10.0 g, 0.12 mol) in CH2Cl2 (50 MI) was then added dropwise maintaining the same temperature. The reaction mixture was allowed to warm up to room temperature and stirred for 8 h. The mixture was then cooled to 0° C. and the Ph was adjusted to ˜3 using 6N HCl. The organic product was extracted with CH2Cl2. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10% MeOH in CH2Cl2), to get 4-oxo-4-(thiophen-2-yl)butanoic acid (8.3 g, yield 38%). 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.00-7.98 (m, 2H), 7.26-7.23 (m, 1H), 3.21-3.18 (m, 2H), 2.58-2.55 (m, 2H). MS (ESI) m/z: Calculated for C8H8O3S: 184.02. found: 184.9 (M+H)+
Reaction SMILES: Cl[Si](C)(C)C.C([BH3-])#N.[Na+].[CH:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:21]3[S:22][C:23]([CH3:66])=[CH:24][C:25]=3[O:26][C@@H:27]3[CH2:32][C@H:31]([CH2:33][O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C@@H:30]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C@H:29]([O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C@H:28]3[O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1.C(Cl)Cl>C(#N)C>[CH:10]1([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][C:21]3[S:22][C:23]([CH3:66])=[CH:24][C:25]=3[O:26][C@@H:27]3[CH2:32][C@H:31]([CH2:33][O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C@@H:30]([O:42][CH2:43][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C@H:29]([O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C@H:28]3[O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:17][CH:18]=2)[CH2:11][CH2:12]1
Reactant: Cc1cc(O[C@@H]2C[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(C(=O)c2ccc(C3CC3)cc2)s1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc(O[C@@H]2C[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(Cc2ccc(C3CC3)cc2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
In a nitrogen stream, chlorotrimethylsilane (0.46 mL, 3.56 mmol) and sodium cyanoborohydride (230 mg, 3.65 mmol) were added to an solution of (4-cyclopropylphenyl)-[5-methyl-3-((1R,2S,3S,4R,5R)-2,3,4-trisbenzyloxy-5-benzyloxymethylcyclohexyloxy)thiophen-2-yl]methanone (237 mg, 0.30 mmol) in acetonitrile (5 mL) under cooling with ice and the reaction mixture was stirred at 0° C. for one hour. Methylene chloride was added thereto and the mixture was subjected to Celite filtration, and the solvent of the filtrate was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (135 mg, 58%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][CH:8]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1>>[CH2:29]([O:28][C:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:9]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:7]([CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)=[CH:8]2)=[CH:25][CH:24]=1)=[O:27])[CH3:30]
Reactant: COc1ccc2[nH]cc(Cc3ncc[nH]3)c2c1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Product: CCOC(=O)c1ccc(Cn2cc(Cc3ncc[nH]3)c3cc(OC)ccc32)cc1

Procedure:
This compound was prepared as described in Example 4 using 3-(1-imidazolylmethyl)-5-methoxyindole and ethyl (α-bromo-p-toluate) as starting materials. The fumarate salt hemihydrate had m.p. 113°-114° C. Found: C, 63.10; H, 5.29; N, 7.82. C23H23N3O3.C4H4O4.1/2H2O requires: C, 63.02; H, 5.48; N, 8.16%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH3:20])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NCC2CCCC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)CC2CCCC2)c1C
Temperature: 80 °C
Yield: 96.6 %

Procedure:
To a stirred solution of methyl 5-chloro-3-((cyclopentylmethyl)amino)-2-methylbenzoate (1.0 g, 3.5 mmol) in acetonitrile (10 mL), cesium carbonate (2.3 g, 7.1 mmol) and methyl iodide (5.0 g, 35 mmol) were added. The mixture was heated at 80° C. for 12 h. cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated and then purified by column chromatography to afford the title compound (1.0 g, 95%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[NH:18][CH:17]=2)[CH2:9][CH2:8]1.CN(C)[CH:27]=[O:28]>>[CH3:6][N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[NH:18][C:17]=2[CH:27]=[O:28])[CH2:11][CH2:12]1
Reactant: CN1CCN(CCCc2c[nH]c3c2CCCC3)CC1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
POCl3 (1.8 mL, 18.9 mmol) was added dropwise to N,N-dimethylformamide(DMF, 3.8 mL, 51.6 mmol) at −5° C. The mixture was then allowed to come to room temperature and then stirred for 30 minutes after which it was again cooled to −5° C. A solution of 3-[3-(4-methylpiperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole (4.5 g, 17.2 mmol) in DMF (9 mL) was added dropwise. The mixture was again allowed to come to room temperature and then stirred at that temperature overnight. The reaction was then quenched with ice, followed by 10 N NaOH to adjust the pH to 10-11. After stirring at room temperature for 1 hr, the reaction was extracted with ethyl acetate (EtOAc), the organic layer separated, washed with brine, dried and concentrated to give 3.1 g (62%) of 3-[3-(4-methylpiperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde.
Reaction SMILES: Br[C@H:2]([CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[C:15]([OH:18])(=[S:17])[CH3:16].[H-].[Na+]>CN(C)C=O>[C:15]([S:17][C@@H:2]([CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[C:3]([OH:5])=[O:4])(=[O:18])[CH3:16]
Reactant: CC(O)=S
Reactant: CCC(c1ccccc1)[C@@H](Br)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(c1ccccc1)[C@H](SC(C)=O)C(=O)O
Reaction time: 3 h
Yield: 78 %

Procedure:
A solution of (R)-2-bromo-3-phenylpentanoic acid in dimethylformamide is added to a solution of thioacetic acid (1.5 equivalents) and sodium hydride (2.5 equivalents) in anhydrous dimethylformamide. The mixture is stirred for 3 hours at a temperature close to 20° C. After customary treatment, (S)-2-acetylthio-3-phenylpentanoic acid is obtained with a yield of 78% in the form of a yellow oil having the following characteristics: Rf =0.44 [methylene chloride/methanol (9:1 by volume)].
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15](C(O)=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1N=C(N2CC[N:31]([CH2:34][C:35]3[CH:43]=[CH:42][C:38](C(O)=O)=[CH:37][CH:36]=3)[C:30]2=[O:44])SC=1.C(N)C1C=CC=CC=1>>[CH2:34]([NH:31][C:30](=[O:44])[C:5]1[CH:4]=[CH:3][C:2]([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])=[CH:7][CH:6]=1)[C:35]1[CH:43]=[CH:42][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1csc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)n1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1csc(N2CCN(Cc3ccc(C(=O)NCc4ccccc4)cc3)C2=O)n1
Yield: 60 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-((3-(4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid to react with benzylamine, the title compound was obtained as a white powder in 60% yield: mp 185-186° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=9.0 Hz, 2H), 7.30-7.28 (m, 6H), 6.73 (t, J=6.0 Hz, 2H), 6.41 (s, 1H), 4.59 (d, J=6.0 Hz, 2H), 4.44 (s, 2H), 4.05-4.00 (m, 2H), 3.40-3.35 (m, 2H), 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 158.7, 155.9, 147.2, 139.6, 138.2, 134.0, 128.7, 128.3, 127.9, 127.6, 127.5, 106.9, 47.6, 44.0, 42.3, 41.9, 17.3; MS (ES+) m/z 407.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](Cl)[CH:7]=[C:6]2[CH3:14].[CH3:15][OH:16].C[O-].[Na+]>O>[CH3:15][O:16][C:8]1[CH:7]=[C:6]([CH3:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2nc(Cl)cc(C)c2c1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2nc(OC)cc(C)c2c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A 1-liter, four-necked round bottom flask equipped with a mechanical stirrer, condenser, thermowatch and addition funnel was charged with 6-methoxy-4-methyl-2-chloroquinoline (3) (20.75 g, 0.1 moles) and methanol (250 ml). Methanolic sodium methoxide (25%, 108 g, 0.5 moles) was added over 15 minutes. The resulting mixture was heated to reflux and held for 24 hours. Additional methanolic sodium methoxide was added (25%, 42 g, 0.2 moles) and the reaction was refluxed an additional 21 hours. The mixture was cooled to 60° C. and water (200 ml) was added slowly. The slurry was cooled to 10° C., the product isolated by suction filtration, washed with water, and air dried. Yield was 17.9 g (88.2%); mp=58-59° C.; purity by HPLC=100 area %.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([CH3:19])(O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[I:25]I>C(#N)C.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:19])[C:9]=2[I:25])=[CH:4][CH:3]=1
Reactant: CC(O)(C#Cc1ccc(Cl)cc1)Cc1ccccc1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1I
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-methyl-1-phenylbut-3-yn-2-ol (3D) (1.77 g, 6.53 mmol) in acetonitrile (50 mL) was added sodium bicarbonate (1.097 g, 13.06 mmol), followed by iodine (4.974 g, 19.60 mmol). The reaction mixture was stirred for 1.5 h, then diluted with diethyl ether. The organic layer was washed with 1 M sodium thiosulfate solution (50 mL). The aqueous layer was back-extracted with diethyl ether and the combined organic layer was dried (MgSO4), filtered, concentrated, adsorbed onto silica gel and purified by flash column chromatography (silica gel, hexanes) to give 3E as an off-white solid (1.8733 g). 1H-NMR: 300 MHz, (CDCl3) δ 7.74 (d, J=6.6 Hz, 1H), 7.73 (s, 1H), 7.48-7.40 (m, 3H), 7.24-7.20 (m, 2H), 7.13 (d, J=8.1 Hz, 2H), 2.64 (s, 3 H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](OB(O)O)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22]1[N:23]=[C:24]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:38]([N:35]1[CH2:34][CH2:33][N:32]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:31]=[C:22]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:12][CH:13]=3)[N:23]=2)[CH2:37][CH2:36]1)[CH3:39]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: OB(O)Oc1ccc(CCOCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1CCN(c2nc(-c3ccc(CCOCc4ccccc4)cc3)cc3ccccc23)CC1
Yield: 72.3 %

Procedure:
4-(2-Benzyloxyethyl)phenylboric acid (0.40 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.65 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.09 g) in toluene (50 ml) and a 10% aqueous solution of sodium carbonate (30 ml) in nitrogen atmosphere for 1 hr. To the mixture was additionally added 4-(2-benzyloxyethyl)phenylboric acid (0.40 g), and the mixture was heated under reflux for 1.5 hr. 4-(2-Benzyloxyethyl)phenylboric acid (0.40 g) was again added, and the mixture was heated under reflux overnight. The organic layer was separated, and it was extracted with 2N hydrochloric acid twice. The resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system, and then ethyl acetate/acetone system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(2-benzyloxyethyl)phenyl]isoquinoline (0.48 g) as a colorless viscous oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][S:10][C:9]1=[N:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH3:25])[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:28][N:29]([CH3:31])[CH3:30])[S:10][C:9]1=[N:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH3:25])[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=CN(C)C)C(=O)N1Cc1ccccc1
Temperature: 125 °C
Reaction time: 20 h
Yield: 61.6 %

Procedure:
To a solution of 3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-ethylamino-benzonitrile (84 mg, 0.24 mmol) in toluene (1.0 mL, anhyd) was added N,N-dimethylformamide dimethyl acetal (1.0 mL, 7.5 mmol). The reaction mixture was heated at 125° C. After 20 h, the mixture was cooled and chromatographed (silica gel, DCM) to afford the title product (60 mg, 62%) as a pale yellow solid. 1H-NMR (CDCl3): δ 7.60 (1H, s), 7.24-7.40 (6H, m), 7.15 (1H, d), 6.46 (1H, d), 5.09 (2H, s), 4.14 (1H, br t), 3.12 (6H, s), 2.98 (2H, m), 0.99 (3H, t); MS (ESI): 406 (MH+).
Reaction SMILES: C([Li])CCC.[CH:6]([O:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[CH:12][CH:11]=1)([CH3:8])[CH3:7].[CH:22](N1CCOCC1)=[O:23]>O1CCCC1>[CH:6]([O:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][C:15]2[S:16][C:17]([CH:22]=[O:23])=[CH:18][N:19]=2)=[CH:12][CH:11]=1)([CH3:8])[CH3:7]
Reactant: CC(C)Oc1ccc(Oc2nccs2)cc1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2ncc(C=O)s2)cc1
Reaction time: 4 h
Yield: 100.3 %

Procedure:
Butyl lithium (20 mL, of 2.5M solution, 0.05 mol) at −78° C. over 15 minutes was added to a solution of Example 1B (11.8 g, 0.05 mol) in dry tetrahydrofuran. After one hour at the same temperature, formylmorpholine (5.8 g, 0.05 mol) was added drop wise and the mixture was stirred for 4 hours and then quenched with sat. NH4Cl. The aqueous layer was extracted with ethyl acetate and the organic phase washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and purified on silica gel (5˜35% ethyl acetate in hexane) to give 13.2 g of product as a yellow oil, 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (d, J=5.88 Hz, 6H) 4.46-4.61 (m, 1H) 6.88-6.98 (m, 2H) 7.12-7.23 (m, 2H) 7.93 (s, 1H) 9.83 (s, 1H). MS (ESI), m/z 264.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:28])([CH2:15][N:16]1[N:20]=[C:19]2[C:21]([Cl:27])=[CH:22][C:23]([Cl:26])=[C:24]([Cl:25])[C:18]2=[N:17]1)[C:13]#[N:14]>C1COCC1>[C:13]([C:12]([NH:11][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:28])[CH2:15][N:16]1[N:20]=[C:19]2[C:21]([Cl:27])=[CH:22][C:23]([Cl:26])=[C:24]([Cl:25])[C:18]2=[N:17]1)#[N:14]
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(I)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-iodobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (3.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=534, RT=0.73 min.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=1)([F:4])[CH3:3].C(OCC)C.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:11]=[O:12])([F:4])[CH3:3]
Reactant: CC(F)(F)c1cccc(CO)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(F)(F)c1cccc(C=O)c1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Add a solution of [3-(1,1-Difluoro-ethyl)-phenyl]-methanol (3.47 mmol) in dichloromethane (10.5 mL) dropwise to a suspension of 3,3,3-triacetoxy-3-iodophthalide (3.64 mmol) in dichloromethane (10.5 mL) at room temperature. Stir for 30 minutes. Add diethyl ether (10 mL) and 5% aqueous sodium bicarbonate (10 mL) containing sodium thiosulfate (3 g). Mix well for 20 minutes. Separate the layers, and extract the aqueous with ethyl ether. Combine the organic layers, wash with brine, dry over sodium sulfate, filter, and evaporate to give a yellow solid. Purify over silica (40 g) eluting with 0 to 50% dichloromethane in hexanes. Evaporate until most solvent is removed being careful not to drive off the volatile product. Dry additionally by blowing a nitrogen stream over the product to give the title compound in 70% yield. 1HNMR (400.43 MHz, CDCl3): δ 10.03 (s, 1H), 8.00 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 1.98-1.89 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH2:29]([O:28][C:26]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@@H:12]([CH3:17])[CH2:13]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: C[C@H]1CNCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1

Procedure:
To a solution of 3.0 g (S)-2-Methyl-piperazine-1-carboxylic acid benzyl ester hydrotrifluoroacetate in 17 ml dichloromethane were added at 0° C. 7.1 ml triethylamine and 1.2 ml ethyl chloroformate. After 12 h the reaction mixture was diluted with dichloromethane and extracted with 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the crude product obtained after evaporation purified by chromatography on silica using heptane/ethyl acetate 2/1 as eluent. Yield: 3.5 g.
Reaction SMILES: CO[C:3](=[O:24])[CH2:4][CH:5]([NH:20]C(=O)C)[CH2:6][CH:7]([OH:19])[CH2:8][CH:9]([NH:15]C(=O)C)[CH2:10][C:11]([O:13][CH3:14])=[O:12].[ClH:25].Cl.[CH3:27][O:28][C:29](=[O:44])[CH2:30][CH:31]([NH2:43])[CH2:32][C:33](=[O:42])[CH2:34][CH:35]([NH2:41])[CH2:36]C(OC)=O>>[ClH:25].[ClH:25].[ClH:25].[ClH:25].[CH3:27][O:28][C:29](=[O:44])[CH2:30][CH:31]([NH2:43])[CH2:32][CH:33]([OH:42])[CH2:34][CH:35]([NH2:41])[CH2:36][C:3](=[O:24])[CH2:4][CH:5]([NH2:20])[CH2:6][CH:7]([OH:19])[CH2:8][CH:9]([NH2:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CC(N)CC(=O)CC(N)CC(=O)OC
Reactant: COC(=O)CC(CC(O)CC(CC(=O)OC)NC(C)=O)NC(C)=O
Agent: Cl
Product: COC(=O)CC(N)CC(O)CC(N)CC(=O)CC(N)CC(O)CC(N)CC(=O)OC

Procedure:
When an equivalent quantity of 3,7-diacetylamino-5-hydroxy-1,9-nonanedioic acid dimethyl ester is substituted for the N-acetyl-3-aminoglutaric acid dimethyl ester of Example 6 and the procedures detailed therein substantially repeated there is obtained 3,7,11,15-tetramino-5,13-dihydroxy-9-oxo-1,17 heptadecanedioic acid dimethyl ester tetrahydrochloride which has the following structural formula ##STR28##
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[H][H]>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccccc1C#CCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1CCCO

Procedure:
Step 2--A mixture of methyl o-(1-hydroxy-2-propyn-3-yl)benzoate (CXIX, 5.91 g) in methanol (60 ml) is hydrogenated at 40 psi hydrogen for 9 hrs using a total of 900 mg. Palladium on carbon (10%) is added in equal portions three times during the course of the reaction. The reaction is filtered and concentrated to give the saturated ester, methyl o-(1-hydroxyprop-3-yl)benzoate (CXXI).
Reaction SMILES: Br.[CH3:2][C@@:3]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4]1.[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:4]2[CH2:5][CH2:6][CH2:7][C@@:3]2([CH3:2])[C:8]([OH:10])=[O:9])=[O:18])=[CH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@@]1(C(=O)O)CCCN1
Agent: Br
Product: C[C@@]1(C(=O)O)CCCN1C(=O)c1ccc(C#N)cc1

Procedure:
By reacting 2-methyl-L-proline hydrobromide with p-cyanobenzoyl chloride analogously to Example 2b) there is obtained 1-(p-cyanobenzoyl)-2-methyl-L-proline, MS (EI): 213 (M--COOH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:26]([Cl:42])=[CH:25][N:24]=1>>[Cl:42][C:26]1[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.025 g, 35%). MP: 54-76° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.34 (s, 1H), 8.53 (d, 1H, J=8.6 Hz), 8.13 (s, 1H), 7.97 (s, 1H), 7.88 (d, 1H, J=7.8 Hz), 7.59-7.53 (m, 1H), 7.48 (s, 1H), 7.26-7.20 (m, 1H), 6.65 (s, 1H), 3.87 (s, 3H), 3.57-3.51 (m, 2H), 3.48-3.42 (m, 2H), 3.33 (s, 6H), 3.06-2.98 (m, 1H), 2.87-2.67 (m, 14H). MS: 605.50 (MH)+.