Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12](B3OC(C)(C)C(C)(C)O3)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[C:32]2=[C:33](Br)[CH:34]=[C:35]([CH:36]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]3)[N:31]2[N:30]=[CH:29][N:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[NH2:26][C:27]1[C:32]2=[C:33]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:34]=[C:35]([CH:36]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]3)[N:31]2[N:30]=[CH:29][N:28]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 100 °C
Yield: 38.1 %

Procedure:
To a stirred suspension of Intermediate C (2.62 g mg, 7.85 mmol) and tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate (2.50 g, 6.54 mmol) in degassed DMF (6.7 mL) was added solid potassium phosphate (4.16 g, 19.62 mmol) followed by water (833 uL, 49 mmol). The reaction mixture was taken through three purge-fill cycles using nitrogen and vacuum. The reaction was then heated (100° C.) for 1 h and then cooled to rt. The mixture was partitioned between ethyl acetate (200 mL) and H2O (100 mL). The layers were separated and the organic layer was washed 6 times with brine to remove DMF (50 mL each), dried (Na2SO4), and concentrated to dryness. The crude residue was purified by ISCO® chromatography using a gradient of 50 to 100% ethyl acetate in dichloromethane to afford 1.27 g (38%) of the desired product as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.93 (s, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.35-7.30 (m, 4H), 7.15 (d, 1 H), 6.66 (s, 1H), 5.64 (s, 2 H), 3.9-3.7 (m, 1 H), 3.50-3.30 (m, 4H), 2.42 (m, 1H), 2.13 (m, 1H), 1.38 (s, 9H); ES-MS m/z 510.3 [M+H]+, HPLC RT (min) 3.16.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:28](Br)[C:29]1[C:30]([CH3:35])=[CH:31][CH:32]=[CH:33][CH:34]=1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C(#N)C.C(O)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4[CH2:35][C:30]5[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: Cc1ccccc1C(Br)Br
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCN4Cc5ccccc5C4)CC3)noc2c1

Procedure:
A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:26].[CH3:27][CH:28]([CH3:33])[CH2:29][CH2:30][CH2:31]N.S>C(O)C>[ClH:26].[CH3:27][CH:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25]
Reactant: CC(C)CCCN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: Cl
Agent: S
Solvent: CCO
Product: CC(C)CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 16 h
Yield: 64.1 %

Procedure:
A solution of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2 g) and 4-methylpentylamine hydrochloride (7.4 g) is absolute ethanol (30 cc) is saturated with hydrogen sulphide. The reaction mixture is then brought for 16 hours to a temperature in the region of 105° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The pasty residue (5 g) is purified by chromatography on a column (height: 35 cm; diameter: 3 cm) of silica gel (0.2-0.063 mm), eluting successively with methylene chloride (500 cc) and then with a mixture (95:5 by volume) (500 cc) of methylene chloride and methanol, collecting 30-cc fractions. Fractions 25 to 28 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (2.16 g) is dissolved in ethyl acetate (10 cc), and a 3.3N solution (1.5 cc) of hydrochloric acid in isopropyl ether is added with stirring, followed by ethyl ether until a persistent cloudiness has formed. After 1 hour at a temperature in the region of 5° C., the solid formed is drained, washed with ethyl ether (3×10 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-(4-Methylpentyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide hydrochloride (1.7 g) is thereby obtained in the form of a yellow solid, m.p. 186° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[C:21]([CH2:22][N:23]3C(=O)C4=CC=CC=C4C3=O)=[N:20][N:19]=[C:18]2[CH2:34][N:35]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=O.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]3[C:18]([CH2:34][NH2:35])=[N:19][N:20]=[C:21]3[CH2:22][N:23]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[C:6]=2[CH:16]=1
Reactant: O=C(c1ccccc1Cl)c1cc(F)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 22, 5-fluoro-2'-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-fluoro-1-(aminomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:12]([CH2:26][NH2:27])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:12]([CH2:26][NH:27][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CNC(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
1H-NMR (300 MHz, CDCl3): δ 7.27 (d, 2H, J=9 Hz), 6.88 (d, 2H, J=9 Hz), 6.01 (s, 2H), 3.81 (s, 3H), 3.78 (d, 1H, J=14 Hz), 3.62 (d, 1H, J=14 Hz), 3.46 (m, 1H), 3.12-2.70 (m, 5H), 2.60 (m, 1H), 1.55 (s, 9H). 2-Amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (70% pure, 0.2 g, 0.347 mmol) was dissolved in a mixture of anhydrous dichloromethane (5 ml) and triethylamine (72 μl) and cooled in an ice-bath and stirred under nitrogen. Benzoyl chloride (40 μl, 1.0 eq) was added dropwise and the reaction was stirred for 5 minutes, then warmed to ambient temperature and stirred for an additional 16 hours. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (20 ml) and washed with 0.5 N hydrochloric acid (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo, which afforded 0.15 g of crude 7-(benzoylamino-methyl)-2-amino-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>CO.O>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][S:12]([O-:15])(=[O:14])=[O:13].[Na+:16]
Reactant: BrCc1nc2ccccc2o1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(=O)([O-])Cc1nc2ccccc2o1
Temperature: 60 °C
Reaction time: 6 h
Yield: 135.2 %

Procedure:
To a solution of 3.0 g of 2-bromomethylbenzoxazole [prepared according to the procedures described in Belgian Pat. No. 624,463] in 40 ml of methanol was added a solution of 1.9 g of sodium sulfite in 40 ml of water. The mixture was heated with stirring at 60° C. for 6 hours and concentrated under reduced pressure to give crude sodium benzoxazole-2-methanesulfonate (4.5 g). To the sodium salt was added 15 ml of phosphorus oxychloride and the mixture was heated under reflux for one hour. The removal of the remaining phosphorus oxychloride by distillation under reduced pressure gave the desired product as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6](=[O:17])[NH:5][C:4](=[O:18])[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:27](Cl)(=O)[C:28]([CH3:31])([CH3:30])[CH3:29]>N1C=CC=CC=1>[CH2:20]([N:19]1[C:3]2[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:2]=2[N:1]=[C:27]1[C:28]([CH3:31])([CH3:30])[CH3:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(Cn2c(N)c(NCc3ccccc3)c(=O)[nH]c2=O)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(Cn2c(=O)[nH]c(=O)c3c2nc(C(C)(C)C)n3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.5 %

Procedure:
Compound C4 (10.2 g, 29.0 mmol) was dissolved in pyridine (10 mL), to the solution was added pivaloyl chloride (3.50 mL, 30.5 mmol, 1.1 equivalents), and then the mixture was stirred at room temperature for 24 hours. After the reaction solution was concentrated, ethyl acetate was added to the resulting residue, and the deposited solid (7.51 g, 59%) was collected by filtration. The resulting solid was dissolved in 2 mol/L aqueous sodium hydroxide (50 mL), the mixture was refluxed with heating for 1 hour, and the reaction mixture was adjusted to pH 6 with 4 mol/L hydrochloric acid under ice cooling. The deposited solid was collected by filtration and dried under reduced pressure to obtain the title compound (6.61 g, 92%).
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13](=[O:22])[NH:12]1.[C:23](Cl)(Cl)=[S:24]>ClCCl>[N:7]([CH2:8][CH2:9][CH2:10][CH:11]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13](=[O:22])[NH:12]1)=[C:23]=[S:24]
Reactant: S=C(Cl)Cl
Reactant: COC(=O)CN1C(=O)NC(CCCN)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CN1C(=O)NC(CCCN=C=S)C1=O
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
100 ml of a saturated solution of sodium hydrogen carbonate are added to a suspension of 2.65 g (10 mmol) of (11.1) in 30 ml of dichloromethane. After stirring for 10 min while cooling with ice, 1.53 ml (20 mmol) of thiophosgene are added to the methylene chloride phase. The mixture is stirred for 10 min, while cooling with ice, the phases are separated and the water phase is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate. 2.04 g (75%) of (11.2) are obtained after filtering and removing the solvent in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[C:6](Cl)[N:7]=1.[F:10][C:11]1[CH:12]=[C:13]([SH:21])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[C:6]([S:21][C:13]2[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=[C:11]([F:10])[CH:12]=2)[N:7]=1
Reactant: Clc1nnc(Cl)c(Cl)n1
Reactant: Fc1cc(S)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cc(Sc2nc(Cl)nnc2Cl)cc(C(F)(F)F)c1

Procedure:
To a solution of 3,5,6-trichloro-1,2,4-triazine (3 mmol) in dry THF (30 mL) at −78° C. under nitrogen atmosphere is added 3-fluoro-5-(trifluoromethyl)benzenethiol (3 mmol) and sodium carbonate (3 mmol). The reaction is allowed to reach room temperature and is stirred at room temperature until formation of the desired compound. The solvent is evaporated. The residue is suspended in water and extracted with CH2Cl2. The dichloromethane solution is dried over MgSO4 and evaporated. The residue is chromatographed on a silica gel column.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.CCN(CC)CC.Cl[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][N:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:37]([O:39][CH3:40])=[O:38])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)Cl
Reactant: COc1c(-c2ccccc2)nc2ccccc2c1C(=O)NNc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N(NC(=O)c1c(OC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
To a solution of 3-methyloxy-N′,2-diphenyl-4-quinolinecarbohydrazide (100 mg, 0.27 mmol) and Et3N (56 μL, 0.41 mmol) in CH2Cl2 (7 mL) was added methyl chloroformate (27 μL, 0.35 mmol). After stirring at room temperature for 4 h the mixture was diluted with CH2Cl2 and washed with 1N HCl (20 mL), 1N NaOH (20 mL) and brine (20 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with isohexane:ethyl acetate (2:1), to afford the title compound (59 mg, 51%) as a colourless foam. 1H NMR (CDCl3, 360 MHz), δ 8.43 (1H, s), 8.16-8.13 (2H, m), 8.02-8.00 (2H, m), 7.69 (1H, dt, J=6.9 and 1.3 Hz), 7.61-7.41 (8H, m), 7.30 (1H, t, J=7.4 Hz), 3.91 (3H, s), 3.57 (3H, s). MS (ES+) C25H21N3O4 requires: 427, found: 428 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>C(O)(=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: O=C1C=CC(=O)N1c1ccc(O)cc1
Yield: 32.8 %

Procedure:
The suspension that consists of 5.0 g (45.8 mmol) of 4-aminophenol, 4.49 g of maleic acid anhydride and 40 ml of acetic acid is refluxed for 3 hours. It is concentrated by evaporation, residual acetic acid is removed azeotropically by repeated distillation with acetic acid, and the residue is purified by chromatography on fine silica gel. 2.83 g (15.0 mmol, 33%) of the title compound is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH:17]([CH:6]([C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)CCCC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCCC(Nc1ccccc1)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
(1)-a) To 19.0 g of methyl 4-(4-chlorobenzoyl)butyrate were added 14.5 g of aniline, 0.6 g of p-toluenesulfonic acid monohydrate and 200 ml of toluene, and the mixture was refluxed with dehydration for 22.5 hours. After removal of the solvent under reduced pressure, 100 ml of methanol and 2.5 g of sodium hydrogencarbonate were added, and the mixture was cooled to -20° C. Subsequently, 6.0 g of sodium borohydride was added portionwise over 1 hour, and the mixture was stirred at -30° to -20° C. for 1 hour and at -20° to -5° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were washed with diluted hydrochloric acid, and aqueous sodium hydrogencarbonate solution and water, and dried, followed by evaporation of the solvent to give 23.7 g of methyl 5-anilino-5-(4-chlorophenyl)pentanoate as a pale brown oily product. Subsequently, to said oily product were added 75 ml of methanol and 100 ml of an aqueous 10% sodium hydroxide solution, and the mixture was heated under reflux for 1 hour. After removal of the solvent, the residue was diluted with 50 ml of water and then ashed with ether. The aqueous layer was adjusted to pH 6 to 7 with hydrochloric acid, extracted with ethyl acetate. The ethyl acetate extract was washed with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried, and treated with activated charcoal. After removal of charcoal and the solvent, the residue was recrystallized from isopropyl ether to give 17.8 g of 5-anilino-5-(4-chlorophenyl)pentanoic acid as colorless prisms.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:32](=[O:33])[N:23]3[CH:24]([C:29](=O)[NH2:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:1]1([C:7]([NH:20][CH:21]2[C:32](=[O:33])[N:23]3[CH:24]([C:29]#[N:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C(N)=O
Agent: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-carbamylpenam (11.01g., 0.024 mole), dry pyridine (4.9g., 0.062 mole) and dry chloroform (250 ml.)is stirred for five minutes and the resulting solution cooled to 0° C. in a wet ice/acetone bath. Phosgene (8.8 ml. of 3.41 molar solution in chloroform) is added by means of a syringe. The reaction mixture is stirred at 5° C. for ten minutes after which the cooling bath is removed and the reaction mixture allowed to warm to room temperature. It is stirred for 30 minutes and then washed successively with water (300 ml.), 1N hydrochloric acid (300 ml.), and water (300 ml.). The chloroform solution is dried (MgSO4), treated with activated charcoal, and filtered through diatomaceous earth. The filtrate is concentrated to reduced pressure and the residue taken up in methylene chloride (450 ml.).The methylene chloride solution is washed successively with 1N hydrochloricacid (150 ml.) and water (300 ml.) and then dried using anhydrous sodium sulfate. The dried solution is then filtered and concentrated under reduced pressure to give the product as a golden foam (7.1 g., 67.3%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])=[CH:17][CH:16]=3)=[N:9][O:10][C:11]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:32][O:33][C:34](=[O:40])[C@@H:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>>[CH3:32][O:33][C:34](=[O:40])[C@@H:35]([NH:39][C:12]([C:11]1[O:10][N:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:23])=[CH:17][CH:16]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:14])[CH:36]([CH3:38])[CH3:37]
Reactant: O=C(Nc1ccccc1)Nc1ccc(-c2noc(C(=O)O)c2-c2ccccc2)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)c1onc(-c2ccc(NC(=O)Nc3ccccc3)cc2)c1-c1ccccc1)C(C)C
Yield: 76.5 %

Procedure:
The title compound was prepared from 4-phenyl-3-[4-(3-phenyl-ureido)-phenyl]-isoxazole-5-carboxylic acid and (S)-2-amino-3-methyl-butyric acid methyl ester hydrochloride using the procedure as set forth in Example 5 and was obtained in 76.5% yield. 1H NMR (DMSO-d6) δ: 0.79 (m, 6H), 2.01 (m, 1H), 4.30 (m, 1H), 6.96 (t, 1H), 7.27 (t, 2H), 7.44 (d, 2H), 7.53 (m, 3H), 7.56 (d, 2H), 7.67 (d, 2H), 7:81 (m, 2H), 8.72 (s, 1H), 8.93 (s, 1H), 9.25 (d, 1H); Mass (ES+), 513 (M++1).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]([S:15]([OH:17])=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:18]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Br)[CH:23]=1)(=[O:20])[CH3:19].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:15]([CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:18](=[O:20])[CH3:19])[CH:23]=2)(=[O:17])=[O:16])=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)O)c2cccnc12
Reactant: CC(=O)Oc1cccc(CBr)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Cc2cccc(OC(C)=O)c2)c2cccnc12
Reaction time: 0.5 h

Procedure:
8-Acetamido-5-quinolinesulfinic acid (10 g, 40 mmole), m-(bromomethyl)phenyl acetate (11 g, 44 mmole), excess sodium bicarbonate (5 g) and dry dimethylformamide (50 ml) were mixed and heated on the steam bath for 11/2 hours. The mixture was slowly poured into 800 ml stirred water and the mixture stirred another 30 min. The solid was filtered off, washed with water, and air-dried overnight. Yield 15.8 g (99 percent) of crude but relatively pure product, m.p. 179°-182° C. A sample recrystallized from toluene, melted 180°-182° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:34]=[CH:33][C:32]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]=2[CH:23]=1.C([Li])CCC.Cl[Si:41]([CH3:44])([CH3:43])[CH3:42].C1(C)C=CC=CC=1>C1COCC1>[CH3:42][Si:41]([CH3:44])([CH3:43])[N:25]1[C:24]2[CH:23]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[N:12]([Si:41]([CH3:44])([CH3:43])[CH3:42])[C:13]=4[CH:1]=3)[CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: C[Si](C)(C)Cl
Reactant: c1ccc2c(c1)[nH]c1cc(OCCCCCCOc3ccc4c(c3)[nH]c3ccccc34)ccc12
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)n1c2ccccc2c2ccc(OCCCCCCOc3ccc4c5ccccc5n([Si](C)(C)C)c4c3)cc21
Yield: 84 %

Procedure:
To a solution of 1,6-bis(carbazol-2-yloxy)hexane (30 g) in dry THF (200 ml) was added butyllithium (56 ml; 1.6M in hexane). Once the butyllithium addition was completed, the solution was heated to reflux for 1.5 hours and then allowed to cool. Chlorotrimethylsilane (12 ml) was added dropwise to the cooled mixture and then heated to reflux for 4 hours. Toluene (150 ml) was added to the cool mixture which was then filtered to remove LiC1. The filtrate was collected and the solvent removed under vacuum leaving a crude gray compound. The crude product was further purified by vacuum distillation to give a white compound (E.1) in an 84% yield.