Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]3[C@H:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:27]3[C@H:23]([CH2:24][N:25]([C:8](=[O:10])[C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:11])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[C@@H](C(=O)O)c1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
N,N'-Carbonyldiimidazole (0.66 g) is added to a solution of (R)-2-phenylpropionic acid (0.62 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.35 g) and triethylamine (0.57 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in ethyl acetate (100 cc) and the solution is washed with water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (4 kPa). The residue is chromatographed on a silica gel column (0.2-0.04 mm, diameter 2.8 cm, height 15 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 50 cc fractions. Fractions 4 to 8 are concentrated to dryness under reduced pressure (4 kPa) to give (3aR,7aR)-7,7-diphenyl-2-[(R)-2-phenylpropionyl]-4-perhydroisoindolone (1.4 g) in the form of a white meringue, the infrared spectrum of which is identical to that of the product from Example 68; [α]D20 =-278° (c=1, methanol).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([CH2:8][C:9]#[N:10])=O.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>C(O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:6]2[CH:8]=[C:9]([NH2:10])[O:23][N:22]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: NO
Reactant: N#CCC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(-c2cccc(C(F)(F)F)c2)no1
Temperature: 25 °C

Procedure:
3-(Trifluoromethyl)benzoylacetonitrile (3.8 grams) and 125 ml. ethanol were placed in a 500 ml. flask. The solution was treated with sodium acetate (12 grams) and hydroxylamine.hydrochloride (9 grams in 125 ml. water) and then heated to reflux for two hours. After cooling to room temperature, the ethanol was removed and the residue extracted with ether. The ether extracts were then washed with water, brine, and dried with MgSO4. The solid residue obtained was recrystallized from an ethanol/water solution, m.p. 89°-90° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH2:7].[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:8][C:9]1[N:14]=[C:13]([NH:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1ncc(Cl)c(Nc2ncccn2)n1
Temperature: 110 °C

Procedure:
The mixture of pyrimidin-2-amine (48 mg, 0.50 mmol), 2,4,5-trichloropyrimidine (57 μL, 0.5 mmol), and potassium carbonate (69 mg, 0.5 mmol) in 3 mL of 1,4-dioxane is heated at 110° C. over night. The precipitate is filtered, washed by cold EtOH, and dried in vacuo to afford N-(2,5-Dichloropyrimidin-4-yl)pyrimidin-2-amine; ESMS m/z 242.0 (M+H+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)(Cl)Cl>[CH2:18]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCBr
Reactant: OCCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCN1CCN(CCO)CC1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
2-(1-Piperazinyl)ethanol (12.2 g) was dissolved in chloroform (60 ml), triethylamine (13.0 ml) and 1-bromobutane (14.1 g) were successively added at room temperature, and the mixture was stirred overnight. The reaction solution was successively washed with a 10 M aqueous solution of potassium hydroxide (15 ml), water (50 ml×2), saturated aqueous sodium chloride (50 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (methylene chloride:methanol:aqueous ammonia=90:10:0.5) to give the title compound (10.8 g) as a pale yellow oily substance. Yield=62%.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].F[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].Cl>CN(C=O)C.O>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:19]([O-:21])=[O:20])[C:12]=1/[C:2](=[C:3](\[OH:4])/[CH3:5])/[C:1]([O:7][CH3:8])=[O:6]
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C(=C(\C)O)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
Methyl acetoacetate (59.82 mmol, 2.1 equiv.) was added dropwise at 0° C. to a suspension of NaH (65.52 mmol, 2.3 equiv.) in DMF (40 ml). Then the mixture was stirred for 10 min and subsequently heated to 25° C. 2-Fluoro-3-chloronitrobenzene (28.49 mmol, 1.0 equiv.) was cooled with an ice bath in a reaction flask, and the NaH suspension was added. Then stirring was carried out for 16 h at 25° C. 2 M HCl (5 ml) and water (10 ml) were then added, and extraction with diethyl ether (3×20 ml) was carried out. The combined organic phases were washed with water (10 ml) and sat. NaCl solution (20 ml), dried over Na2SO4 and reduced under reduced pressure. The residue was purified by column chromatography (5% ethyl acetate in hexane). Yield: 51%
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11]Cl>>[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][N:1]1[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: c1c[nH]nn1
Reactant: COCCOCCl
Product: COCCOCn1ccnn1

Procedure:
The title compound was prepared from 1,2,3-triazole and 2-methoxyethoxymethyl chloride, by a similar method to that of Preparation 40, as a colourless oil which was characterised by 1H-NMR spectroscopy (300 MHz, CDCl3): δ=3.31(s,3H), 3.46(m,2H), 3.62(m,2H), 5.77(s,2H), 7.73(s,1H),7.75(s,1H) ppm.
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[CH2:18][CH2:17][N:16]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:15](=[O:26])[C:14]=2[C:13]([CH3:27])=[C:12]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][S:35]([CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])(=[O:37])=[O:36])=[CH:30][CH:29]=1>C(O)(=O)C.C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[CH:18]=[CH:17][N:16]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:15](=[O:26])[C:14]=2[C:13]([CH3:27])=[C:12]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][S:35]([CH2:38][CH2:39][C:40]([F:42])([F:43])[F:41])(=[O:36])=[O:37])=[CH:30][CH:29]=1
Reactant: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Agent: BrBr
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(OS(=O)(=O)CCC(F)(F)F)cc2)n(-c2ccc(F)cc2Cl)c2ccn(N3CCCCC3)c(=O)c12
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
Bromine (39.0 mg, 0.244 mmol) dissolved in acetic acid (0.556 ml) was added to a solution of 4-[1-(2-chloro-4-fluorophenyl)-3-methyl-4-oxo-5-piperidin- 1-yl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl]phenyl 3,3,3-trifluoropropane-1-sulfonate (75 mg, 0.122 mmol) (Example 3 ) in THF (3 ml) at −78° C. After 30 min at −78° C. the reaction mixture was allowed to reach rt. After 3 h at rt more bromine (19.5 mg, 0.122 mmol) dissolved in acetic acid (0.278 ml) was added and the reaction continued at rt for 5 h before the solvent was removed by evaporation. Purified by hplc to yield the title compound as a solid (22 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH3:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][N:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C1(C)CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 65 °C
Reaction time: 6 h
Yield: 83.1 %

Procedure:
To a round bottom flask was added ethyl 3-methylpiperidine-3-carboxylate (2.040 g, 11.91 mmol), 1-fluoro-4-nitrobenzene (1.765 g, 12.51 mmol), DMF (20 ml) and K2CO3 (2.140 g, 15.49 mmol). The reaction was stirred at 65° C. for 6 hrs. After this time, the reaction was diluted with EtOAc. The resulting solution was washed with water (2×) and saturated aqueous NaCl. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex to give product, ethyl 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylate (2.922 g, 9.90 mmol, 83% yield) as a yellow oily residue. Anal. Calcd. for C15H20N2O4 m/z 292.3, found: 293.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (d, J=9.34 Hz, 2 H), 6.87 (d, J=9.34 Hz, 2 H,) 4.18 (d, J=13.19 Hz, 1 H), 4.11 (q, J=7.15 Hz, 2 H), 3.80-3.58 (m, 1 H), 3.00 (s, 1 H), 2.90 (d, J=13.19 Hz, 1 H), 2.40-2.23 (m, 1 H), 1.75 (dd, J=8.52, 4.12 Hz, 2 H), 1.42 (s, 1 H), 1.26-1.14 (m, 6 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:35]=[CH:34][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:35][CH:34]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(Cl)CCCCCOc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCCCCOc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a mixture of 4-nitrophenol (10.8 g), triethylamine (22 ml) in ethyl acetate (200 ml) at 0° C. was added 6-(4-nitrophenoxy)-hexanoyl chloride (20 g) dropwise, and the mixture was further stirred at room temperature for 16 hours. The reaction mixture was filtered to remove the salts, washed with 5% sodium bicarbonate, water and dried over anhydrous sodium sulphate. The solvent was distilled off under vacuum and the pure compound was precipitated by adding cold methanol. After filtration and drying, the compound was further recrystallized from a mixture of chloroform and methanol (1:1) to give pure 6-(4-nitrophenoxy)-hexanoic acid 4-nitrophenyl ester (15 grams) as white powder with a melting point of 73-76° C. The product was also characterized by 1H NMR (CDCl3) δ 1.60 (m, 2H, CH2), 1.85 (m, 6H, CH2X2), 2.70 (t, 2H, CH2), 4.10 (t, 2H, CH2), 6.95 (d, 2H, Ar), 7.30 (d, 2H, Ar), 8.25 (m, 4H, Ar).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1)=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[C:14]([O:13][C:11]([NH:10][C@@H:9]1[CH2:8][CH2:7][C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5][C@@H:4]1[NH2:1])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@H](N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](N)C1
Yield: 104.8 %

Procedure:
Methyl (1R*,3R*,4S*)-3-azido-4-(N-tert-butoxycarbonylamino)cyclohexane-1-carboxylate (230 mg) was dissolved in ethyl acetate (8 ml), and a catalytic amount of 10% palladium on carbon was added to stir the mixture at room temperature for 20 hours in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (220 mg) as a pale yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:14][O:13][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][CH:2]=[N+:1]2[O-:20])=[CH:6][CH:7]=1)=[O:12]
Reactant: COC(=O)c1ccc2cccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2ccc[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of the methyl quinoline-7-carboxylate from above in DCM (10 mL) was added 3-chlorobenzoperoxoic acid (1.991 g, 11.54 mmol). The reaction was stirred for 21 h at rt. The mixture was then diluted with saturated aqueous NaHCO3 (40 mL) and the mixture was extracted with DCM (2×30 mL). The organic layers were combined, washed with saturated aqueous NaCl (40 mL), dried (MgSO4), and concentrated. The N-oxide was isolated as an orange solid which was used without purification in the next step.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O:33]O)(C)(C)C.Cl[O-].[Na+]>ClCCl>[O:33]=[C:14]1[CH:15]=[C:16]2[C@:22]([CH3:23])([CH2:21][CH2:20][C@H:18]([OH:19])[CH2:17]2)[C@@H:24]2[C@@H:13]1[C@H:12]1[C@:27]([CH3:28])([CH2:26][CH2:25]2)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:10][CH2:11]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 2.5 °C
Yield: 67.4 %

Procedure:
Cholesterol (13, 1.93 gm, 0.005 mol) and tert-butyl hydroperoxide (4.2 ml of 70% aq. solution, 0.03 mol) were dissolved in dichloromethane (20 ml). The mixture was stirred vigorously, cooled to 0-5° C. and a dilute solution of sodium hypochlorite (15 ml, 5.25% available chlorine) was added slowly in the form of fine, small droplets during ten hours at 0-5° C. After completion of addition, the dichloromethane layer was separated, washed with water, aqueous sodium bisulfite solution (10%, 2×10 ml) and water. The organic solvent was evaporated under reduced pressure to yield a crude product, which was chromatographed on a silica gel column utilizing 20% acetone in petroleum-ether to afford 1.35 gm (67.5%) of 7-oxo-cholesterol (14) as a snow white solid having a melting point of 169-70° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[F:11][C:12]1([F:16])[CH2:15][NH:14][CH2:13]1.Br[CH2:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[C:21]#[N:22]>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:19]([CH2:18][N:14]2[CH2:15][C:12]([F:16])([F:11])[CH2:13]2)=[C:20]([CH:23]=1)[C:21]#[N:22]
Reactant: N#Cc1cc(Cl)ccc1CBr
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)ccc1CN1CC(F)(F)C1
Yield: 55.9 %

Procedure:
DIEA (0.196 mL, 1.12 mmol) was added to a stirred mixture of 3,3-difluoroazetidine hydrochloride (64.8 mg, 0.50 mmol) and 2-bromomethyl-5-chlorobenzonitrile (121.0 mg, 0.52 mmol) in CH2Cl2 (7 mL). After 16 h the reaction was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was partitioned between 1N HCl and ether. The aqueous layer was made neutral with NaHCO3 and was extracted with CH2Cl2. The organic layer was dried with Na2SO4 and then evaporated to give 5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzonitrile (67.8 mg) as a glass: 1H NMR (CDCl3, 400 MHz) δ 3.68 (t, J=11.9 Hz. 4H), 3.93 (s, 2H), 7.54 (m, 2H), 7.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([N:9]=[C:10]=[O:11])[CH2:6][CH2:7][CH3:8].C(=O)=O>ClCCl>[OH:2][CH2:1][CH2:3][NH:4][C:10]([NH:9][CH2:5][CH2:6][CH2:7][CH3:8])=[O:11]
Reactant: CCCCN=C=O
Reactant: NCCO
Agent: O=C=O
Solvent: ClCCl
Product: CCCCNC(=O)NCCO
Temperature: 30 °C
Yield: 113 %

Procedure:
61.7 Grams (1 mole @ 99% purity) of ethanolamine and 170 grams of dichloromethane were charged to a flask equipped with stirrer, thermometer, feed tank, distillation head and condenser. 101 Grams (1 mole @ 98% purity) of butyl isocyanate was fed dropwise with stirring and cooling (dry ice bath) during 1.5 hrs. such that the temperature of the reaction mixture was maintained at about 30° C. At this time some solid had been formed and it was redissolved by heating to 46° C. The mixture was stirred at 46° C. for an additional two hours and then freed of volatile materials by stripping at 90° C. and 2 mm Hg leaving 181 g of solid product. This material could be recrystallized from 2-butanone giving tiny white crystals melting at 67° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[C:14](O)(=[O:18])[C:15]([CH3:17])=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>C(Cl)(Cl)Cl.O>[CH3:17][C:15](=[CH2:16])[C:14]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:18]
Reactant: C=C(C)C(=O)O
Reactant: O=C(O)c1ccc(OCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OCCOc1ccc(C(=O)O)cc1

Procedure:
50 g of p-(2-hydroxyethoxy)-benzoic acid, 130 g of methacrylic acid, 5 g of p-toluenesulfonic acid and 5 g of hydroquinone as an inhibitor are dissolved in 200 ml of CHCl3 and the solution is refluxed in a 500 ml flask, fitted with a water separator and reflux condenser, until about 6 ml of water have separated out (about 20 hours). The cooled solution is introduced into about 1 liter of ether and is washed with 5 portions of water each of about 200 ml. After drying the solution with Na2SO4, the solvents are stripped off and the crude product is recrystallized as described under 1.1.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].[O:14]([C:16]#[N:17])[K]>CC(O)=O.O>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:16]([NH2:17])=[O:14])[CH:3]=2)[NH:7][CH:6]=1)#[N:13]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: N#CO[K]
Solvent: CC(=O)O
Solvent: O
Product: N#CCc1c[nH]c2ccc(NC(N)=O)cc12
Reaction time: 14 h
Yield: 52.7 %

Procedure:
To a solution of 21.3 g (0.124 mole) of 5-aminoindole-3-acetonitrile in 400 ml of 25% aq HOAc cooled to 0° was added 10.5 g (0.13 mole) of KOCN in 30 ml of H2O. The reaction mixture was stored at 0° for 14 hours after which a beige solid was filtered and recrystallized from methanol to give 14.0 g (53% yield) of N-(3-cyanomethyl-1H-indol-5-yl)urea. Further recrystallization affords an analytical sample: m.p. 219°-220°; i.r. (Nujol) 3455, 3300, 2250 and 1650 cm-1 ; nmr (d6 -DMSO) δ(TMS) 11.06 (1,S,indole NH ), 8.46 (1,S, --NHCO--), 7.70 (1,d,Jmeta =2 Hz), 7.37 (1,d,Jortho =9 Hz), 7.30 (1,S,indole C2H), 7.18 (1,d of d,Jortho =9 Hz, Jmeta =2 Hz), 5.73 (2,S,--CONH2) and 4.00 ppm (2,S,--CH2CN).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[I:13]N1C(=O)CCC1=O>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([I:13])=[C:4]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[NH2:5]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(C(F)(F)F)cc(Br)c1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Bromo-5-(trifluoromethyl)aniline (20 g, 83 mmol) in acetic acid (150 ml) was treated portionwise with N-iodosuccinimide (20.62 g, 92 mmol). The reaction was stirred 24 h at ambient temperature. The reaction was diluted with ethyl acetate (600 mL) and was washed with aqueous sodium bisulfie (100 mL) and brine (100 mL). The organic layer was dried with magnesium sulfate and evaporated. The residue was purified on a silica gel column with a gradient of ethyl acetate/hexanes from 7% to 15% to give 23.5 g (77%) of slightly impure product. 1H-NMR (CDCl3, 400 MHz) δ 7.21 (d, J=1.3 Hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 4.57 (bs, 2H); LC/MS (HPLC method 4): tR=3.578 min, 365.80(MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.I[CH2:11][C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].P(=O)(O)(O)O>C(OCC)(=O)C.O>[C:12]([CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([OH:14])=[O:13]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(O)CI
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCC(=O)O)cc1
Temperature: 60 °C

Procedure:
To a solution of p-hydroxybenzaldehyde (49 g, 0.40 mol) were added iodoacetic acid (75 g, 0.40 mol) and potassium carbonate (anhydrous, 120 g), and the magnetically stirred mixture was warmed at 60° C. for three days. The resulting solid was dispersed mechanically in a mixture of ethyl acetate (400 ml) and water. The mixture was neutralized cautiously with phosphoric acid. After the dissolution of the solid mass, the neutral aqueous layer was withdrawn. The organic layer was extracted repeatedly with a concentrated solution of dibasic sodium phosphate, to remove additional acidic organic material. The aqueous extracts were combined, filtered through glass wool, and acidified to pH 1 using 6N HCl. This solution was placed in the refrigerator overnight, and a product of tan crystals (21.85 g) was collected. Unreacted p-hydroxybenzaldehyde was recovered upon evaporation of the organic layer. Yield based on recovery of starting material was 60%. Mp 191°-193° C. Analysis (C9H8O4): calc. 60.00% C, 4.48% H; found 59.66% C, 4.37% H.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2[C:12](=S)[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23]>C(O)CCC>[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH:23][C:12]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:18][C:7]=2[NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[N:11]=1
Reactant: COC(CN)OC
Reactant: COc1ccc2c(c1)Nc1ccccc1NC2=S
Solvent: CCCCO
Product: COC(CNC1=Nc2ccccc2Nc2ccccc21)OC

Procedure:
In the manner given in Example 4, 3-methoxy-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with amino acetaldehyde dimethyl acetal in n-butanol to give [(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyl acetal.