Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[OH:34][CH:32]([CH3:33])[CH2:31][NH:30][C:19]([C:18]1[C:11]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:15][CH:14]=[N:13][C:12]=2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:17]=1)=[O:21]
Reactant: CC(O)CN
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CNC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (2.00 g, 4.83 mmol) in THF (50 mL), was added 1-aminopropan-2-ol (543 mg, 7.23 mmol), EDCI (1.12 g, 5.84 mmol), HOBt (800 mg, 5.92 mmol) and DIPEA (2.48 g, 19.2 mmol). The reaction was stirred for 12 hours at 25° C. and then concentrated in vacuo and quenched by addition of water. The reaction was extracted with DCM (×3) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 33% ethyl acetate/petroleum ether. The product was collected and concentrated in vacuo to afford N-(2-hydroxypropyl)-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide as a yellow solid. LRMS (ESI) calc'd for C22H30N5O5Si [M+H]+: 472, found 472.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:24])[CH2:4][N:5]1[CH2:23][CH2:22][N:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:7]2[CH2:6]1.C(=O)([O-])[O-].[Na+].[Na+].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>[I-].[Na+].CC(C)CC(=O)C>[OH:24][CH:3]([CH2:2][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:4][N:5]1[CH2:23][CH2:22][N:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:7]2[CH2:6]1
Reactant: OC(CCl)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: OC(CN1CCOCC1)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Yield: 87.1 %

Procedure:
0.5 g of 2-(3-chloro-2-hydroxypropyl)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine (prepared as described in Example 41), 2.7 g of sodium carbonate, 0.014 g of sodium iodide and 0.254 g of morpholine were added to 10 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was filtered, and then the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, using ethyl acetate as the eluent, to afford 0.50 g (yield 87%) of the title compound as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:12])[CH:10]=[CH2:11].CCN(C(C)C)C(C)C.[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([Cl:30])=[CH:25][N:24]=1.C(OCC)(=O)C.CCCCCC>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:12])[CH:10]=[CH2:11])[C:26]([Cl:30])=[CH:25][N:24]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C=CC(=O)Nc1ccccc1N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
To a solution of N-(2-aminophenyl)acrylamide (TFA salt) (10 g, 38.6 mmol) in N-methyl pyrrolidinone (30 mL) was added DIPEA (12.6 g, 98.36 mmol), and 2,4,5-trichloropyrimidine (9.5 g, 49.18 mmol), and the mixture was stirred at rt for 16 h. TLC showed completion of starting material (TLC system: 50% ethyl acetate/hexane, (Rf): 0.5). The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3×50 mL). The organic layer was separated, dried over sodium sulfate and concentrated to obtain the crude compound (11 g). MS m/z: 309.1 (ES+, M+1).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:33]=[C:32]([CH3:34])[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]([C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)OC(OC3C=CC=CC=3)=S)=[C:9]([CH3:35])[CH:8]=2)=[N:3]1.CC(N=NC(C#N)(C)C)(C#N)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:33]=[C:32]([CH3:34])[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[C:9]([CH3:35])[CH:8]=2)=[N:3]1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(OC(=S)Oc1ccccc1)c1nccn1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCCc1nccn1C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
To a solution of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-1-phenoxythiocarbonyloxy-butyl]-1-methylimidazole (1.94 mmol) in 35 ml of toluene was added AIBN (159 mg, 0.97 mmol) and n-tributyltin hydride (1.69 g), and the mixture was stirred at 75°-80° C. for 4 h. An aqueous sodium bicarbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate, and then methylene chloride (2×). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, methylene chloride/methanol, 30/1-15/1) to afford 440 mg (67%) of 2-[4-[4-(2-methyltetrazol-5-yl)-2,6-dimethylphenoxy]-butyl]-1-methylimidazole, m.p. 100°-102° C. (from methylene chloride/hexane).
Reaction SMILES: [CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][NH:5][C@H:4]1[CH3:8])[CH3:2].[F:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[C:15]([F:20])[C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][N:5]([C:17]2[CH:18]=[C:11]([F:10])[C:12]([C:13]#[N:14])=[C:15]([F:20])[CH:16]=2)[C@H:4]1[CH3:8])[CH3:2]
Reactant: CC[C@]1(O)CCN[C@H]1C
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2cc(F)c(C#N)c(F)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-methylpyrrolidin-3-ol 0.5 oxalate (257 mg), 2,4,6-trifluorobenzonitrile (464 mg) and lithium carbonate (218 mg), the title compound was obtained as a colorless solid (yield: 207 mg, yield: 53%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([NH2:18])=[C:10]([NH2:19])[CH:9]=2)[CH:7]=1.O=[C:21]([C:27](OCC)=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:9]=[C:10]3[C:11]([NH:18][C:27](=[O:28])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:19]3)=[CH:12][C:13]=2[C:14]([F:16])([F:15])[F:17])[CH:7]=1
Reactant: Nc1cc(-n2cnc(CO)c2)c(C(F)(F)F)cc1N
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1nc2cc(-n3cnc(CO)c3)c(C(F)(F)F)cc2[nH]c1=O
Yield: 43 %

Procedure:
To a solution of 4-(4-(hydroxymethyl)imidazole-1-yl)-5-trifluoromethyl-1,2-phenylenediamine (200 mg, 781 μmol) in ethanol (10 ml) was added diethyl ketomalonate (142 μl, 937 μmol), and the mixture was refluxed for 4 hours. After cooling, solvent was distilled off and the residue obtained was purified by means of silica gel column chromatography [methylene chloride-methanol (50:1→10:1)] to obtain 129 mg of the the title compound as pale yellow powder. Yield 43%.
Reaction SMILES: [C:1]1(C=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13](O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[C:9]1([C:14](=[CH2:13])[C:15]([OH:17])=[O:16])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(C(=O)O)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
1-Naphthyl acrylic acid was prepared by reaction of 1-naphthaldehyde and malonic acid. 1-Naphthaldehyde (46.8 g.), malonic acid (60.0 g.), pyridine (120 ml.), and piperidine (3 ml.) were charged into a 500 ml. round bottom flask and refluxed on a water bath for 4 hours. The reaction solution was cooled to room temperature and poured onto a mixture of 175 ml. concentrated hydrochloric acid and 300 g. of crushed ice. A white precipitate formed and the slurry was stirred until all the ice had melted. The precipitate was separated from the slurry by filtration and washed with one portion of 10% hydrochloric acid (75 ml.) and two portions of deionized water (each 75 ml.). The 1-naphthyl acrylic acid precipitate was fully dewatered by continued application of suction on the filter, and then vacuum dried at 40°C. for 24 hours.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[CH2:10][B-:11]([F:14])([F:13])[F:12].[K+:15].F.[K]>C1COCC1>[F:12][B-:11]([F:14])([F:13])[CH2:10][O:6][CH2:5][C:4]([F:8])([F:7])[F:3].[K+:15]
Reactant: OCC(F)(F)F
Reactant: F[B-](F)(F)CBr
Agent: F
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: F[B-](F)(F)COCC(F)(F)F
Temperature: 25 °C
Reaction time: 22 h
Yield: 96.4 %

Procedure:
To a suspension of sodium hydride (0.5377 g, 60 mass %, 13.44 mmol) in anhydrous THF (45 mL) at 0° C. is added dropwise 2,2,2-trifluoroethanol (1.345 g, 13.44 mmol). The resulting reaction mixture is slowly warmed to ambient temperature over 1 hour and then re-cooled to 0° C. Further potassium bromomethyl(trifluoro)boranuide (1.000 g, 4.481 mmol) is added in one portion and the resulting reaction mixture is stirred at ambient temperature for a further 22 h. The reaction is quenched with potassium hydrogen fluoride (2 mL, 4.5 M, 9.1 mmol) and stirred for 30 min. The suspension was concentrated in vacuo and diethyl ether was added to the solid residue. The resulting suspension is filtered, washing with more diethyl ether and the washed solid was re-dissolved in acetonitrile and filtered. The filtrate was concentrated in vacuo and triturated with diethyl ether to yield potassium trifluoro(2,2,2-trifluoroethoxymethyl)boranuide (0.950 g, 4.32 mmol, 96.4% Yield).
Reaction SMILES: C(Cl)CCl.[S:5]1(=[O:12])(=[O:11])[CH:9]=[CH:8][C:7](=[O:10])[NH:6]1.[CH3:13][C:14]([C:16]([CH3:18])=[CH2:17])=[CH2:15]>CCOCC>[CH3:13][C:14]1[CH2:15][CH:8]2[C:7](=[O:10])[NH:6][S:5](=[O:12])(=[O:11])[CH:9]2[CH2:17][C:16]=1[CH3:18]
Reactant: C=C(C)C(=C)C
Reactant: O=C1C=CS(=O)(=O)N1
Solvent: CCOCC
Solvent: ClCCCl
Product: CC1=C(C)CC2C(C1)C(=O)NS2(=O)=O

Procedure:
A 40 ml solution of ethylene dichloride containing 5.3 g (0.04 mole) of 4-isothiazolin-3-one 1,1-dioxide and 3.3 g (0.04 mole) of 2,3-dimethyl-1,3-butadiene is heated at 45°-50° C. overnight. The golden solution is cooled and concentrated to give an oil. Trituration of the oil with ether gives a white solid, 7.7 g (80%), m.p. 110°-112° C., which can be recrystallized from ethyl acetate.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH3:10])=[N:7][CH:6]=[CH:5][N:4]=1)C.CC1C(CC)=NC=CN=1>>[CH3:1][C:3]1[C:8]([CH:9]=[CH2:10])=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: CCc1nccnc1CC
Agent: CCc1nccnc1C
Product: C=Cc1nccnc1C

Procedure:
r. 2-Methyl-3-vinyl-pyrazine is prepared from 2,3-diethylpyrazine by the same method as used for compound (1) q. It has a b.p. of 66°-67°C./13 mm. Hg.
Reaction SMILES: [Br:1]Br.[CH3:3][S:4][C:5]1[N:10]=[C:9]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][N:6]=1>C(O)(=O)C>[Br:1][CH:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:3])[N:10]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: CSc1nccc(CC(=O)c2ccccc2)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: CSc1nccc(C(Br)C(=O)c2ccccc2)n1

Procedure:
Bromine (24.1 g, 0.15 mol) is added with stirring to 2-(2-methylthio-pyrimidin-4-yl)-1-phenyl-ethanone (36.8 g, 0.15 mol) in acetic acid (300 ml) in such a way that the reaction temperature does not exceed +25° C. and the color of the bromine is discharged immediately. After the addition of the bromine solution the solvent is removed by evaporation under vacuum. The pH of the resulting oil is adjusted to 8 using an aqueous saturated sodium bicarbonate solution and the product is extracted several times with diethylther. Drying the combined extracts with magnesium sulfate, filtering and evaporation of the solvent gives the crude 2-bromo-2-(2-methylthio-pyrimidin-4-yl)-1-phenyl-ethanone in form of an oil of sufficient purity for the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)[C:21]1=O>C(O)C>[Cl:32][C:30]1[CH:31]=[C:26]([CH:22]2[C:21]3[N:18]=[C:16]([NH:15][C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[S:17][C:20]=3[CH2:25][CH2:24][CH2:23]2)[CH:27]=[C:28]([Cl:33])[CH:29]=1
Reactant: O=C1C(Br)CCCC1c1cc(Cl)cc(Cl)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2cc(Cl)cc(Cl)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (58 mg, 0.22 mmol) and of crude 2-bromo-6-(3,5-dichloro-phenyl)-cyclohexanone (75 mg, 0.23 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (30 mg, 28%) as a yellow solid. MS ISP (m/e): 485.3/487.3 (100/72) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.35 (s, 1H), 7.20 (s, 1H), 7.11 (d, 1H), 7.04 (s, 2H), 6.84 (s, 1H), 6.69 (d, 1H), 3.98 (m, 1H), 3.63 (s, 3H), 2.75 (m, 2H), 2.30 (s, 3H), 2.22 (m, 1H), 1.83 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22].S(=O)(=O)(O)O.C(O)(=O)C.[N:32]([O-])=O.[Na+]>O1CCCC1.O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=[CH:12][C:2]=2[N:1]=[N:32]1
Reactant: CCOC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2nnn(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
Ethyl 4-amino-3-(2,4-dichlorobenzylamino)benzoate (0.89 g), concentrated sulfuric acid (1.0 g) were stirred in a mixed solvent of acetic acid (20 ml), water (10 ml) and tetrahydrofuran (20 ml). Sodium nitrite (3.0 g) was added thereto, and the mixture was stirred at room temperature for 30 min. The solvent was distilled away, and water was added to separate the toluene layer. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. The toluene layer was concentrated to give the objective compound (0.64 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11](Cl)=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:14][C:15]1[N:20]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:19][N:18]=[C:17]2[O:28][CH:29]=[CH:30][C:16]=12>>[NH2:14][C:15]1[N:20]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:11]([C:8]3([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:10][CH2:9]3)=[O:12])=[CH:25][CH:26]=2)[CH2:19][N:18]=[C:17]2[O:28][CH:29]=[CH:30][C:16]=12
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Reactant: O=C(Cl)C1(c2cccc(Cl)c2)CC1
Product: NC1=c2ccoc2=NCN1c1ccc(NC(=O)C2(c3cccc(Cl)c3)CC2)cc1

Procedure:
The compound was prepared following the procedure described in Example 474, using 1-(3-chloro-phenyl)-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) as the diamine of choice. MS(ES) m/e 405 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C)C=O.[C:14]([NH:17][C:18]1[CH:19]=[C:20]([OH:28])[C:21](=[CH:26][CH:27]=1)[C:22]([O:24][CH3:25])=[O:23])(=[O:16])[CH3:15]>C(OCC)(=O)C>[C:14]([NH:17][C:18]1[CH:19]=[C:20]([OH:28])[C:21](=[CH:26][C:27]=1[Br:1])[C:22]([O:24][CH3:25])=[O:23])(=[O:16])[CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(NC(C)=O)cc1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(NC(C)=O)cc1O
Temperature: 72.5 °C
Yield: 44.4 %

Procedure:
N-Bromosuccinimide (0.94 g, 5.3 mmol) was added to an N,N-dimethylformamide (8 ml) solution of methyl 4-acetylaminosalicylate (I-248) (1.1 g, 5.0 mmol), followed by stirring with heating under reflux at 70 to 75° C. for 2 hours and a half. After cooling to room temperature, ethyl acetate was added, followed by washing twice with saturated brine and drying over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with chloroform/methanol (100:1) gave the entitled compound (0.64 g, 45%) as a pale red solid.
Reaction SMILES: [Cl:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:10])=[O:9])[CH2:4][CH:3]=1.BrBr>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC=C(Cl)CC1
Agent: BrBr
Product: O=C(Cl)c1ccc(Cl)cc1

Procedure:
To a 25 ml three-necked flask equipped with an equal pressure additional funnel, a dry-ice condenser with a gas outlet and a stopper, is charged 17.9 g (0.1 mole) of 1-chloro-4-chloroformyl cyclohex-1-ene (I). The solution is heated to 90°-100° C. with stirring, using a magnetic stirring bar. Bromine, 32 g (0.2 mole), is added dropwise, sub-surface. The color dissipates quickly and a gas evolution occurs. When about 24 g of bromine has been added, the pot temperature is raised to 120°-130° C. The remaining bromine is added in the same fashion. The pot temperature may then be raised to 150°-160° C. fro 2-4 hours. During this period, an additional amount of bromine, such as about 1-2 g, may be added to complete the conversion of (I). A good yield of 4-chlorobenzoyl chloride will be obtained by the fractional distillation of the mixture.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]O)=[CH:18][CH:17]=1)([O-:15])=[O:14].Cl.C(N=C=NCCCN(C)C)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:11][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of N-(t-butoxycarbonyl)glycine (1.51 g, 8.62 mmol) in anhydrous methylene chloride (75 ml) were added p-nitrobenzyl alcohol (2.63 ml, 17.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter referred to as WSC) (3.3 g, 17.2 mmol) and 4-dimethylaminopyridine (106 mg, 0.87 mmol) in an ice bath. The mixture was stirred at room temperature under an atmosphere of nitrogen overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (2:1) as the eluant to afford N-(t-butoxycarbonyl)glycine p-nitrobenzyl ester (2.67 g, yield 100%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].Cl.[CH3:26][NH:27][CH3:28].[OH-].[Na+].Cl>O1CCOCC1>[CH3:26][N:27]([CH3:28])[S:16]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH:6]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(Cl)cc2Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(2,4-Dichlorophenoxy)-4-methylsulphonylaminobenzene-sulphonic acid chloride (1.12 g, 2.6 mmol) was dissolved in dioxan (5 ml) and at 0° C. added dropwise to a solution of dimethylamine hydrochloride (1.10 g, 13.4 mmol) in 1N aqueous NaOH (13 ml, 13 mmol) and dioxan (13 ml). The mixture was stirred for 1 hour at 0° C., acidified with 1N HCl and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvent was evaporated off. The residue was purified by chromatography (silica gel, petroleum ether/ethyl acetate 6/4). Yield: 0.27 g=24% 13C (100 MHz, DMSO-d6) δ 150.02, 147.24, 133.01, 130.81, 130.42, 129.53, 129.18, 126.03, 123.74, 123.17, 122.57, 115.72, 41.03, 37.59
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH:6]2[CH2:18][C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N+:19]([O-])=O)[CH:15]=4)[NH:10][C:9]=3[CH2:8][CH2:7]2)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12>C(OCC)(=O)C.[Ni]>[C:4]1(=[O:22])[N:5]([CH:6]2[CH2:18][C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=4)[NH:10][C:9]=3[CH2:8][CH2:7]2)[C:1](=[O:27])[C:2]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1C1CCc2[nH]c3ccc([N+](=O)[O-])cc3c2C1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)CC3
Yield: 8.5 %

Procedure:
3-phthalimido-6-nitro-1,2,3,4-tetrahydrocarbazole (4.00 g) was dissolved in hot ethyl acetate (130 ml). To the cooled solution was added raney nickel, and the mixture was hydrogenated at an initial pressure of 39 psi at room temperature for 4 hr. After filtering off the insoluble materials, the filtrate was evaporated to dryness, and extracted twice into 20% aqueous methanol and the extracts combined and reduced in volume to give 3-phthalimido-6-amino-1,2,3,4-tetrahydrocarbazole (0.31 g).
Reaction SMILES: [C:1]([O:4][CH:5]1[N:8](C(C(OC)=O)=C(C)C)[C:7](=[O:17])[CH:6]1[NH:18][C:19](=[O:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.O>[C:1]([O:4][CH:5]1[NH:8][C:7](=[O:17])[CH:6]1[NH:18][C:19](=[O:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(=C(C)C)N1C(=O)C(NC(=O)Cc2ccccc2)C1OC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1NC(=O)C1NC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a stirred solution of 4-acetoxy-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-3-phenylacetamidoazetidin-2-one (709 mg, 1.9 mmol [R. J. Stoodley and N. R. Whitehouse, J. Chem. Soc., Perkin I, 32 (1973).] in 5 ml dimethylformamide, 5 ml pyridine and 1 ml water at 0° C. in an ice-water bath is added 497 mg (3.15 mmol) solid potassium permanganate. The mixture is stirred at 0° C. under a nitrogen atmosphere for 1.0 hour. The mixture is treated with sufficient aqueous sodium thiosulfate to destroy the excess permanganate and is diluted with ethylacetate. The mixture is filtered and the filtrate is partitioned between ethylacetate and dilute aqueous hydrochloric acid. The organic phase is separated and is washed successively with dilute aqueous sodium bicarbonate and brine. The organic phase is dried (MgSO4), filtered, and evaporated. The residue is purified by plate layer chromatography [1 development φH-EtOAc (1:1)] to give 95.1 mg (19%) of 1; nmr (CDCl3) 2.03, 3H(s); 3.5, 2H(s); 4.67; 1H(dd, J=1 Hz,7 Hz); 5.73, 1H(d, J=1 Hz); 7.17, 6H(s); 7.53, 1H(bs). ##STR29##