Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:13]C1C=CN=CC=1.[C:20](Cl)(Cl)=[O:21].CC1C=CC=CN=1.C(Cl)(=O)C1C=CC(C(Cl)=O)=CC=1>ClCCl>[C:6]([O:21][CH3:20])(=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:10][CH:9]=1
Reactant: Cc1ccncc1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)Cl
Agent: O=C(Cl)c1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccn1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)OC)cc1
Yield: 100 %

Procedure:
Following the general procedure of Example 1 for the preparation of the diacid chloride, 9.06 parts of terephthalic acid were added to a mixture of 11.82 parts of 4-methylpyridine and 14.1 parts phosgene in 200 parts dry dichloromethane at 25° to 30° C. The ratio of equivalents of methylpyridine base/COOH acid group was 1.16. After carrying out the reaction and esterifying the resulting diacid chloride by the procedure described in Example 1, a 100% yield of dimethyl terephthalate was obtained corresponding to a quantitive yield of terephthaloyl chloride formed initially in the reaction.
Reaction SMILES: NC1C=CC=CC=1.Cl[C:9]1[N:10]=[C:11](Cl)[C:12]2[N:17]=[C:16](Cl)[N:15]=[C:14](Cl)[C:13]=2[N:20]=1>C(Cl)(Cl)Cl>[N:17]1[C:12]2[CH:11]=[N:10][CH:9]=[N:20][C:13]=2[CH:14]=[N:15][CH:16]=1
Reactant: Clc1nc(Cl)c2nc(Cl)nc(Cl)c2n1
Solvent: Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: c1ncc2ncncc2n1
Yield: 199.2 %

Procedure:
8.7 mL (95 mmol) of aniline may be slowly added dropwise to a solution of 4 g (19 mmol) of 2,4,6,8-tetrachloropyrimidopyrimidine in 50 mL of chloroform in a water bath at about 0° C. The results of the reaction may be verified by thin layer chromatography (TLC). The reaction mixture may be washed with an aqueous ammonium chloride solution and extracted with chloroform. The organic layer may be separated, distilled under reduced pressure to remove the solvent, and dried in an oven to yield approximately 5 g of Compound 5a. Compound 5a may be a substantially pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[C:15]#[N:16])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[C:15]#[N:16])=[CH:7][CH:8]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C#N)n1-c1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C#N)n1-c1ccc(COS(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
To a solution of 1-(4-hydroxymethylphenyl)-5-methylpyrrole-2-carbonitrile (890 mg) in dichloromethane (9 ml) was added triethylamine (794 μl) and methanesulfonyl chloride (343 μl) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for an hour and then dichloromethane was added therein. The mixture was stirred and washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo to give 1-(4-methanesulfonyloxymethylphenyl)-5-methylpyrrole-2-carbonitrile (1.19 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[NH:10][CH:11]=O.P(Cl)(Cl)(Cl)=O.N1C(C)=CC=CC=1C>C1COCC1>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([CH:9]([N+:10]#[C-:11])[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(F)cc2F)cc1
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]C(c1ccc(F)cc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of N-[(2,4-Difluoro-phenyl)-(toluene-4-sulfonyl)-methyl]-formamide (2.07 g, 6.36 mmol) and THF (15 mL) is added phosphorous oxychloride (POCl3)(1.19 mL, 12.7 mmol) over a period of 5 minutes, and the resulting mixture stirred at room temperature for 10 minutes. The reaction is then cooled to 4° C. using an ice/water bath and 2,6-lutidine (4.45 mL, 38.2 mmol) is added over 30 minutes, maintaining the temperature less than 12° C. The cooling bath is removed and the mixture stirred at room temperature for 18 hours. The reaction mixture is poured into a stirred, ice water cooled, solution of ice and saturated aqueous NaHCO3. The mixture is extracted with ethyl acetate (2×). The combined organic extracts are washed with 1N aqueous hydrochloric acid, saturated aqueous NaHCO3, brine and dried (MgSO4). The solvents are removed in vacuo, and isopropanol (18.0 mL) added to the residual brownish solid. The resulting slurry is stirred at room temperature for 2 hours, then water (9.0 mL) is added and the slurry stirred for an additional 30 minutes at room temperature. The slurry is filtered, the cake washed with 2:1 isopropanol-water (2×) and dried in a vacuum-oven (30° C.) for 48 hours. The title compound may be obtained as a tan solid (1.33 g, 68%).
Reaction SMILES: C1([C:4]2([N:7]([CH2:40][C:41]3[CH:46]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:44]=[C:43]([OH:52])[CH:42]=3)[C:8](=[O:39])[CH:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]2)CC1.Cl[C:54](Cl)([O:56]C(=O)OC(Cl)(Cl)Cl)Cl.[OH-].[Na+].[NH2:67][CH2:68][C:69]([CH3:74])([CH3:73])[C:70]([NH2:72])=[O:71]>ClCCl>[NH2:72][C:70](=[O:71])[C:69]([CH3:74])([CH3:73])[CH2:68][NH:67][C:54](=[O:56])[O:52][C:43]1[CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=[C:41]([CH2:40][N:7]([C:8](=[O:39])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=3[Cl:38])=[CH:22][CH:21]=2)[CH2:10][NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:18])[CH:4]2[CH2:5][CH2:6]2)[CH:42]=1
Reactant: COCCCc1cc(O)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2(C3CC3)CC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CN)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC(=O)NCC(C)(C)C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl] (cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in dichloromethane (0.13 M) was added triphosgene (0.3 eq.) and then sodium hydroxide (1 M aq. solution, 3 eq.). The resulting mixture was stirred at RT for 2 h. The reaction was quenched with brine. The organic phase was separated and then added 3-amino-2,2-dimethylpropanamide (4 eq.). The resulting suspension was allowed to stir at RT for 16 h. The reaction was quenched with water and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the filtrate concentrated in vacuo. The crude product thus obtained was purified further by way of column chromatography (SiO2, 1:1 (v/v) Hex:EtOAc→EtOAc) to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2[NH:15][CH:16]=[CH:17][C:18](=O)[C:13]=2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6].S(Cl)([Cl:26])=O.CN(C=O)C.O>C(Cl)(Cl)Cl>[Cl:26][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[N:10]([C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[CH3:1])[N:11]=[C:12]([C:20]([F:23])([F:22])[F:21])[C:13]=12
Reactant: Cc1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(=O)cc[nH]c21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(Cl)ccnc21
Yield: 71 %

Procedure:
Compound (154d) (2.20 g) was dissolved in chloroform (14 mL), and thionyl chloride (1.00 mL) and DMF (0.148 mL) were added to the resulting solution, followed by reflux for 3 hr. Water was added to the reaction solution for distribution. The organic layer was washed with saturated sodium bicarbonate water. The organic layer after the washing was dried over anhydrous sodium sulfate, and the solvent was distilled away. 2-Propanol was added to the residue, and the precipitate was collected by filtration and then dried under reduced pressure to obtain compound (154e) (1.60 g, 71%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1C(=NO)C.P(Cl)(Cl)Cl.C([O-])(=O)C.[Na+].[C:22](#[N:24])[CH3:23].CC(N(C)C)=O>>[CH3:23][C:22]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:24]=1
Reactant: CC(=NO)c1ccc(O)cc1O
Reactant: CC#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClP(Cl)Cl
Product: Cc1nc2ccc(O)cc2o1
Temperature: 22.5 °C

Procedure:
To a mixture of 1-(2,4-dihydroxy-phenyl)-ethanone oxime (4.2 g, 25 mmol) and acetonitrile/dimethylacetamide (20 mL, 3:1) cooled by a water bath (20-25° C.) was added dropwide phosphorus chloride (2.4 mL, 26.2 mmol) over a period of fifteen minutes. The mixture was stirred for an additional thirty minutes before it was poured into ice water containing sodium acetate (6 g). The mixture was stirred for ten minutes, filtered, and the filter cake was washed with water and dried in vacuo to give the title compound as a yellow solid (3.15 g): 1H NMR (CDCl3, 200 MHz): δ=7.45 (m, 1H), 6.96 (m, 1H), 6.80 (m, 1H), 2.60 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][C:26](=[O:28])[NH2:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:30](=[O:32])[CH3:31])[CH2:25][C:26](=[O:28])[NH2:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(N)=O)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC(N)=O)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {2′-[(carbamoylmethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.CC(C)([O-])C.[K+].[C:20]([O:23][CH2:24][CH2:25]Br)(=[O:22])[CH3:21].C(OCC)(=O)C>C1COCC1>[CH2:24]([O:23][C:20]([C:21]1[N:8]([C:9](=[O:11])[CH3:10])[C:6]2[C:5]([C:12]=1[NH2:13])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)=[O:22])[CH3:25]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)Nc1cc(Cl)ccc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(N)c2ccc(Cl)cc2n1C(C)=O
Temperature: 0 °C
Yield: 45 %

Procedure:
Stir and cool to 0° C. a mixture of N-(5-chloro-2-cyanophenyl)acetamide (see Example 8, 1.0 g, 5.14 mmol) and THF (10 mL) and add potassium tert-butoxide (6.2 mL, of a 1M solution in THF) and stir at 0° C. for 30 min. Add bromoethyl acetate (0.6 mL) in one portion. Stir at room temperature for 2 h. Quench the reaction with water (40 mL) and stir with ethyl acetate. Separate the layers and reextract the aqueous with ethyl acetate. Combine the organic extracts and wash with water and brine. Dry over MgSO4 and concentrate under reduced pressure to obtain a brown solid. Triturate the solid with ether and collect a beige solid. Chromatograph the solid on silica gel with 2% ethyl acetate/dichloromethane followed by 10% ethyl acetate/dichloromethane to obtain 0.65 g (45%) of the title compound as a beige solid: MS 281(M+H), HPLC: Rt=3.20 min., TLC (silica gel, 10% ethyl acetate/dichloromethane) Rf=0.53.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].C(OP(Cl)(OCC)=O)C.[CH3:23][N:24]1[C:30](=[O:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[NH:27][C:26](=O)[CH2:25]1>O1CCCC1.O.C(O)(=O)C>[CH3:23][N:24]1[C:30](=[O:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[NH:27][C:26](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:25]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CN1CC(=O)Nc2ccccc2C1=O
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)=C1CN(C)C(=O)c2ccccc2N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 910 ml of diethyl malonate and 3.0 liters of tetrahydrofuran is cooled to 0° C. while stirring under argon and treated portionwise with 350 g of sodium hydride (55 percent oil dispersion) in such a manner that the temperature does not exceed 15° C. Thereafter, the mixture is stirred at room temperature overnight, cooled to 0°-5° C. and 290 ml of diethylchlorophosphate are added dropwise over a period of 15 minutes. After a further 2 hours at room temperature, the mixture is treated slowly with a suspension, warmed to ca 45° C., of 190 g of 4-methyl-3H-1,4-benzodiazepine-2,5(1H,4H)-dione in 2 liters of tetrahydrofuran, the addition taking ca 1 hour. The mixture is stirred at room temperature overnight, cooled to 5° C. and treated dropwise with 350 ml of glacial acetic acid. There is thus obtained a thick slurry which is again made well stirrable by the addition of 500 ml of water. The tetrahydrofuran is distilled off from the mixture and the partially crystalline residue is partitioned between ether and water. The organic phase is washed with water, dried and concentrated. The red-brown coloured residue is dissolved in 2 liters of boiling n-hexane and then cooled. The mixture is left to stand at 2° C. overnight and the resulting crystalline is filtered off under suction. The light yellow crystals are subsequently dissolved in 800 ml of hot toluene and crystallised by the addition of 600 ml of n-hexane and scratching. After standing in the cold overnight, the crystals are filtered off under suction and dried at 50° C. in vacuo. There is obtained diethyl (1,3,4,5-tetrahydro-4-methyl-5-oxo-2H-1,4-benzodiazepin-2-ylidene)malonate in the form of white crystals of melting point 139° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].[CH2:18]([NH:20]CC)[CH3:19]>C1COCC1>[CH2:18]([NH:20][C:8]1[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:19]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous K2CO3 (19 g, 144.5 mmol) is suspended in a solution of 3-Chloro-4-nitro-pyridine-1-oxide (10 g, 57.8 mmol) in anhydrous acetonitrle (100 mL). Excess diethyl amine (2.0 M) in THF is added to the above suspension under cold conditions (ice-bath). After complete addition of diethyl amine, the reaction mixture is allowed to warm to room temperature and left stirring overnight. The reaction mixture is filtered to remove K2CO3 and the filtrate evaporated under reduced pressure to remove volatile solvents. The organic residue is subjected to chromatography, eluting with 30% EtOAc-hexanes to afford 3-Ethylamino-4-nitro-pyridine-1-oxide as an orange solid. 1H NMR (300 MHz, CDCl3): δ8.0 1 (d, J=7.5 Hz, 1H), 7.91 (s, 1H), 7.8 (brs, NH), 7.44 (d, J=7.2 Hz, 1H), 3.30 (t, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), m/z 184 [M+1]
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: COc1cccc(CN)c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(CNC(=O)c2ccc3cnccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 3-methoxybenzylamine (56.6 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a clear oil (79.1 mg, 94%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[Br:17][CH:18](Br)[CH3:19]>CC(C)=O>[Br:17][CH2:18][CH2:19][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(Br)Br
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCBr)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
A mixture of 4-hydroxyacetophenone (20 g, 147 mmol) and potassium carbonate (81 g, 588 mmol) was placed into 2 L round bottomed flask and acetone (1 L) was added. To this reaction mixture dibromoethane (38 mL) was added in one portion, and then the reaction mixture was allowed to reflux for 36 hours, under nitrogen atmosphere. The reaction mixture was cooled to room temp, and filtered off, residue was washed with acetone (2×100 mL), and the filtrates were combined and concentrated under reduced pressure. The crude was chromatographed over silica gel by using 10-15% ethyl acetate/pet. ether (2 L), affording the title compound 7 g (20%) as a white solid. Mp. 58-61° C.
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[CH3:9][O:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[CH3:9][O:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[N:13]1[C:6]([CH3:7])=[CH:5][CH:1]=[C:2]1[CH3:4]
Reactant: CC(=O)CCC(C)=O
Reactant: COc1ccc(N)c(OC)c1
Product: COc1ccc(-n2c(C)ccc2C)c(OC)c1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 1, acetonyl acetone (5.88 mL, 50 mmol) and 2,4-dimethoxyaniline (7.12 mL, 50 mmol) reacted to give 1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 7.08 (dd, 1H), 6.59 (d, 1H), 6.55 (dd, 1H), 5.90 (s, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 1.97 (s, 6H); MS (ESI) 232 (M+H)+.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH3:19])=[CH:17][N:18]=[C:14]3[CH:13]([OH:20])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3Cl)[C:10]=2[CH:28]=1.C(O)C.[OH-].[Na+]>O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH3:19])=[CH:17][N:18]=[C:14]3[CH:13]([OH:20])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH:28]=1
Reactant: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2O

Procedure:
A stirred suspension of 294 mg. of 8-chloro-4-hydroxy-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine acetate (1b) in 25 ml. of absolute ethanol under nitrogen is stirred for about 3 hours at room temperature (about 25° C.) with 2.2 ml. of 0.5N aqueous sodium hydroxide, poured into water and extracted with methylene chloride. The extract was dried and concentrated and the residue chromatographed on silica gel, eluting with ethyl acetate to yield 8-chloro-4-hydroxy-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22].O>O1CCCC1>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:15]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reaction time: 0.08 h
Yield: 92 %

Procedure:
Lithium hexamethyldisilazane [1.0 M] (44.7 mL, 44.4 mmol) was added to a solution of 5-bromo-1H-indole (7.30 g, 37.0 mmol) in tetrahydrofuran (50 mL) at room temperature. After stirring for 5 minutes, triisopropylsilyl chloride (8.62 g, 44.4 mmol) was added to reaction mixture and stirred for 30 minutes. Water was added to quench the reaction and the solvent was removed under reduced pressure to give the crude mixture, which was purified via column chromatography on silica gel (9:1 Hexane/ethyl acetate) to give the title compound in 92% yield. 1H NMR (CDCl3) δ 7.74 (d, J=1.8, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.22 (m, 2H), 6.55 (d, J=3.1 Hz, 1H), 1.65 (m, 3H), 1.12 (d, J=7.5 Hz, 18H).
Reaction SMILES: C([Li])CCC.[CH:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22]>>[F:15][C:16]1[C:17]([F:22])=[CH:18][CH:19]=[CH:20][C:21]=1[CH:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCC=O
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Product: CCCCCCCC(O)c1cccc(F)c1F

Procedure:
Quantities: n-butyllithium (30 cm3, 10.0M in hexanes, 0.3 mol), octanal (38.5 g, 0.3 mol) and 1,2-difluorobenzene (34.5 g, 0.3 mol). The experimental procedure was as described in Example 16.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[CH2:19]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:20]([CH3:22])[CH3:21]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)CNCC(C)C
Solvent: CCO
Product: CC(C)CN(CC(C)C)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
A mixture of 26 g of 3-nitro-4-chloro-benzophenone, 20 ml. of ethanol and 35 ml. of diisobutylamine is heated to 80° to 85°C under stirring, and the raction mixture is kept at this temperature for 6 hours. When the reaction is over, the ethanol is distilled off under reduced pressure, and 260 ml. of petroleum ether (b.p.: 40° to 100°C) are added to the solid residue. The separated diisobutylamine hydrochloride is removed by filtration, the filtrate is evaporated, and the residue is recrystallized from ethanol. 32.7 g. of 3-nitro-4-(N,N-diisobutylamino)-benzophenone are obtained; m.p.: 80°-81°C (compound B9 supra).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[C:7]1[CH:27]=[CH:26][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18](C(OCC)=O)[CH2:17][CH2:16]2)=[CH:9][CH:8]=1.[OH-].[K+]>CC(O)C>[NH:18]1[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:26]=[CH:27][C:7]([C:2]3[O:1][CH2:6][CH2:5][CH2:4][N:3]=3)=[CH:8][CH:9]=2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)N1CCC(CCCOc2ccc(C3=NCCCO3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1cc(C2=NCCCO2)ccc1OCCCC1CCNCC1
Yield: 100 %

Procedure:
A mixture of ethyl 4-[3-[4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenoxy]propyl]-1-piperidinecarboxylate, 26,3 parts of potassium hydroxide and 200 parts of 2-propanol was stirred and refluxed for 3 hours. After evaporation, water was added ant eh solvent was distilled off till all traces of 2-propanol were removed. After cooling, ice water was added to the product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated, yielding 14.5 parts (100%) of 5,6-dihydro-2-[4-[3-(4-piperidinyl) propoxy]phenyl]-4H-1,3-oxazine as a residue (int. 60).