Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][NH:30][CH2:31][CH2:32][C@H:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:34]([OH:36])=[O:35])[C:26]([OH:28])=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1.O>[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][N:30]([C:14]([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH2:31][CH2:32][C@H:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:34]([OH:36])=[O:35])[C:26]([OH:28])=[O:27])=[O:23])([CH3:19])([CH3:20])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC[C@H](NC(=O)OC(C)(C)C)C(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)C(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
1M NaHCO3 (5.9 ml, 5.92 mmol ) and benzyloxycarbonyl chloride (0.5 g, 0.42 ml, 2.96 mmol) were added to a solution of (S,S)-2,7-bis (tert-butyloxycarbonylamino)-4-azaoctanedioic acid (0.6 g, 1.48 mmol) in dioxane (40 ml ) and H2O (30 ml ) at 0° C. The mixture was stirred at 0° C. for 3 hours, at ambient temperature for 6 hours, evaporated, the residue triturated with chloroform (5 ml) and acetic acid to pH 5. The chloroform solution was evaporated and the product isolated after chromatography on silica gel (CHCl3 : MeOH 4:1).
Reaction SMILES: [OH-].[Na+].C1C(S(C2C=CC(Cl)=CC=2)(=O)=O)=CC=C(Cl)C=1.[C:20]([OH:25])(=O)[C:21](O)=O.C[C:27]1[C:32]([OH:33])=[C:31](C)[C:30](C)=[C:29]([C:36]([C:39]2C=CC(O)=C[CH:40]=2)(C)[CH3:37])[C:28]=1C>C1(C)C=CC=CC=1.O>[C:32]1([OH:33])[CH:31]=[CH:30][C:29]([C:36]2[CH:37]=[CH:21][C:20]([OH:25])=[CH:40][CH:39]=2)=[CH:28][CH:27]=1
Reactant: O=C(O)C(=O)O
Reactant: Cc1c(C)c(C(C)(C)c2ccc(O)cc2)c(C)c(C)c1O
Agent: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(-c2ccc(O)cc2)cc1
Temperature: 130 °C

Procedure:
This mixture was stirred and heated under a nitrogen atmosphere. To it was added over 8 minutes at 40°-49° C. aqueous sodium hydroxide (49.47%, 36.31 g, 447.8 mmole); the contents of the addition funnel were rinsed in with a total of about 6 ml of hot deionized water. Temperature was raised over 29 minutes to 109° C. and then over 1.5 hours to 122° C. while water was periodically drained from the Dean-Stark trap. Toluene was then removed over 27 minutes, the temperature rising to 160° C. A hot solution of 4,4'-dichlorodiphenylsulfone (64.62 g, 225.0 mmole) in toluene (75 ml) was then added over 25 minutes at a reactor temperature of 160° C., and the addition funnel was rinsed with about 10 ml of hot toluene. The mixture was stirred for 4 hours at 160°-162° C., becoming very viscous. To it were added in quick succession aqueous sodium hydroxide (49.47%, 0.19 g, 2.3 mmole), hot deionized water (about 1 ml), and toluene (5 ml). The added water was readily removed by distillation. The mixture was stirred about one hour longer at 160° C., then allowed to cool overnight. On the second day, chlorobenzene (195 g) was added, and the temperature was raised to 130° C. to effect complete solution. Methyl chloride was sparged in for one hour at 111°-114° C. to endcap the polymer; then oxalic acid 1.0 g (11 mmole) was added, and the mixture was stirred for 30 minutes at 109°-111° C. The solution was filtered through a layer of filter aid on a coarse porosity fritted-glass funnel. The polymer was recovered by coagulation in a Waring blender, washed thoroughly with water and methanol, and dried in a vacuum oven at about 150° C. Yield 66.98 g (63.4%), reduced viscosity (1 g/dl in N-methylpyrrolidone at 25° C.) 0.53 dl/g. The composition of the diphenol mixture used to make this copolymer was 70 mole percent tetramethylbisphenol A/30 mole percent bisphenol. Test results on the polymer containing tetramethylbisphenol A are given in Table 6.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O[CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:38][N:34]1[CH2:35][CH2:36][CH2:37][CH:33]1[CH2:32][CH2:31][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ccccc1CCCCc1ccccc1
Reactant: CN1CCCC1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCCC1CCOc1ccccc1CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 38.6 %

Procedure:
522 mg of diethyl azodicarboxylate were added, whilst ice-cooling and stirring, to a solution of 226 mg of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3), 390 mg of 2-(2-hydroxyethyl)-1-methylpyrrolidine and 790 mg of triphenylphosphine in 40 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 14 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The resulting yellow oily concentrate was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 130 mg (yield 38%) of the title compound as an oil.
Reaction SMILES: CN1CCCC1=O.[C:8]([NH:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15](F)[N:14]=1)([CH3:11])([CH3:10])[CH3:9].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[CH2:22]([NH:29][C:15]1[C:16]([F:20])=[CH:17][C:18]([F:19])=[C:13]([NH:12][C:8]([CH3:11])([CH3:10])[CH3:9])[N:14]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)Nc1nc(F)c(F)cc1F
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(NCc2ccccc2)c(F)cc1F
Temperature: 160 °C
Reaction time: 24 h
Yield: 119.2 %

Procedure:
To 20 ml of N-methylpyrrolidone were added 9.7 g of 2-(t-butylamino)-3,5,6-trifluoropyridine together with 15.5 g of benzylamine, and the mixture was stirred at 160° C. for one day and allowed to cool. After adding 50 ml of chloroform, the mixture was washed three times with 500 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain about 16.5 g of the title compound as a dark green oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.C([Li])CCC.CON(C)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][CH:23]=1)=[O:21].C(O)(C)C>C1COCC1.O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:20]([C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[CH:27][NH:28]3)=[CH:24][CH:23]=2)=[O:21])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: CON(C)C(=O)c1ccc2cc[nH]c2c1
Reactant: COc1cc(Br)cc(OC)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=O)c2ccc3cc[nH]c3c2)c1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A solution of 1-bromo-3,5-dimethoxybenzene (12.86 g, 59.3 mmol) in THF (60 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (23.7 mL, 59.3 mmol) and stirred for 30 min. Then a mixture of 1H-Indole-6-carboxylic acid methoxy-methyl-amide (5.50 g, 26.9 mmol) in THF (40 mL) was added and stirred for 3 h at −78° C. The mixture was quenched with isopropanol (12.5 mL, 162 mmol) and added water (40 mL). It was extracted with ether (3×50 mL), washed with water (2×50 mL), dried and concentrated to an oil, which was purified by flash column chromatography (EtOAc/Hexane) to give (3,5-dimethoxy-phenyl)-(1H-indol-6-yl)-methanone as an oil (3.70 g, 49% yield). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4]([C:10](OC)=O)=[CH:5][CH2:6]2.C1(C#[N:22])C=CC=CC=C1.CN.[OH-].[Na+]>CO>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4]([C:10]#[N:22])=[CH:5][CH2:6]2
Reactant: N#CC1C=CC=CC=C1
Reactant: COC(=O)C1=CCC2CCC1N2C
Agent: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C2CC=C(C#N)C1CC2

Procedure:
The reaction scheme C shown below is an example of reaction scheme for synthesizing an anhydroecgonine derivative (the formula 3) and a phenyltropane derivative (the formula 6) without producing cocaine as an intermediate. In detail, the reaction scheme C is a scheme in which methyl (1RS)-8-methyl-8-azabicyclo-[3.2.1]oct-2-ene-2-carboxylate (7:(1RS)-AECG ; such an abbreviation of a compound name is hereinafter described in a parenthesis and properly used) is synthesized, and then a fluoropropyl group is introduced thereinto at the N-8 position to synthesize methyl [1RS-(2-exo,3-exo)]-8-(3-fluoropropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (12:(1RS)-β-CIT-FP). Specifically, 2,4,6-cycloheptatriene-1-carbonitrile (4:CHT-CN) is allowed to react with methylamine in methanol solvent in the presence of sodium hydroxide to obtain (1RS)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carbonitrile (6:(1RS)-AECG-CN). The cyano group of this compound is hydrolyzed and then converted to a methyl ester group to obtain methyl (1RS)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate (7:(1RS)-AECG), which is allowed to react with phenylmagnesium bromide (PhMgBr) by a well-known method to obtain methyl [1RS-(2-exo,3-exo)]-3-phenyl-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (8:(1RS)-β-CPT). The tropane portion of this compound is converted to nortropane at the N-8 position, followed by substitution by a fluoropropane group at the N-8 position, whereby (1RS)-β-CIT-FP 12 can be obtained. optically active (1R)-β-CIT-FP can be obtained by optical resolution of (1RS)-β-CIT-FP 12 or by subjecting (1RS)-nor-β-CIT 11 to optical resolution to obtain an optically active substance in the course of the synthesis and continuing reactions shown in Reaction scheme C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]([CH3:26])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH2:24][CH3:25])([CH3:23])[C:20](O)=[O:21])[C:10](O)=[O:11])[CH3:8].S(=O)(=O)(O)O>C(OCC)C>[CH2:24]([C:19]([CH3:23])([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:9]([CH2:7][CH3:8])([CH3:26])[CH2:10][OH:11])[CH2:20][OH:21])[CH3:25]
Reactant: CCC(C)(CCCCCCC(C)(CC)C(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCC(C)(CO)CCCCCCC(C)(CC)CO
Temperature: 25 °C

Procedure:
A suspension of 1.6 grams (0.0425 mole) of lithium aluminum hydride in 40 ml of anhydrous diethyl ether was added, under vigorous stirring, with a solution of 4.87 grams (0.0170 mole) of 2,9-diethyl-2,9-dimethyl-1,10-decanedioic acid, and the resulting mixture was refluxed for 1 hour. After cooling to room temperature, the suspension was added with 12 ml of a 25% (v/v) aqueous solution of sulphuric acid. The obtained precipitate was removed by filtration and the filtrate was poured into 50 ml of a 20% aqueous solution of sodium carbonate under cooling and stirring. The organic layer was separated, washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under vacuum. 4.0 Grams (90.5% of theoretical) of the chromatographycally pure title compound were obtained.
Reaction SMILES: [OH-].[NH4+].[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:7]=[C:6]1S)[CH3:4]>[Ni].C(O)C>[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:7]=[CH:6]1)[CH3:4]
Reactant: CCn1cc(-c2ccc(O)cc2)nc1S
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cnc(-c2ccc(O)cc2)c1
Reaction time: 2 h

Procedure:
To a stirred mixture of 10 parts Raney-nickel catalyst and 96 parts of ethanol are added successively 9 parts of ammonium hydroxide and 9 parts of 4-(1-ethyl-2-mercapto-1H-imidazol-4-yl)phenol. Stirring is continued for 2 hours at reflux temperature. The reaction mixture is filtered and the filtrate is evaporated. The precipitated product is filtered off, washed with a small amount of a mixture of 2,2'-oxybispropane and ethanol, and dried, yielding 6.7 parts of 4-(1-ethyl-1H-imidazol-4-yl)phenol.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[N:11]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]2[C:3]=1[NH:4][N:11]=[CH:10]2
Reactant: O=N[O-]
Reactant: Cc1cc(Cl)cc(Br)c1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1cc(Br)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
2.20 g (10 mmol) of 2-bromo-4-chloro-6-methyl aniline were dissolved in 125 ml acetic acid. 0.69 g (10 mmol) of sodium nitrite dissolved in 2 ml water were added dropwise. The reaction mixture was stirred at rt for 4 h. Acetic acid was evaporated and the residue dissolved in EtOAc. The organic layer was washed with water, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was several times evaporated with heptane to yield 2.04 g (88%) of 7-bromo-5-chloro-1H-indazol as a light brown solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.23 (s, 1H), 7.91 (s, 1H), 7.67 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C:33](Cl)=[O:34])[CH:29]=1>>[CH3:27][C:28]1[O:32][N:31]=[C:30]([C:33]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=2)=[O:34])[CH:29]=1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5cc(C)on5)c4)CC3)cccc2n1
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 5-methyl-3-isoxazolecarbonyl chloride.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)(Cl)Cl.N1(C2C=CN=CC=2)CCCC1>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CCCCCCCBr
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCCCCCCBr)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
There were dissolved 11.6 g (52 mmol) of 8-bromooctanoic acid in 100 ml of CCl4 and around 5° C. (ice bath), there were added to the solution 5.41 g (50 mmol) of benzyl alcohol and 2.5 mmol of 4-pyrrolidino-pyridine catalyst. Thereafter, a solution of 10.73 g (52 mmol) of dicyclohexylcarbodiimide (DCC) in 10 ml of carbon tetrachloride was added portion-wise under stirring. The precipitation of the expected dicyclohexylurea (DCU) was effective after a few min and the temperature was allowed to come back to room temperature. After ½ hr, the reaction was complete as checked by TLC (hexane/ether 1:1). Then after about 1 hr, 0.5 ml of AcOH were added to quench remaining DCC and the DCU was filtered out after about one hour (yield 11.2 g=100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.CCN(CC)CC.[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:30](Cl)=[O:31])=[CH:24][CH:23]=1>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:30]([O:29][CH2:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[O:31])[CH2:2]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of tert-butyl(S)-piperidin-3-ylcarbamate (1.0 g, 5.0 mmol) and Et3N (0.76 mL) in CH2Cl2 was added Cbz-Cl (50% solution in toluene, 5.49 mmol, 0.78 mL) at 0° C. The reaction mixture was then warmed to rt and stirred for 3 h, diluted with CH2Cl2 (50 mL) and washed with water (3×5 mL). The organic layer was then dried over Na2SO4 and concentrated in vacuo to give (1.5 g, 89%) of the titled compound which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 7.35-7.38 (m, 5H), 5.13-5.12 (d, 2H), 4.61 (bs, 1H), 3.73-3.67 (m, 2H), 3.51-3.46 (m, 2H), 3.26-2.23 (m, 2H), 1.86-1.80 (m, 2H), 1.66-1.50 (m, 1H), 1.42 (s, 9H). LC-MS: m/z [M-100]=235 & [M+23]=357.
Reaction SMILES: BrBr.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8].C1OCCOCCOCCOCCOCCOC1.[F-:34].[K+]>C(OCC)(=O)C.O.O1CCOCC1>[Cl:3][CH2:4][CH2:5][CH:6]([F:34])[C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)=[O:8]
Reactant: [F-]
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: BrBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(F)cc1)C(F)CCCl
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A 1,4-dioxane (50 mL) solution of bromine (8.76 g, 54.8 mmol) was added to a 1,4-dioxane (50 mL) solution of 4-chloro-4′-fluorobutyrophenone (10.0 g, 49.8 mmol) at room temperature over 15 minutes, and the mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction twice with hexane. The organic layer thus obtained was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, an aqueous solution of 1.5 M sodium sulfite, and brine, and then was dried over anhydrous sodium sulfate. A portion (13.0 g) of a crude product (14.3 g) obtained by distilling off the solvent under reduced pressure was dissolved in N,N-dimethylformamide (90 mL), and 18-crown-6 (18.4 g, 69.8 mmol) and potassium fluoride (4.05 g, 69.8 mmol) were added to the mixture at room temperature. The mixture was stirred at the same temperature for 2 and a half hours, and then 18-crown-6 (6.15 g, 23.3 mmol) and potassium fluoride (1.35 g, 23.3 mmol) were added to the mixture, and the mixture was further stirred at the same temperature for one hour. Water was added to the reaction mixture, and the mixture was subjected to extraction twice with hexane. The organic layer thus obtained was washed with water and brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5, v/v) to give the title compound (5.47 g, yield: 55%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:16]([CH3:17])=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH3:18])[C:4]([CH3:7])=[CH:5][CH:6]=1.C(Cl)(=O)C(Cl)=O.[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[NH:31][CH2:30][C:29]=12.CCN(C(C)C)C(C)C>O1CCCC1.ClCCl.CN(C)C=O>[CH3:7][C:4]1[N:3]([C:8]2[C:9]([CH3:18])=[CH:10][C:11]([C:12]([N:31]3[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[CH2:34][N:28]4[CH:27]=[CH:26][CH:25]=[C:29]4[CH2:30]3)=[O:14])=[CH:15][C:16]=2[CH3:17])[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)cc(C)c1-n1c(C)ccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)cc(C)c1-n1c(C)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
A solution of 4-(2,5-dimethyl-1H-pyrrol-1-yl)-3,5-dimethylbenzoic acid of Step B (0.495 g, 2 mmol) was dissolved in tetrahydrofuran (10 mL) and treated with N,N-dimethylformamide (10 μL) followed by oxalyl chloride (250 μL, 2.85 mmol) added dropwise to control gas evolution. When the gas evolution subsided, the solution was warmed to reflux for 5 minutes. The solution was then concentrated in vacuo, the residue was dissolved in tetrahydrofuran and evaporated to dryness. The residue was redissolved in dichloromethane and the solution added dropwise to a cold solution (0° C.) of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.372mg, 2 mmol) and Hünig's base (0.5 mL) in dichloromethane. The solution was stirred overnight at room temperature, washed successively with 1N hydrochloric acid, saturated aqueous bicarbonate, and brine. The sample was then dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a yellow foam (0.75 g). Flash chromatography of this material on silica gel eluting with a solvent gradient of 10 to 20% of ethyl acetate in hexane, provided a white solid (0.130 g). Recrystallization of this material from ethyl acetate/hexane provided the title compound (0.120 g) as flat crystals, m.p. 197–199° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O1CCCC1.C(O)C>[N:1]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ccccc2n1
Yield: 84.7 %

Procedure:
3 g (31.9 mmol) of 2-aminopyridine were dissolved in 65 ml of tetrahydrofurane with magnetic stirring. The addition of 4.44 ml (31.9 mmol) of ethyl bromopyruvate caused precipitation of a solid. The heterogenous mixture was stirred with reflux for 4 h. After returning to r.t., the solid was isolated by filtration and taken up in 65 ml of ethanol in order to be stirred with reflux in 65 ml of ethanol for 16 h. After returning to r.t., the solid was isolated by filtration. The filtrate was placed in ice in order to facilitate crystallization of the product which was collected by filtration and thus so forth until the liquid phase remained limpid. The solid was rinsed with 30 ml of diisopropyl ether and dried in a vacuum bell jar in order to obtain 5.14 g (yield=84%) of ethyl imidazo[1,2-a]pyridine-2-carboxylate as a white powder. LC-MS: m/z=191 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.95 (s, 1H), 8.84 (d, J=6.8 Hz, 1H), 7.98-7.80 (m, 2H), 7.46 (t, J=7.2 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 1.35 (d, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Mg].II.[CH2:20]1[O:23][C@@H:21]1[CH3:22].[Cl-].[NH4+].[OH-].[NH4+]>O1CCCC1.[Cu]I.[Cu]>[Si:7]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([CH2:20][CH:21]([OH:23])[CH3:22])[CH:16]=[CH:15][CH:14]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Reactant: C[C@@H]1CO1
Agent: [Cu]
Agent: [Cu]I
Agent: II
Solvent: C1CCOC1
Product: CC(O)Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of (3-bromobenzyloxy)-tert-butyldimethylsilane (7.0 g, 24 mmol) in tetrahydrofuran (100 mL) under an atmosphere of nitrogen was added magnesium turnings (0.73 g, 30 mmol) and a crystal of iodine. The mixture was heated to reflux for 1 h, cooled to 0° C. and copper (I) iodide (4.57 g, 24 mmol) was added. After stirring at 0° C. for 5 min, (R)-(+)-propylene oxide was added and the mixture was stirred for 2 h. A mixture of ammonium chloride and ammonium hydroxide (5:1, 100 mL) was added, the biphasic mixture was stirred vigorously until the copper salts dissolved, and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the organic extracts were dried over magnesium sulfate and purified by flash column chromatography (ethyl acetate/hexanes). 1H NMR (CDCl3) 7.28 (m, 1H), 7.22 (m, 1H), 7.17 (s, 1H), 7.10 (d, 1H) 4.73 (s, 2H), 4.00 (m, 1H), 2.77 (d, 1H), 2.70 (d, 1H), 1.60 (s, 1H), 1.24 (d, 3H), 0.94 (s, 9H), 0.10 (s, 6H).