Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:40][N:41]([CH3:44])C=O>>[CH3:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=[C:10]([CH2:9][CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:28]2[N:29]([CH2:4][C:1]3[CH:3]=[CH:44][N:41]=[CH:40][CH:2]=3)[CH:30]=[CH:31][N:32]=2)[CH:18]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccncc2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (25 mg, 0.53 mmol), (4-bromomethyl) pyridine (14.1 mg 0.055 mmol, 1.05 equiv), and potassium carbonate (22.0 mg, 0.16 mmol) were combined in dimethylformamide (1.0 mL). After stirring at room temperature for 3 d, the solvents were removed and the residue purified by column chromatography to afford 23.0 mg (77%). Mass spec.: 563.3 (MH)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].O.[NH2:16][NH2:17]>>[NH:16]([C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8])[NH2:17]
Reactant: NN
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Solvent: O
Product: Cc1cc(-c2ccccc2)nnc1NN
Reaction time: 1 h

Procedure:
The mixture of 5 g of 3-chloro 4-methyl 6-phenyl pyridazine and 12 ml of hydrazine hydrate is taken to reflux. After one hour thirty minutes, the reaction medium is left to cool. A solid separates, which is drained and washed with a little water. The product is recrystallized in the mixture of isopropanol-isopropyl ether. Weight 4.5 g. m.p.: 162° C.
Reaction SMILES: [C:1]([C:4]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:14][CH2:15][CH:16]=[C:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[OH-:30].[Na+].[BH4-].[Na+].[OH-]>O.O1CCCC1>[C:1]([C:4]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH2:14][CH2:15][CH2:16][C:17]([OH:30])([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CCCCCC(C)=CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(C)(O)CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Mercuric acetate (3.8 g., 0.012 mole) is dissolved in water (12ml.) and tetrahydrofuran (20 ml.) is added to give a suspension of a yellow solid. Then, 8-acetyl-8-phenyl-12-methyl-11-heptadecenoic acid (4.8 g., 0.012 mole) in tetrahydrofuran (20 ml.) is added, and the mixture stirred at room temperature for 24 hours. After 6 hours, the yellow suspended solid has disappeared and a cloudy solution results. To the solution is added 3M sodium hydroxide solution (12 ml.), followed by 0.5M sodium borohydride solution in 3M solution hydroxide (12 ml.). Liquids are decanted from the precipitated mercury. The organic layer is taken up in ether, washed with three portions of water and dried over sodium sulfate. Evaporation of the ether leaves 8-acetyl-8-phenyl-12-hydroxy-12-methyl-heptadecanoic acid as a yellow viscous oil which is purified by chromatrography on silica gel with 4% methanol in chloroform as eluant.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].Cl>O.C(Cl)(Cl)(Cl)Cl>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:5](=[O:7])[CH3:6])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
514 grams (3.85 mol) of anhydrous aluminum chloride was put into 2 liters of carbon tetrachloride. While stirring vigorously, 302 grams (3.85 mol) of acetylchloride was added over a period of 1 hour at a temperature below 10° C. Subsequently, 469 grams (3.5 mol) of tert.butylbenzene was added to the reaction mixture over a period of 3 hours at a temperature below 5° C. After stirring for 1 hour without cooling, the reaction mixture was poured into a mixture of 500 milliliters of water, 1.7 kilograms of ice and 150 milliliters of 35% hydrochloric acid. The organic phase was separated, washed to neutrality and dried. After the solvent had been distilled off, 600 grams of 4'-tert.butylacetophenone was obtained having a refractive index nD20 = 1.5212. 444 grams (2.02 mol) of the above-described 4'-tert.butylacetophenone was mixed with 1.25 liters of glacial acetic acid and heated to 60° C. while stirring. Subsequently, at a reaction temperature of about 60° C., 375 grams (5.28 mol) of gaseous chlorine was passed into the reaction mixture for 41/2 hours. After the reaction mixture had been freed from hydrogen chloride gas and the excess of chlorine by passing through nitrogen, 414 grams (5.05 mol) of anhydrous sodium acetate was added and then the reaction mixture was heated to 95° C. Subsequently, another 185 grams (2.60 mol) of gaseous chlorine was passed into the reaction mixture for 2 hours at a temperature of about 95° C. The excess of chlorine was again removed with the aid of nitrogen and then the hot reaction mixture was filtered. After the addition of 63 milliliters of water, the clear filtrate was cooled to room temperature, which caused 2,2,2-trichloro-4'-tert.butylacetophenone to crystallize out. After filtering off by suction, washing and drying, 530 grams of white crystalline final product was obtained, having a melting point of 61.5° - 62.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[C:3]([CH2:8][N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ncccc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To a stirred suspension of 0.10 g (0.54 mmol) of 3-bromopyridine-2-carbaldehyde in 10 mL of dichloromethane was added activated powdered 4 Å molecular sieves, 0.20 mL (1.1 mmol) of N,N-diisopropylethylamine and 0.10 g (0.54 mmol) of tert-butyl piperazine-1-carboxylate. The resulting solution was stirred at ambient temperature for 1 h, then 0.34 g (1.6 mmol) of solid sodium triacetoxyborohydride was added in one portion. The heterogeneous reaction was allowed to stir at ambient temperature overnight and was then filtered through a pad of Celite®. The pad was washed with dichloromethane and the combined filtrates were washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-100% ethyl acetate in hexanes gradient to afford the title compound as a colorless gum (0.055 g, 29%). LC-MS: m/z (ES) 356.2, 358.2 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([OH:15])=O)[CH:8]=2)[NH:3]1.C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([Cl:19])=[O:15])[CH:8]=2)[NH:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (0.300 g, 1.455 mmol) in DCM (3 mL) was added oxalyl chloride (0.387 mL, 4.37 mmol) and a drop of DMF (anhydrous). The resulting mixture was then stirred at room temperature for 2 h, then the mixture was concentrated in vacuo to give 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carbonyl chloride. A solution of (S)-4-(3-fluoro-4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (50 mg, 0.137 mmol) in DCM (1 mL) at 0° C. was added 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carbonyl chloride (326 mg, 1.453 mmol), and DIEA (0.072 mL, 0.411 mmol). The resulting mixture was stirred at 0° C. for 30 min and then at room temperature for overnight. The reaction was diluted with H2O (5 mL) and EtOAc (7 mL). The mixture was then stirred at room temperature for 30 min. The mixture was then filtered and the organic layer was dried over MgSO4, and concentrated in vacuo. The residue was dissolved in DMSO (2 mL) and solution was purified by preparative HPLC (0-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 517.0 (MH+). 1H NMR (400 MHz, d4-MeOH) δ: 8.27 (dd, J=4.8, 1.3 Hz, 1H), 7.60-7.69 (m, 3H), 7.51-7.58 (m, 1H), 7.42-7.48 (m, 2H), 7.24 (d, J=8.4 Hz, 2H), 4.45-4.59 (m, 1H), 4.16-4.35 (m, 1H), 3.07-3.27 (m, 1H), 2.84-3.05 (m, 1H).
Reaction SMILES: [CH2:1]([NH:10][C:11](=[O:14])[CH2:12][Cl:13])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O>O>[Cl:13][CH2:12][C:11]1[O:14][C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:1][N:10]=1
Reactant: O=C(CCl)NCC(=O)c1ccccc1
Solvent: O
Product: ClCc1ncc(-c2ccccc2)o1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
N-Phenacyl chloroacetamide (22.6 g; 0.107 mole) was mixed with polyphosphoric acid (200 g) and the mass heated with stirring for 30 minutes at 150° C. The hot liquid was then poured with vigorous stirring into water (800 ml). The mixture so formed was extracted with 3 × 100 ml chloroform, the extracts washed by shaking with water and dried over magnesium sulphate. The CHCl3 was evaporated off and the remaining oil extracted with 400 ml boiling 60°-80°0 C. petroleum ether. The resultant solution was treated with decolourising charcoal to remove tarry matter and evaporated, giving a pale yellow oil which crystallized rapidly. Yield 18.8 g (91%) m.p. 70°-1° C.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:14]([O:16][C:17](=[O:25])[CH2:18]N1CCNCC1)[CH3:15].O.Cl>CN(C)C=O>[CH2:14]([O:16][C:17]([CH2:18][CH:9]1[CH2:5][CH2:4][N:3]([C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:2][CH2:10]1)=[O:25])[CH3:15]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCN(c2ncc(C(=O)O)cc2[N+](=O)[O-])CC1
Temperature: 130 °C
Yield: 162.2 %

Procedure:
A mixture of 2.00 g (9.87 mmol) of 6-chloro-5-nitro-nicotinic acid and 2.03 g (11.8 mmol) of piperazin-1-yl-acetic acid ethyl ester in N,N-dimethylformamide (10 mL) are heated to 130° C. in a microwave reactor for 1 hour. The resulting dark mixture is poured into water which forms a precipitate. The pH of the mixture is adjusted to approximately pH 2 by adding concentrated hydrochloric acid. The precipitated solid is collected by filtration, washed with water, and dried under reduced pressure to give 2.70 g (81.1%) of 4-ethoxycarbonylmethyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.Cl.[O-:24][C:25]#[N:26].[Na+]>>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[C:25]([NH2:26])=[O:24]
Reactant: Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Product: NC(=O)Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a mixture of 5-amino-3-(quinol-4-ylmethylene)-2-oxindole (2.873 g, 10 mmol) in ice water (20 ml) was added 5N HCl (2 ml, 10 mmol) under stirring. Then the mixture was heated to 70°-80° C., sodium cyanate (0.715 g, 11 mmol) was added portionwise and the stirring was continued for further 4 h at this temperature. After cooling, the raw product was extracted with CHCl3, the organic layer washed to neutrality with saline solution, dried and evaporated in vacuo. The residue was chromatographed on silica gel, using CHCl3 --MeOH mixtures as eluant to give pure title compound in about 50% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Na].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[O:14][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: COc1ccccc1CBr
Agent: [Na]
Product: COc1ccccc1COC(=O)Cc1ccc(Cl)cc1

Procedure:
4-Chlorophenylacetic acid, sodium salt, is reacted with 2-methoxybenzyl bromide to obtain 2-methoxybenzyl 4-chlorophenylacetate.
Reaction SMILES: Cl.O1CCCC1.COC[O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][S:44]([CH2:47][CH2:48][CH2:49][C:50]([F:56])([F:55])[C:51]([F:54])([F:53])[F:52])(=[O:46])=[O:45])=[CH:34][CH:33]=3)[C:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28]COC)=[CH:24][CH:23]=3)([CH3:21])[CH2:17][S:18]2)=[CH:13][CH:12]=1>O>[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][S:44]([CH2:47][CH2:48][CH2:49][C:50]([F:55])([F:56])[C:51]([F:52])([F:53])[F:54])(=[O:46])=[O:45])=[CH:34][CH:33]=3)[C:16]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)([CH3:21])[CH2:17][S:18]2)=[CH:13][CH:12]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1c1ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Aqueous 6N--HCl solution (1 ml) was added to tetrahydrofuran solution (1.5 ml) of (3RS,4RS)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-4-[4-(5-(4,4,5,5,5-pentafluoropentylsulfonyl)pentyloxy)phenyl]thiochroman (37 mg, 0.050 mmol) and then stirred for one hour. After adding water, the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The crude product thus obtained was purified using silica gel plate (ethyl acetate:hexane=1:2) to obtain 22 mg (yield: 70%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH:7]=O.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].N1CCCC1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[C:9]([C:11](=[CH:7][C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: Cc1nnsc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCOC(=O)C(C#N)=Cc1snnc1C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To 50 ml of toluene were added 1.5 g (12 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbaldehyde, 1.5 g (13 mmol) of ethyl cyanoacetate, 0.40 g (6.0 mmol) of pyrrolidine and 0.20 g (1.2 mmol) of tosylic acid. In a reactor equipped with a Dean-Stark dehydrating apparatus, the mixture obtained above was stirred for 2 hours with heating under reflux. After the reaction was completed, a saturated aqueous solution of sodium chloride was added to the reaction mixture, the objective product was extracted with ethyl acetate, the organic layer was washed successively with dilute hydrochloric acid, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.73 g of the objective compound was obtained.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]2[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=2)=[CH:15][CH:16]=1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: COc1ccccc1CN
Product: CCCCCCCCc1noc(-c2ccc(CNCc3ccccc3OC)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-methoxybenzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 408.4. HPLC (Condition A), Rt: 4.12 min (HPLC purity: 91.9%).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:19])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:16]([O-:18])=[O:17])[CH:5]=2.[CH:20]1(C2C3C(=CC(C([O-])=O)=CC=3)N(C)C=2)[CH2:24]CC[CH2:21]1.BrBr>>[Br:1][C:2]1[N:3]([CH3:19])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:16]([O:18][CH:20]([CH3:24])[CH3:21])=[O:17])[CH:5]=2
Reactant: Cn1c(Br)c(C2CCCC2)c2ccc(C(=O)[O-])cc21
Reactant: Cn1cc(C2CCCC2)c2ccc(C(=O)[O-])cc21
Agent: BrBr
Product: CC(C)OC(=O)c1ccc2c(C3CCCC3)c(Br)n(C)c2c1

Procedure:
This process identified the optimal conditions for the synthesis of 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate via bromination of the corresponding 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate with bromine. It's very important to control the reaction temperature and to quench the reaction mixture with a mixture of aqueous sodium thiosulfate and 4-methylmorpholine to minimize the formation of the dibromo- and 2-indolone impurities. Further neutralization of the crude product with NaOH in isopropanol greatly increases the stability of the isolated product.
Reaction SMILES: C([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)=O.C1C[O:22][CH2:21]C1.CO.[BH4-].[Na+]>O>[OH:22][CH2:21][C:5]1[CH:4]=[CH:3][CH:18]=[CH:17][C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.3 g (43 mmol) of benzyl 4-formylbenzoate, 50 ml of THF and 50 ml of methyl alcohol are introduced into a round-bottomed flask. While cooling in an icebath, 820 mg (21.5 mmol) of sodium borohydride are added in small portions and the mixture is stirred at room temperature for two hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. 10.4 g (100%) of the expected product, melting point 55°-56° C., are collected.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[CH2:16][C:17]([O:19]CC)=O)[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[NH:11]3)=[CH:4][CH:3]=1.[CH3:26][NH2:27]>CO>[CH3:26][NH:27][C:17](=[O:19])[CH2:16][C:15]1[N:14]2[C:10]([NH:11][C:12]3[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=32)=[N:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CCOC(=O)Cc1c(-c2ccc(C)cc2)nc2[nH]c3ccccc3n12
Reactant: CN
Solvent: CO
Product: CNC(=O)Cc1c(-c2ccc(C)cc2)nc2[nH]c3ccccc3n12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g of ethyl 2-(4-methylphenyl)-9H-imidazo[1,2-a]benzimidazole-3-acetate in 60 ml of methanol are treated with 60 ml of liquid methylamine, while stirring the mixture at room temperature for 16 h. The solvent is evaporated under reduced pressure. The residue is washed with water and recrystallized twice from N,N-dimethylformamide. 0.8 g of compound is finally isolated. Melting point: 303°-308° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH:13]=[CH:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1.N1CCCCC1>CO>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C=CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C\CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-enyl]piperidine-1-carboxylate (0.0265 g, 0.0660 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.00964 g, 0.0660 mmol) and piperidine (0.0800 mL, 0.810 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((Z)-4-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-enyl)piperidine-1-carboxylate (0.0293 g, 84%).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCCCCCc1ccccc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCCCCCCCc2ccccc2)c(Nc2ccncc2)c1=O
Yield: 59 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 7-phenylheptylamine.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[I:18]I>CO.O>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[C:4]([I:18])[CH:3]=1
Reactant: Oc1c(Cl)ccc2cncnc12
Reactant: II
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Oc1c(Cl)cc(I)c2cncnc12

Procedure:
To a solution of 7-chloro-8-hydroxy-quinazoline (A69) (0.1 mol) and potassium acetate (0.15 mol) in MeOH and H2O (19:1, 250 mL) was added, over 30 min, a solution of iodine (0.095 mol) in MeOH and H2O (19:1, 350 mL). The mixture was then heated under reflux for 15 min, cooled and H2O (400 mL) was added. The precipitate was isolated by filtration, washed with saturated sodium thiosulfate and H2O, and dried. This provided 7-chloro-8-hydroxy-5-iodo-quinazoline (A70) as a solid.