Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15]2)=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:15]2[CH3:26])=[C:11]([Cl:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2c(Cl)cc(OCc3ccccc3)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(OCc3ccccc3)cc2n1C
Temperature: 25 °C

Procedure:
After 3.70 g (11.2 mmol) of ethyl 6-benzyloxy-4-chloro-2-indolecarboxylate was added to a suspension of 0.45 g (11.2 mmol) of 60% sodium hydride in 70 ml of dimethylformamide, the mixture was stirred at room temperature. After the mixture became an almost transparent solution, a solution of 3.18 g (22.4 mmcol) of methyl iodide in 10 ml of dimethylformamide was dropwise added to the transparent solution at room temperature followed by stirring for 5 hours at the same temperature. The reaction solution was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate and the combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was isolated and purified by silica gel column chromatography to give 3.72 (96.4%) of ethyl 6-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].[F-].C[N+](C)(C)C>COCCOC>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:33]([F:35])([F:34])[F:32]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(C=O)c(Cl)c4)ccc3=O)ccnc2c1
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: COCCOC
Product: COc1ccc2c(OCCn3nc(-c4ccc(C(O)C(F)(F)F)c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 0 °C

Procedure:
To a stirring solution of 2-chloro-4-(1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzaldehyde (370 mg, 849 μmol) and (trifluoromethyl)trimethylsilane (121 μL, 849 μmol) in DME (10 mL) at −50° C. under nitrogen was added solid tetramethylammonium fluoride (79 mg, 849 μmol). The reaction was then removed from cooling bath and slowly warmed to 0°C. The reaction was then partitioned between DCM (100 mL) and 5% NaHCO3 (50 mL). The organic was dried over MgSO4, concentrated under reduced pressure, then purified on silica (40 g) eluting with 2 to 3% of MeOH/DCM. Product was isolated as an off white solid. MS (ESI pos. ion) m/z: 506 (MH+); calc'd for C24H19ClF3N3O4: 505.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[P:13]([O-:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN1CCOCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([P:13]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:20])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(P(=O)(OCC)OCC)cc1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A sealed pressure flask, flushed with N2, containing a mixture of 4-bromo-benzoic acid ethyl ester (2a) (5 g, 0.0218 mol), diethyl phosphite (3.093 mL, 0.024 mol), NMM (2.88 mL, 0.0262 mmol) and Pd(PPh3)4 (2.017 g, 0.00175 mol) in acetonitrile (20 mL) was stirred at ambient temperature for 5–10 min, then heated at 90° C. for 18 hours. The reaction mixture was filtered through celite, and the celite was washed with EtOAc (3—30 mL) until the filtrate showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on a rotary evaporator. The desired product was purified by silica gel flash chromatography to give a pale yellow oil (4.24 g). 1H NMR (300 MHz, CDCl3) δ (ppm)) 1.36 (m, 6H), 1.42 (t, J=7 Hz, 3H), 4.16 (m, 4H), 4.42 (q, J=7 Hz, 2H), 7.93 (m, 2H), 8.15 (m, 2H). 31P NMR (121 MHz, CDCl3) δ 17.63.
Reaction SMILES: CO[C:3]([C:5]1([CH3:30])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:14]=3)[NH:9][C:8]=2[CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[NH:6]1)=[O:4].C(N(CC)CC)C.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42].[C:44](=O)([O-])[O-:45].[Na+].[Na+]>ClCCl.O>[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][N:42]1[C:44](=[O:45])[N:6]2[CH:7]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[CH2:17][C:5]2([CH3:30])[C:3]1=[O:4])=[CH:14][C:13]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:12][CH:11]=4
Reactant: O=C([O-])[O-]
Reactant: CN(C)CCN
Reactant: COCCOc1ccc2[nH]c3c(c2c1)CC(C)(C(=O)OC)NC3c1cccc(O)c1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCCOc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCN(C)C)C(=O)N1C3c1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 100 mg (240 μmol) (1RS,3SR)-1-(3-hydroxy-phenyl)-6-(2-methoxy-ethoxy)-3-methyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester in 4 ml dichloromethane are added 126 μl (970 μmol, 4.00 eq.) triethylamine. The solution is cooled to 0° C. and a solution of 123 mg (610 μmol, 2.5 eq.) 4-nitrophenyl chloroformiate in 1 ml dichloromethane is added dropwise. The mixture is stirred for 10 min at 0° C. and for additional 30 min at room temperature. The solution is cooled again to 0° C. and 72.0 μl (660 μmol, 2.7 eq) 2-dimethylaminoethyl amine in 1 ml dichloromethane are added slowly. The mixture is allowed to warm up to room temperature over night. Water and a saturated aqueous solution of sodium carbonate are added and the aqueous layer is extracted with dichloromethane. The combined organic layers are dried with magnesium sulphate and the solvent is removed under reduced pressure (210 mg crude intermediate).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH2:20][CH2:21][OH:22])[C@@H:7]2[C@H:8]([O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13])[O:9][CH:10]=1)=[O:4].N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH2:20][CH2:21][O:22][C:29](=[O:31])[CH3:30])[C@@H:7]2[C@H:8]([O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13])[O:9][CH:10]=1)=[O:4]
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CCO)[C@H]12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CCOC(C)=O)[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
1.63 g of the above (1S,4aS,7aR)-1-[1-(ethoxy)ethoxy]-7-[2-(hydroxy)ethyl]-1,4a,5,7a-tetrahydrocyclopenta[c]pyrane-4-carboxylic acid methylester were dissolved in dichloromethane followed by addition of 1.7 ml of pyridine and DMAP. Next, 1.0 ml of acetic anhydride were added followed by stirring for 3 hours at room temperature. The reaction mixture was then extracted with ether. After washing the organic phase with 2N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ether eluate in the form of (1S,4aS,7aR)-7-[2-(acetoxy)ethyl]-1-[1-(ethoxy)ethoxy]-1,4a,5,7a-tetrahydrocyclopenta[c]pyrane-4-carboxylic acid methylester (1.65 g, yield: 89%). The physicochemical properties of this compound are described below.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:18])[CH:9]([NH:19]C(OCC3C=CC=CC=3)=O)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br>C(Cl)Cl.C(O)(=O)C>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:18])[CH:9]([NH2:19])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=S)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC1N=C(C2CCCCC2)c2ccccc2NC1=S
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
1,3-Dihydro-5-cyclohexyl-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-thione (787mg, 1.93 mmole) was dissolved in 40 ml of a 1:1 mixture of methylene chloride and acetic acid. The resulting solution was cooled to 0° C. and a continuous stream of hydrogen bromide gas was passed into the stirred solution for 10 minutes. The reaction vessel was capped and the reaction mixture was allowed to warm to ambient temperature over 5 hours. All volatiles were removed under reduced pressure and the yellow residual solid was azeotropically dried with toluene. This material was partitioned between 180 ml of ethyl acetate and 7.3 ml of 10% sodium carbonate solution. The resulting suspension was stirred for 5 minutes and then filtered. The filter cake was washed with ethyl acetate, dried in vacuo over phosporus pentoxide (40° C.), and triturated with ethyl acetatehexane (1:1) to give 492 mg of the title compound (93% yield).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.[CH3:25][C:26]1[C:31](C)=[C:30](O)[CH:29]=[CH:28][C:27]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:13])([F:12])[F:1])=[C:4]2[CH2:8][O:10][C:11]2[CH:29]=[CH:28][C:27]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:26]([CH3:25])[C:31]=2[CH3:30])=[CH:18][CH:17]=1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-n2ccc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared by (a) reacting the product prepared in Step B of Example 1 and 4-methoxyphenylboronic acid according to the procedure described in Example 1, Step C, (b) then reacting the resulting product according to the procedure in Example 1, Step D, and (c) then reacting the resulting product with ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate according to the procedures described in Example 1, Steps E and F.
Reaction SMILES: BrC1[C:3](OCC)=[CH:4][C:5]([N:10]([CH3:12])[CH3:11])=[C:6](C=1)[C:7]#[N:8].C[O-].[Na+].[CH:19]([O:21][CH3:22])=[O:20].O1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:22][O:21][C:19](=[O:20])[C:24]1[CH:3]=[CH:4][C:5]([N:10]([CH3:12])[CH3:11])=[C:6]([C:7]#[N:8])[C:25]=1[O:26][CH2:27][CH3:28]
Reactant: COC=O
Reactant: CCOc1cc(N(C)C)c(C#N)cc1Br
Reactant: C1COCCO1
Agent: C[O-]
Agent: [Na+]
Product: CCOc1c(C(=O)OC)ccc(N(C)C)c1C#N
Temperature: 60 °C
Yield: 12 %

Procedure:
To a solution of 5-bromo-2-dimethylamino-4-ethoxy-benzonitrile (1.95 g, 7.3 mmol) in 7.25 mL of dioxane was added sodium methoxide (581 mg, 10.77 mmol), methyl formate (1.85 mL, 30 mmol), and trans-dichlorobis(triphenylphosphine) palladium(II) (281 mg, 0.4 mmol). The mixture was agitated by bubbling nitrogen gas through the solution. To the opening of the vial is affixed a balloon. The reaction was cautiously warmed to 60° C. as gas evolution can cause a froth to enter the balloon. The reaction mixture was stirred for 20 h at 65° C. It was diluted with dioxane and stirred for an additional 5 min. The warm solution was filtered through Celite, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave cyano-4-dimethylamino-2-ethoxy-benzoic acid methyl ester (218 mg, 12%).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([NH:7]C2CCNCC2)=[CH:3][CH:2]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([CH2:48][CH:49]=O)([CH2:28][CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](O[C:61](=O)[CH3:62])OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(N(CC)CC)C>[CH2:15]([N:22]1[CH2:23][CH2:24][C:25]([CH2:48][CH2:49][C:1]2([CH3:14])[CH:2]=[CH:3][C:4]([NH:7][N:7]3[CH2:62][CH2:61][CH2:2][CH2:3][CH2:4]3)=[CH:5][CH2:6]2)([CH2:28][CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:26][CH2:27]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)[Si](OCCC1(CC=O)CCN(Cc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC1(CCC2(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CCN(Cc3ccccc3)CC2)C=CC(NN2CCCCC2)=CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 85.7 %

Procedure:
To a suspension of 4-(p-toluidino)piperidine ditrifluoroacetate (synthesized in Preparation Example 4-5) (0.63 g) in 1,2-dichloroethane (3 mL) was added triethylamine (0.42 mL). The suspension was stirred at room temperature for 25 minutes. Then, to the suspension was added [1-benzyl-4-[2-(tert-butyldiphenylsiloxy)ethyl]piperidin-4-yl]acetaldehyde (synthesized in Example 85) (0.75 g) in 1,2-dichloroethane (1.5 mL), and it was stirred at room temperature for additional 5 minutes. The reaction solution was ice-cooled, to which sodium triacetoxyborohydride (0.50 g) was added. After allowing the temperature to rise to room temperature, the solution was stirred for additional 15 hours. Saturated aqueous sodium bicarbonate solution was and it was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, ethyl acetate-chloroform (5:95)] to give the title compound (0.87 g).
Reaction SMILES: [CH2:1]1[CH:8]2[NH:9][CH:3]([CH2:4][C:5]([CH2:7]2)=[O:6])[CH2:2]1.Cl.O.C(Cl)Cl.[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([N:9]1[CH:8]2[CH2:1][CH2:2][CH:3]1[CH2:4][C:5](=[O:6])[CH2:7]2)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC2CCC(C1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1C2CCC1CC(=O)C2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A suspension of nortropinone hydrochloride (1 g, 6.187 mmol) in acetic anhydride was stirred at 70° C. for 3 h. Water was added, the mixture was boiled for 30 min and cooled down to room temperature. CH2Cl2 and 1N aqueous NaOH was added until pH 9 was reached. The mixture was extracted 2 times with CH2Cl2, the combined organic layers were dried over Na2SO4, filtrated and the solution was evaporated to dryness to give 0.7 g of 8-Acetyl-8-aza-bicyclo[3.2.1]octan-3-one (4a).
Reaction SMILES: [F:1][CH:2]([F:15])[S:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][CH:5]=1.S(=O)(=O)(O)[OH:17].[N+]([O-])(O)=O>>[F:15][CH:2]([F:1])[S:3]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][CH:5]=1)=[O:17]
Reactant: O=S(=O)(O)O
Reactant: FC(F)Sc1ccc(-n2cnnn2)cc1
Solvent: O=[N+]([O-])O
Product: O=S(c1ccc(-n2cnnn2)cc1)C(F)F

Procedure:
1-[p-(Difluoromethylthio)phenyl]-1H-tetrazole (1.0 gram) was added to a cold mixture of 5 ml. of concentrated sulfuric acid and 5 ml. of concentrated nitric acid and stirred for 40 minutes in the cold, then for 40 minutes at room temperature. The reaction mixture was poured onto ice and extracted with ethyl acetate. The ethyl acetate solution was extracted with water, dried over magnesium sulfate, and evaporated to afford an oil which was crystallized from ethyl acetate-hexane. Two recrystallizations from the same solvents gave 143 mg. of product, m.p. 109°-112° C.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2OC(=O)[S:21][N:20]=2)=[CH:15][CH:14]=1)#[N:12]>ClC1C=CC=CC=1Cl>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:1]([C:7]([O:9][CH3:10])=[O:8])[S:21][N:20]=2)=[CH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1ccc(-c2nsc(=O)o2)cc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1snc(-c2ccc(C#N)cc2)c1C(=O)OC

Procedure:
Dimethyl acetylenedicarboxylate (42.63 g, 0.4 mol) and 5-(p-cyanophenyl)-1,3,4-oxathiazol-2-one (20.42 g, 0.1 mol) were heated at reflux in o-dichlorobenzene for 10 hours. Volatile materials were removed under reduced pressure (1 mm). The red-brown residue contained at least three contaminants (g.c.) which were removed by crystallization from methanol. Four recrystallizations resulted in 18.1 g (0.0598 mol, 59.8%) of light yellow solid, m.p. 134°-135°.
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[F:6][C:7]1[C:12](F)=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17].C(=O)=O.CC(C)=O>C1CCCCC1>[CH:1]([C:12]1[C:11]([F:14])=[C:10]([F:15])[C:9]([F:16])=[C:8]([F:17])[C:7]=1[F:6])([CH2:3][CH3:4])[CH3:2]
Reactant: [Li]C(C)CC
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: CCC(C)c1c(F)c(F)c(F)c(F)c1F

Procedure:
A solution of sec-butyl lithium (350 ml; 12% in cyclohexane) was added over a period of 1 hour to a stirred mixture of hexafluorobenzene (80 g) in cyclohexane (750 ml) at a temperature of 0° C. On warming the reaction mixture above 0° C. a violently exothermic reaction took place which was brought under control by external cooling (Cardice-acetone). The reaction mixture was subsequently brought to room temperature (no further reaction occurred) and was quenched with water (600 ml). The organic layer was separated, washed with dilute hydrochloric acid (2N; 2×200 ml) and water (2×200 ml) and dried over anhydrous magnesium sulphate, and afterwards distilled through a 15 cm vigreux column. The fraction distilling at 160°-170° C. was collected to give sec-butylpentafluorobenzene (50.3 g), b.p. 162°-164° C. (760 mm), in the form of a colourless liquid.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:13][C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]=1>C1(C)C=CC=CC=1>[BrH:1].[CH2:19]([N:18]1[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:2][CH:3]([OH:12])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:14]1=[NH:13])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC(CBr)COc1ccccc1
Reactant: Nc1nc2ccccc2n1Cc1ccccc1
Solvent: Cc1ccccc1
Product: Br
Product: N=c1n(Cc2ccccc2)c2ccccc2n1CC(O)COc1ccccc1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
To a solution of 1-bromo-3-phenoxy-propan-2-ol (5) (248 mg., 1.07 mmol.) in toluene (2 mL.) was added 2-amino-1-benzylbenzimidazole (3) (200 mg., 0.90 mmol) and the mixture was heated at reflux overnight under N2 gas. The reaction mixture was cooled to room temperature and filtered. Crystallization of the collected solid from isopropanol gave 1 as white crystals (85 mg., 23%). Recrystallization of the mother liquor afforded additional 1 as white crystals (70 mg., 19%). 1H-NMR (DMSO-d6) δ 4.12 (s, 2H), 4.33 (s, 1H), 4.43 (s, 2H), 5.57 (s, 2H), 6.96 (m, 3H), 7.21-7.38 (m, 10H), 7.46 (d, J=8.0 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 9.18 (s, 2H); 13C-NMR (DMSO-d6) δ 45.58, 46.10, 66.54, 69.43, 110.53, 111.11, 120.71, 123.39, 123.47, 127.11, 127.91, 128.72, 129.39, 129.45, 130.39, 134.56, 150.27, 157.67, 158.33.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)n1ccc2c(C(=O)O)cc(Br)cc21
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a solution of methyl 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylate (0.52 g, 1.756 mmol) in methanol (15 mL) and tetrahydrofuran (3 mL) was added 3 M NaOH (1.756 mL, 5.27 mmol) via syringe drop wise (over 2 min) The solution was maintained at RT for 2 h, at which time LCMS showed only 12% conversion to product. Then 1.5 mL 3 M NaOH was added and the solution was maintained at RT overnight. LCMS showed complete conversion to product. Removed volatiles in vacuo and dissolved the residue in water and slowly acidified with 1 M HCl (solids precipitated). Extracted with EtOAc (2×), combined organics and dried over MgSO4. Filtered and concentrated in vacuo to give 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylic acid (0.50 g, 1.737 mmol, 99% yield) as a white solid.
Reaction SMILES: [IH:1].[C:2]1([CH:8]2[CH2:12][NH:11][C:10]([NH:13][NH2:14])=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2CN[C:23](=[S:26])N2)C=CC=CC=1.CI>C(O)C>[IH:1].[CH3:23][S:26][C:10]1[NH:11][CH2:12][CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1.[NH2:13][NH2:14]
Reactant: NNC1=NC(c2ccccc2)CN1
Reactant: S=C1NCC(c2ccccc2)N1
Agent: I
Solvent: CCO
Solvent: CI
Product: CSC1=NC(c2ccccc2)CN1
Product: NN

Procedure:
The starting material, 4-phenyl-2-imidazolin-2-ylhydrazine hydroiodide, is prepared as follows: 4-phenylimidazolidine-2-thione and methyliodide in refluxing ethanol yield 2-methylthio-4-phenyl-2-imidazolin hydroiodide, which upon treatment with hydrazine in boiling ethanol yields the desired intermediate, melting at 107°-108° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.[CH:30](O)=O>C(OC)(OC)OC.C(Cl)Cl.[Fe]>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:12]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=3[N:1]=[CH:30]2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(Nc2ccc(OCCOc3ccccn3)cc2)c([N+](=O)[O-])c1
Reactant: O=CO
Agent: [Fe]
Solvent: ClCCl
Solvent: COC(OC)OC
Product: O=C(O)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Nitro-4-({4-[2-(pyridin-2-yloxy)ethoxy]phenyl}amino)benzoic acid (6.00 g, 15.20 mmol), iron powder (8.49 g, 152.00 mmol), and formic acid (68 mL) were dissolved in dry trimethyl orthoformate (175 mL). The reaction was allowed to stir at rt. After 18 h, the reaction mixture was diluted with CH2Cl2 and filtered through Celite to give a bright orange solid. The crude mixture was recrystallized from methanol to give 1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxylic acid as a yellow-tan powder. 1H NMR (d6-DMSO, 400 MHz): δ 8.61 (d, J=2.4 Hz, 1H), 8.32 (d, J=1.6 Hz, 1H), 8.19 (ddd, J=5.2, 1.6, 0.8 Hz, 1H), 7.93 (dd, J=8.8, 1.6 Hz, 1H), 7.73 (ddd, J=8.8, 6.8, 1.8, Hz, 1H), 7.61 (ddd, J=4.8, 2.8, 2.8 Hz, 2H), 7.58 (s, 1H), 7.24 (ddd, J=5.2, 3.2, 3.2 Hz, 2H), 7.01 (ddd, J=6.8, 5.2, 1.2 Hz, 1H), 6.88 (dd, J=8.4, .4.0 Hz, 1H), 4.64 (t, J=4.2 Hz, 2H), 4.43 (t, J=4.6 Hz, 2H). MS(ES+): m/z 376.47 (10) [MH+].