Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2>C(O)(=O)C.O.[Zn]>[ClH:1].[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(NC1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2sc(C(=O)NC3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
129 mg (0.35 mmol) of rac-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-nitro-1-benzothiophene-2-carboxamide hydrochloride are dissolved in a mixture of 5 ml of acetic acid and 3 ml of water. 114.7 mg (1.75 mmol) of zinc are added, and the mixture is stirred at RT for 5 h. The reaction mixture is filtered through kieselguhr, the solvent is removed and the residue is taken up in dichloromethane. The resulting solution is washed with 1N aqueous sodium hydroxide solution. The organic phase is dried over sodium sulfate and the solvent is then removed under reduced pressure. The resulting solid is dissolved in a little THF, and an excess of 1N HCl in diethyl ether is added. The THF is then distilled off. 103 mg (80% of theory) of the title compound are isolated.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C@H:11]([C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.Cl[Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27]>CN(C)C=O>[C:1]1([S:7]([CH2:10][C@H:11]([C:13]2([O:18][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](CS(=O)(=O)c1ccccc1)C1(O)CCCC1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC1([C@H](C)CS(=O)(=O)c2ccccc2)CCCC1
Temperature: 0 °C
Yield: 123.9 %

Procedure:
To a solution of 6a (2.40 g, 8.94 mmol) and imidazole (1.22 g, 17.9mmol) in N,N-dimethylformamide (20 mL) was added chlorotriethylsilane (2.2 mL, 13.1 mmol) in one portion. The mixture was stirred at ambient temperature for 3d. The mixture was poured into ice water, and extracted with diethyl ether. The combined organic layers were washed with water and brine, and dried over sodium sulfate. Filtration and concentration gave 4.24 g of an oily material, which was purified by column chromatography (silica gel 40 g, ethyl acetate in n-hexane, 10%) to give 3.67 g (quantitative) of 7a, as a colorless oil.
Reaction SMILES: [F:1][B-](F)(F)F.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([N+]#N)=[CH:11]2.C(OCC)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:12]1[CH:13]=[N:14][C:15]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:7][CH3:6])=[CH:17][CH:16]=2
Reactant: COc1ccc2ncc([N+]#N)cc2c1
Reactant: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(F)cc2c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A suspension of 1007 g of 6-methoxy-3-quinolinediazonium fluoroborate taken in 9 l of toluene is heated to 60° C. in 85 minutes. A release of gas is observed at 60° C. The reaction medium is then gradually heated further for 90 minutes to 70-72° C. After having been kept at 72° C. for 90 minutes, the medium is then gradually heated again to 85° C. After cooling and stirring overnight, 4 l of ice-cold water are added to the suspension. After having stirred for 15 minutes, 2.5 l of ethyl acetate are added. After having stirred for 45 minutes, the pH is adjusted to pH=7-7.5 by adding 47% sodium hydroxide (250 ml). The medium is stirred for 30 minutes and then separated by settling out for 1 hour. The lower aqueous phase is re-extracted with ethyl acetate. The organic phases are combined together and washed with water. The solution is filtered and then concentrated under reduced pressure so as to give 655 g of crude 3-fluoro-6-methoxyquinoline. The crude product is distilled under reduced pressure. The distillation fractions (bp 103-110° C. under 1 mbar) containing the expected product are combined together. 498.9 g of 3-fluoro-6-methoxyquinoline (76%) are thus obtained in the form of a white solid which melts at 51-53° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1.[Cl:17][C:18]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:19]=1[CH2:20][NH:21][CH2:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][C:18]1[C:39]([C:40]([F:41])([F:42])[F:43])=[CH:38][CH:37]=[CH:36][C:19]=1[CH2:20][N:21]([CH2:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: FC(F)(F)c1cccc(CNCC(c2ccccc2)c2ccccc2)c1Cl
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reaction time: 96 h
Yield: 81.5 %

Procedure:
A solution of methyl [3-(3-bromopropoxy)phenyl]acetate (1.0 g, 3.48 mmole) and [2-chloro-3-(trifluoromethyl)benzyl]-2,2-diphenylethylamine (1.63 g, 4.18 mmole) in 20 mL of acetonitrile was treated with potassium carbonate (0.72 g, 5.2 mmol). The reaction mixture was heated to reflux and stirred for 4 days. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel cartridge, Biotage 32-63 um, 60A) with 10% ethyl acetate:hexanes as the eluent to afford 1.69 g (81% yield) of the title compound as a viscous oil: 1H NMR (CDCl3, 400 MHz) δ 7.46-7.44 (d, 1H, J=7.7), 7.25-7.14 (m, 12 H), 6.91-6.84 (m, 2 H), 6.666.62 (m, 2 H) 4.154.09 (t, 1 H, J=7.6), 3.78 (s, 1 H), 3.69-3.66 (m, 5 H), 3.59 (S, 2 H), 3.15-3.13 (d, 2 H, J=7.7), 2.72-2.68 (t, 2 H, J=6.6), 1.87-1.80 (m, 2 H); MS (ESI) 597 (MH+); TLC (hexanes:Ethy acetate/9:1) Rf=0.36.
Reaction SMILES: [S:1]1[C:5]([C:6]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([O:24]C)[CH:18]=[C:17]3[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)([C:8]2[N:9]([CH3:13])[CH:10]=[N:11][CH:12]=2)[OH:7])=[CH:4][C:3]2[CH:33]=[CH:34][CH:35]=[CH:36][C:2]1=2.Cl>C1COCC1>[S:1]1[C:5]([C:6]([OH:7])([C:8]2[N:9]([CH3:13])[CH:10]=[N:11][CH:12]=2)[C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[C:17]3[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[CH:4][C:3]2[CH:33]=[CH:34][CH:35]=[CH:36][C:2]1=2
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3cc4ccccc4s3)c3cncn3C)ccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1)c1cc2ccccc2s1
Yield: 28 %

Procedure:
Following the same procedure as described in example 1F, benzo[b]thiophen-2-yl-[4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(3-methyl-3H-imidazol-4-yl)-methanol (147.2 mg, 0.287 mmol) was treated with HCl in aqueous THF to yield the title compound of 41B as a yellow solid (40 mg, 28% yield).
Reaction SMILES: [Na].[CH3:2][N:3]1[S:7](=[O:9])(=[O:8])[NH:6][C:5](=[O:10])[CH:4]1[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[F:16][C:17]1[N:22]=[C:21]([F:23])[C:20]([F:24])=[C:19](F)[C:18]=1[F:26].C1OCCOCCOCCOCCOC1>C(#N)C>[F:23][C:21]1[C:20]([F:24])=[C:19]([N:6]2[C:5](=[O:10])[CH:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:3]([CH3:2])[S:7]2(=[O:9])=[O:8])[C:18]([F:26])=[C:17]([F:16])[N:22]=1
Reactant: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: C1COCCOCCOCCOCCO1
Agent: [Na]
Solvent: CC#N
Product: CC(C)CCC1C(=O)N(c2c(F)c(F)nc(F)c2F)S(=O)(=O)N1C
Yield: 40.6 %

Procedure:
To a mixture of the sodium salt of 5-methyl-4-(3-methylbutyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 4.13 mmol, prepared by treatment with sodium methoxide), pentafluoropyridine (0.54 ml, 4.97 mmol), and 0.91 g (4.13 mmol) of 15-Crown-5 suspended in 30 ml of acetonitrile was refluxed for 17 hours. The mixture was cooled, concentrated in vacuo, and the residue extracted with methylene chloride, and the organic layer was washed with water (3×) and brine. After drying over sodium sulfate, the organic layer was concentrated in vacuo and a crude product was purified by flash chromatography (10% ethyl acetate in hexane) to afford 0.62 g (41%) of 2-(2,3,5,6-tetrafluoro-4-pyridyl)-5-methyl-4-(3-methylbutyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide. (Formula I: R1 =(CH2)2 CH(CH3)2 ; R2 =H; R3 =CH3), as a solid, m.p. 80.5°-81.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][N:15]([C:17](=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28][C:29]1[N:34]=[C:33]([C:35](Cl)=[O:36])[CH:32]=[CH:31][N:30]=1>N1C=CC=CC=1.Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:35]([C:33]2[CH:32]=[CH:31][N:30]=[C:29]([S:28][CH3:27])[N:34]=2)=[O:36])[N:15]([C:17](=[O:26])[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nccc(C(=O)Cl)n1
Reactant: CN(NC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)Cc1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CSc1nccc(C(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)N(C)C(=O)Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a stirred solution of 4-{N′-[2-(4-fluoro-phenyl)-acetyl]-N′-methyl-hydrazino}-piperidine-1-carboxylic acid tert-butyl ester, 9, (3.7 g, 10.1 mmol) in pyridine (10 mL) is added 2-methylsulfanyl-pyrimidine-4-carbonyl chloride (2.9 g, 15.2 mmol). The reaction mixture is stirred at room temperature for 2 hours then diluted with 0.1 N HCl and extracted three times with CH2Cl2. The combined organic layers are dried (MgSO4), filtered and concentrated in vacuo. Purification over silica (EtOAc/hexanes 1:1) affords 1.058 g (20% yield) of the desired product. ESI/MS: 518.2 (M+H).
Reaction SMILES: [K].[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][Br:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: BrCCCCCCBr
Reactant: CC(C)c1ccc(O)cc1
Agent: [K]
Product: CC(C)c1ccc(OCCCCCCBr)cc1

Procedure:
The intermediate 6-(4-isopropylphenoxy)hexyl bromide was prepared from the potassium salt of 4-isopropylphenol and 1,6-dibromohexane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[SH:18].[O-]CC.[Na+].[CH2:23]1O[CH:24]1[CH3:25]>C(O)C>[CH3:23][CH:24]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:4][C:3]=2[S:18][CH2:25]1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1S
Reactant: CC1CO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1CSc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1

Procedure:
To a solution of 4-amino-3-mercapto[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-benzene in ethanol containing a trace of sodium ethoxide can be added propylene oxide to the cold solution. An exothermic reaction occurs. When reaction subsides, the solution is heated on the steam bath. The product can be isolated and distilled to give 3,4-dihydro-3-methyl-7-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-2H-1,4-benzothiazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH2:14])[CH2:6]2.C(N(CC)CC)C.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][C:24](=[O:25])[C:23]([F:30])([F:29])[F:22])[CH2:6]2
Reactant: COc1cc2c(cc1OC)[C@@H](CN)C2
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc2c(cc1OC)[C@@H](CNC(=O)C(F)(F)F)C2
Reaction time: 2 h

Procedure:
To 2.9 g (15 mmol) of {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}amine in 7.5 mL of methanol, at ambient temperature, there are added, all at once, 2.1 mL (15 mmol/1 eq.) of triethylamine, and then, dropwise, over 20 minutes, 2.3 mL (19 mmol/1.25 eq.) of ethyl trifluoroacetate. Stirring is carried out at ambient temperature for 2 hours, followed by evaporating to dryness. The residue is taken up in 100 mL of dichloromethane, and washing with 50 mL of 1N hydrochloric acid and then 50 mL of water and drying over magnesium sulphate are carried out. After filtration and concentration, the desired product is collected.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[CH:11]=[N:10]2)=[C:4]([F:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[CH:6][C:5]([N:9]2[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[CH:11]=[N:10]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cn1c(=O)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cnn(-c2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2F)c1=O

Procedure:
2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione is reacted with potassium carbonate and 4-fluoronitrobenzene in N,N-dimethylformamide to form 2-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. 2-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione is reduced with iron powder in acetic acid and water to produce 2-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. To a mixture of 2-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione in hydrochloric acid is added acetone. The mixture is cooled to about 5° C., and in succession a solution of sodium nitrite in water and methyl acrylate is added. The resultant mixture is stirred for 15-30 minutes. Thereafter, copper (I) chloride is added slowly. This mixture is stirred at room temperature for approximately 30 minutes and then is poured into ice water. Extraction with an organic solvent (e.g., ethyl acetate) and subsequent purification yields methyl 2-chloro-3-[4-[2-chloro-4-fluoro-5-(4-methyl-3,5-dioxo-2H,4H-1,2,4-triazin-2-yl)-phenoxy]phenyl]-propionate.
Reaction SMILES: C([SiH](CC)CC)C.[I:8][C:9]1[C:18]([O:19][CH2:20][CH2:21][C:22]2[N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=[CH:25][N:26]=2)=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1.FC(F)(F)C(O)=O>>[NH:23]1[CH:24]=[CH:25][N:26]=[C:22]1[CH2:21][CH2:20][O:19][C:18]1[C:9]([I:8])=[N:10][CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cnc(I)c(OCCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc(I)c(OCCc2ncc[nH]2)c1
Reaction time: 4 h
Yield: 62.5 %

Procedure:
Triethylsilane (0.160 mL, 1.00 mmol) was added to a solution of 1.45 g (2.36 mmol) of methyl 6-iodo-5-(2-(1-trityl-1H-imidazol-2-yl)ethoxy)nicotinate in trifluoroacetic acid (30.0 mL, 389 mmol). The mixture was stirred for 4 hours, concentrated in vacuum and triturated with 50 ml of anhydrous ethyl ether. The solid material was collected, washed with several portions of ether and partitioned between 1 M of aqueous sodium carbonate and ethyl acetate. The organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuum to give a residue (0.55 g, 62%) of methyl 5-(2-(1H-imidazol-2-yl)ethoxy)-6-iodonicotinate. MS(ESI+): 374.0
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH3:20])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:19][CH3:20])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CN(C)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CN(C)C(=O)OC(C)(C)C)ccc1N

Procedure:
In a 250 mL Parr apparatus, 0.98 g (3.5 mmol) of (3-methoxy-4-nitro-benzyl)-methylcarbamic acid tert-butyl ester in 40 mL of ethanol was hydrogenated at 2 atm over 300 mg of 10% Pd on carbon for 15 minutes. The catalyst was removed by filtration through a glass fiber filter and the filtrate was concentrated to give a crude product as light yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.69 (m, 3H), 3.95 (s, 2H), 3.84 (s, 3H), 2.8 (m, 2H), 2.75 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH:39]([OH:42])[CH2:40][CH3:41]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH:39]([OH:42])[CH2:40][CH3:41])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCC(O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Product: CCC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-amino-2-butanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.48 Hz, 3 H), 1.33-1.48 (m, 2 H), 1.49-1.59 (m, 4 H), 1.60-1.75 (m, 4 H), 2.37-2.44 (m, 2 H), 3.17-3.27 (m, 1 H), 3.33-3.42 (m, 4 H), 3.45-3.59 (m, 2 H), 4.16-4.24 (m, 4 H), 4.96 (d, J=5.26 Hz, 1 H), 7.14 (ddd, J=8.95, 6.63, 2.11 Hz, 2 H), 7.38-7.44 (m, 2 H), 8.00 (d, J=1.47 Hz, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.44 (t, J=5.16 Hz, 1 H), 17.22 (s, 1 H); ES+ MS: 539 (M+H+).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[O:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][OH:32]>C(#N)C>[CH3:9][C:7]1([CH3:8])[C:3]([CH3:22])([CH3:2])[O:4][B:5]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH2:30][CH2:31][OH:32])[CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[O:6]1
Reactant: OCCBr
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)cc2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(N3CCN(CCO)CC3)cc2)OC1(C)C
Temperature: 60 °C

Procedure:
To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine hydrochloride (500 mg, 1.54 mmol) and potassium carbonate (430 mg, 3.1 mmol) in acetonitrile (20 mL) was added 2-bromoethanol (388 mg, 3.1 mmol), then the mixture was heated at 60° C. overnight under an atmosphere of nitrogen. Then the mixture was filtered over celite and washed with DCM, concentrated to give product as a light brown solid. MS (m/z): 333 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([O:21]C)[CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[BrH:23]>>[BrH:23].[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:21])[CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CNCC2c1ccc(OC)c(OC)c1
Agent: Br
Product: Oc1ccc2c(c1)CNCC2c1ccc(O)c(O)c1

Procedure:
640 mg of 7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 13 ml of 48% aqueous hydrogen bromide, and the mixture was heated under reflux under an argon gas stream for 3 hours. The reaction solution was cooled, and crystals which separated out were collected, affording 580 mg of 7-hydroxy-4-[3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15]([Si:17]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:18]1[O:19][CH:20]=[C:21]([CH:23]=[O:24])[CH:22]=1)[CH3:16]>O1CCCC1>[OH:24][CH:23]([C:21]1[CH:22]=[C:18]([Si:17]([CH2:25][CH3:26])([CH2:15][CH3:16])[CH2:27][CH3:28])[O:19][CH:20]=1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(O)c1coc([Si](CC)(CC)CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dodecylmagnesium bromide (a 1M solution in tetrahydrofuran: 14.3 ml, 14.3 mmol) was added dropwise to a solution of 2-triethylsilyl-4-furaldehyde (2.0 g, 9.52 mmol) in THF (20 ml) at 0 degrees C under argon. After stirring at room temperature for 2 hours, the mixture was quenched with dilute HCl and extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 30% ethyl ether/hexane to give the titled alcohol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][CH:22]=1>>[N:21]1([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[CH:5]=[N:4][CH:3]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Clc1cncc(Nc2ccc(N3CCOCC3)cc2)n1
Product: c1ccc2c(c1)ncn2-c1cncc(Nc2ccc(N3CCOCC3)cc2)n1
Yield: 31 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-(4-morpholin-4-ylphenyl)pyrazin-2-amine (150 mg, 0.52 mmol) and benzimidazole (67 mg, 0.57 mmol) furnished the product (60 mg, 31%).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(C)(C)C.[CH3:18]I>>[N+:14]([C:10]1[CH:9]=[C:8]([CH:7]([CH3:18])[C:6]([OH:5])=[O:17])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Cc1cccc([N+](=O)[O-])c1
Product: CC(C(=O)O)c1cccc([N+](=O)[O-])c1

Procedure:
Using 3-nitrophenylacetic acid t-butyl ester as a starting material and methyl iodide (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 2-(3-nitrophenyl)propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br:13]Br>C(O)(=O)C.Br>[Br:13][CH:10]([CH3:11])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:12]
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(C)Br)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
0.30 mol of 4'-methoxypropiophenone is dissolved in 230 ml of glacial acetic acid and mixed with 3 drops of 48% HBr solution. In the stirred mixture, 0.30 mol of bromine is now slowly added in drops while being cooled in an ice bath such that the temperature in the flask does not exceed 15° C. The ice bath is removed, and it is stirred for about another 45 minutes in a continuous nitrogen stream to remove the HBR that is produced in the reaction. Then, it is carefully poured onto 300 ml of ice water. The settled precipitate is suctioned off, washed with several portions of water to remove all bromine and dried in a desiccator overnight. The crude product is recrystallized from 96% ethanol.