Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]Br.Br[C:14]1[C:15](=[O:31])[NH:16][C:17](=[O:30])[C:18]=1[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[NH:21][CH:20]=1>C1C=CC=CC=1.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:14]2[C:15](=[O:31])[NH:16][C:17](=[O:30])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[NH:21][CH:20]=2)=[CH:2]1
Reactant: COc1ccc2[nH]cc(C3=C(Br)C(=O)NC3=O)c2c1
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg]Br
Solvent: c1ccccc1
Solvent: CCOCC
Product: COc1ccc2[nH]cc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2c1
Reaction time: 0.5 h
Yield: 2.7 %

Procedure:
To a suspension of 105 mg of indole in 20 ml of benzene were added 0.6 ml of a 3M solution of methylmagnesium bromide in diethyl ether under nitrogen. The mixture was stirred for 0.5 hour. 100 mg of 3-bromo-4-(5-methoxy-3-indolyl)-1H-pyrrole-2,5-dione were added and the mixture was heated to reflux for 5 days. After cooling the residue was partitioned between dichloromethane and 2M hydrochloric acid. The organic extracts were washed with water, dried and evaporated. The residue was purified on silica gel with 1% methanol in dichloromethane and then with 50% methanol/0.1% trifluoroacetic acid/water on Spherisorb to give 3 mg of 3-(3-indolyl)-4-(5-methoxy-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 280° C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:1]1([C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][C:22]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:24][CH:23]=4)[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2cc3ccccc3cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3cc4ccccc4cc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Under an argon atmosphere, 14.5 g of phenylboronic acid, 25.7 g of 2-bromoanthracene, 4.62 g of tetrakis(triphenylphosphine)palladium(0), 400 mL of toluene and 200 mL of a 2M aqueous solution of sodium carbonate were charged, and the mixture was refluxed with stirring for 8 hours. After cooling to room temperature, deposited crystals were separated by filtration. The resulting solids were recrystallized with toluene-hexane and washed repeatedly, whereby 19.1 g (yield: 75%) of 2-phenylanthracene was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1.[CH3:18][Li].O>O1CCCC1.C(OCC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7]([CH3:18])([OH:16])[C:6]=2[CH:17]=1
Reactant: [Li]C
Reactant: Cc1ccc2ccc3ccccc3c(=O)c2c1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(C)(O)c1ccccc1C=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the ketone from Step C (22 g) in dry tetrahydrofuran (400 ml) at 0° C. under nitrogen was added a solution of methyl lithium in diethyl ether (100 ml of 1.4M). The solution was stirred for 1 hr at 0° C. then water was cautiously added and solvents evaporated to give an aqueous mixture which was extracted with ether (2×150 ml). The combined extracts were washed with water, dried and evaporated. Crystallisation from ether/hexane gave 3,5-dimethyl-5H-dibenzo[a,d]cyclohepten-5-ol (20.18 g), m.p. 102°-103° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])N(C3C4CCCCC=4C(C#N)=CC=3)[C:36]2=[O:38])[CH2:32][CH2:31]1>>[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])[N:1]([C:2]3[C:7]4[N:8]=[C:9]([CH3:11])[O:10][C:6]=4[C:5]([C:12]#[N:13])=[CH:4][CH:3]=3)[C:36]2=[O:38])[CH2:32][CH2:31]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: Cc1nc2c(N)ccc(C#N)c2o1
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: Cc1nc2c(N3C(=O)[C@@H]4[C@H](O)CCN4C3=O)ccc(C#N)c2o1

Procedure:
The title compound was prepared from 11C by procedures analogous to those described in Example 2 (2E to 2F) to give the product as a white foam. HPLC: 99% pure at 10.55 min (retention time) (CHIRALPAK® OD column 4.6×250 mm; 25% isopropanol in hexane over 30 min, 1 ml/min, monitoring at 220 nm); MS (ES) m/z 313 [M+1]+.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[Br:22]Br.O>C(Cl)Cl>[CH2:20]([O:19][C:13](=[O:18])[CH:14]([Br:22])[C:15](=[O:16])[CH3:17])[CH3:21]
Reactant: BrBr
Reactant: CCOC(=O)CC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(Br)C(C)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
At −5° C. trimethylsilyl trifluoromethanesulfonate (36.9 mmol) is added dropwise to a solution of ethyl acetoacetate (30.7 mmol) and TEA (36.9 mmol) in DCM (50 mL). The solution is stirred for 90 min at 0° C. and treated over 30 min with a solution of bromine (30.7 mmol) in DCM (20 mL). After 60 min water (100 mL) is added, the layers are separated and the aq. layer is extracted three times with water (100 mL each). The organic layer is dried over MgSO4 and concentrated under reduced pressure to give the desired product which is used without further purification. 1H-NMR (CDCl3): δ=1.34 (t, J=7.16 Hz, 3H); 2.46 (s, 3H); 4.31 (q, J=7.20 Hz, 2H); 4.77 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH:6]=1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:8]([N:15]1[CH:2]2[CH:6]1[CH2:5][CH2:4][C:3]2=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC=C1Br
Reactant: NCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Product: O=C1CCC2C1N2Cc1ccccc1
Reaction time: 24 h

Procedure:
To a stirred solution of 2-bromocyclopent-2-enone (1.00 g, 6.21 mmol) in H2O (25 mL), tetrabutylammonium bromide (400 mg, 1.24 mmol) and benzyl amine (790 mg, 7.45 mmol) were added at room temperature. The reaction mixture was stirred for 24 hours and then extracted with EtOAc (100 mL). The organic layer was separated, washed with brine, and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 30% EtOAc/Hexanes afforded 6-benzyl-6-azabicyclo[3.1.0]hexan-2-one. MS ESI calc'd. for C12H13NO [M+H]+ 188. found 188.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][NH:22][C:23](Cl)=[O:24]>ClCCl>[CH3:21][NH:22][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CNC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution (ice bath) of piperazine-1-carboxylic acid tert-butyl ester (9.0 g, 48.32 mmol) and triethylamine (9.8 g, 96.64 mmol) in dichloromethane (100 mL) was slowly added a solution of methylaminoformyl chloride (5.0 g, 53.5 mmol) in dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight, and then partitioned in dichloromethane (200 mL) and water (100 mL). Organic layer was separated, dried (MgSO4), and concentrated to yield tert-butyl 4-(methylcarbamoyl)piperazine-1-carboxylate as a solid which was dissolved in dichloromethane (100 mL) and TFA (20 mL). The solution was stirred for 12 h and the volatiles were evaporated under pressure, the oily residue was dissolved in methanol and 1N hydrogen chloride solution was added. The solid formed was filtered and washed with ether, dried to give N-methylpiperazine-1-carboxamide hydrochloride, 8.12 g (93%)
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(C)(C)C)cc1Br
Yield: 102.3 %

Procedure:
Iodomethane (10.0 mL, 0.161 mol) was added to a mixture of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (29.5 g, 0.129 mol) and potassium carbonate (42.7 g, 0.309 mol) in dry acetone (400 mL) and the reaction mixture refluxed under nitrogen for 22 hours. The cooled reaction mixture was then concentrated and the residue partitioned between ethyl acetate (400 mL) and 0.3 M aqueous sodium hydroxide solution (300 mL). The organic phase was separated, washed with water (300 mL) and saturated brine (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)-1-methoxybenzene (32.09 g, 100% yield) as a light yellow oil.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:13])=[CH:4][C:3]=2[O:2]1.S(Cl)(Cl)=O.[CH3:18][C:19]1[O:20][CH2:21][CH2:22][N:23]=1>C(Cl)(Cl)Cl>[CH3:18][C:19]12[O:20][CH2:21][CH2:22][N:23]1[C:7](=[O:9])[C:6]1[CH:10]=[C:11]3[O:12][CH2:1][O:2][C:3]3=[CH:4][C:5]=1[O:13]2
Reactant: O=C(O)c1cc2c(cc1O)OCO2
Reactant: CC1=NCCO1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC12OCCN1C(=O)c1cc3c(cc1O2)OCO3
Reaction time: 1 h
Yield: 60.7 %

Procedure:
4,5-Methylenedioxysalicylic acid (0.472 g; 2.59 mmol) was suspended in 8 mL dry chloroform to which was added 0.476 g (4.00 mmol) thionyl chloride. The reaction mixture was heated at reflux for 3 h, during which time the suspension turned into a dark solution. The solution was allowed to cool to ambient and the solvent and excess thionyl chloride were removed in vacuo. The residue was dissolved in 8 mL methylene chloride and 0.392 g (4.60 mmol) 2-methyl-2-oxazoline was added dropwise. The solution was stirred for 1 h and then concentrated onto silica gel for subsequent purification by column chromatography (hexane/ethyl acetate=2:1) to yield 0.500 g of crude product. The product was recrystallized from ethyl acetate/hexane (1:10) to give 0.392 g (64% yield) of white crystalline solid with mp 132-133° C. IR (thin film): 1659, 1629, 1454, 1376, and 1267 cm-1. 1H NMR (500 MHz; CDCl3) δ 7.28 (1H, s), 6.48 (1H, s), 6.00 (2H, AB quartet), 4.27 (1H, dd, J=10.5 & 5.6 Hz), 4.17-4.23 (1H, m), 4.05-4.13 (1H, m), 3.55 (1H, td, J=10.6 & 6.5 Hz), and 1.59 ppm (3H, s).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[I:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[CH:14][C:13]=1[OH:20]>CC(C)=O>[I:11][C:12]1[C:13]([O:20][CH:2]([CH3:4])[CH3:3])=[CH:14][N:15]=[C:16]([O:18][CH3:19])[CH:17]=1
Reactant: COc1cc(I)c(O)cn1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(I)c(OC(C)C)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At 0° C., 758 mg (4.5 mmol) of 2-iodopropane and 948 mg (6.9 mmol, 2 eq.) of potassium carbonate were added to a solution of 861 mg (3.4 mmol) of 4-iodo-6-methoxypyridin-3-ol in 15 ml of acetone and the mixture was stirred at 80° C. overnight and concentrated under reduced pressure. After addition of water/ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 741 mg (73% of theory)
Reaction SMILES: C([S:4][CH:5]1[CH2:22][CH2:21][C:8]2([CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=O)C.[H][H].N>CO.O1CCCC1>[SH:4][CH:5]1[CH2:6][CH2:7][C:8]2([CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)[CH2:12][CH2:13]2)[CH2:21][CH2:22]1
Reactant: CC(=O)SC1CCC2(CCC(CCc3ccoc3)CC2)CC1
Reactant: [H][H]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: SC1CCC2(CC1)CCC(CCc1ccoc1)CC2
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A solution of 0.100 g of 9-acetylthio-3-(2-(3-furyl)ethyl)-spiro[5.5]undecane in 5 ml of methanol/tetrahydrofuran 3/1, was saturated with hydrogen and successively with gaseous ammonia and kept on standing for 3 hrs at room temperature. The mixture was evaporated to dryness and purified by flash chromatography (SiO2 ; n-hexane/diethylether 80/20) to give 0.080 g of 9-mercapto-3-(2-(3-furyl)ethyl)-spiro[5.5]undecane as a white sticky oil. TLC: Rf=0.38 (SiO2 plates, n-hexane/diethylether 80/20). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 7.36 (1H, m), 7.20 (1H, m), 6.27 (1H, m), 2.90 (1H, m), 2.48 (2H, t), 1.90-0.85 (19H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>CO.O.C(O)C>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[CH2:13][CH2:14][NH:15][CH:16]([CH3:17])[C:11]3=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=NCCn2c1ccc2-c1cccc(Cl)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CC1NCCn2c(-c3cccc(Cl)c3)ccc21
Yield: 57 %

Procedure:
6-(m-Chlorophenyl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine (2.0 g) was dissolved in a mixture of 100 ml of methanol and 10 ml of water under argon. The solution was treated portionwise with 0.9 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 150 ml of methylene chloride and washed with 50 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 70 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 2.0 g of yellow oil, was dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. The solution was concentrated to 10 ml and boiled briefly with 100 ml of ethyl acetate. There were obtained 1.7 g (57%) of 6-(m-chlorophenyl)-1,2,3,4-tetrahydro-1 -methylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 165°-167° C. (dec.).
Reaction SMILES: C[C:2]1[CH:18]=[C:5]2[N:6]([CH3:17])[C:7]3[CH:14]=[C:13]([S:15][CH3:16])[N:12]=[CH:11][C:8]=3[C:9](=[O:10])[N:4]2[N:3]=1.ClC1N=CC2C(=O)N3N=CC=C3N(C)C=2C=1>>[CH3:17][N:6]1[C:7]2[CH:14]=[C:13]([S:15][CH3:16])[N:12]=[CH:11][C:8]=2[C:9](=[O:10])[N:4]2[N:3]=[CH:2][CH:18]=[C:5]12
Reactant: CSc1cc2c(cn1)c(=O)n1nc(C)cc1n2C
Agent: Cn1c2cc(Cl)ncc2c(=O)n2nccc12
Product: CSc1cc2c(cn1)c(=O)n1nccc1n2C
Yield: 68 %

Procedure:
When 6-chloro-2,4-dimethylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 9 is replaced by 6-chloro-4-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 6, 4-methyl-6-(methylthio)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is obtained, yield: 68%; m.p. 267.4° (butyl alcohol).
Reaction SMILES: Br.[C:2]([CH:4]([NH:14][CH2:15][C:16]([NH2:18])=[NH:17])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:6]=1[Cl:13])#[N:3].O.[OH-].[Li+]>CO>[NH2:3][C:2]1[C:4]([C:5]2[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:6]=2[Cl:13])=[N:14][CH:15]=[C:16]([NH2:18])[N:17]=1
Reactant: N#CC(NCC(=N)N)c1cc(Cl)cc(Cl)c1Cl
Agent: Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine hydrobromide (95.36 g, 0.256 mole) was added in portions to a solution of lithium hydroxide monohydrate (16.11 g, 0.384 mole) in methanol (1.9 litres) at room temperature. The resulting solution was stirred at room temperature for 3 hours before being evaporated to dryness in vacuo. The resulting solid was slurried in water (1.15 litres) and collected by filtration. After drying at 50° C. in vacuo the crude material was purified by recrystallisation from toluene to give the desired product. Yield 69.51 g (93.8%), M.p. 178-180° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][N:22]=3)[N:17]([CH2:24][CH3:25])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH2:24]([N:17]1[C:18]2=[N:19][CH:20]=[CH:21][N:22]=[C:23]2[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1)[CH3:25]
Reactant: CCn1nc(-c2ccc(OCc3ccccc3)cc2)c2nccnc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCn1nc(-c2ccc(O)cc2)c2nccnc21
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-1H-pyrazolo[3,4-b]pyrazine (570 mg) and 10% Pd—C (50% wet, 200 mg) in MeOH (8 mL) and AcOEt (8 mL) was hydrogenated under balloon pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (240 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[NH:8][C:7]1=[O:17])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:21][CH2:22][Cl:23].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[N:8]([CH2:21][CH2:22][Cl:23])[C:7]1=[O:17])=[O:5])[CH3:2]
Reactant: ClCCBr
Reactant: CCOC(=O)n1c(=O)[nH]c2cc(OC)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(=O)n(CCCl)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-methoxy-2-oxo-2,3-dihydrobenzimidazole-1-carboxylic acid ethyl ester and 80% NaH (0.38 g; 0.013 mol) in anhydrous DMF was stirred 20 minutes at room temperature. Then 1-bromo-2-chloroethane (1.1 ml; 0.013 moles) was added and the solution was stirred overnight. After cooling, the reaction mixture was poured into water and the separated oil was extracted into ethyl acetate. The organic layer was dried over MgSO4 and evaporated under vacuum to give the crude title compound which was crystallized with diisopropyl ether. White solid. 1.35 g; m.p. 116-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:21]([O:22][CH3:23])=[CH:20][C:6]2[CH:7]3[N:12]([CH2:13][CH2:14][C:5]=2[CH:4]=1)[CH:11]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:10]1[C:9](=[O:19])[CH2:8]3.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-:32].[NH4+].Cl>O1CCCC1.CCOCC>[ClH:32].[CH3:1][O:2][C:3]1[C:21]([O:22][CH3:23])=[CH:20][C:6]2[CH:7]3[N:12]([CH2:13][CH2:14][C:5]=2[CH:4]=1)[CH:11]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:10]1[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:19])[CH2:8]3
Reactant: Br[Mg]c1ccccc1
Reactant: [Cl-]
Reactant: COc1cc2c(cc1OC)C1CC(=O)C3CCCCC3N1CC2
Agent: Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2c(cc1OC)C1CC(O)(c3ccccc3)C3CCCCC3N1CC2

Procedure:
To 6.3 g (0.02 mole) of 2,3,4,4a,6,7,11b,12,13,13a-decahydro-9,10-dimethoxy-1H-dibenzo[a,f]quinolizin-13-one in 100 ml of tetrahydrofuran is added dropwise 30 ml of a 2N solution of phenylmagnesium bromide in tetrahydrofuran. When the addition is complete, the mixture is refluxed for three hours and cooled after which 100 ml of saturated ammonium chloride solution is added. The organic and aqueous layers are separated and the aqueous layer is extracted with ether. The combined organic layers are dried over magnesium sulfate, filtered and evaporated in vacuo leaving an oily residue which is dissolved in dry ether and treated with excess ethereal hydrochloric acid. The resulting precipitate is collected and recrystallized from benzene-methanol to give 2,3,4,4a,6,7,11b,12,13,13a-decahydro-9,10-dimethoxy-13-phenyl-1H-dibenzo[a,f]quinolizin-13-ol hydrochloride, M.P. 227°-228° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].Cl[CH2:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=1>>[CH3:15][N:14]1[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=[C:10]1[CH2:9][CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC#C[Si](C)(C)C
Reactant: Cn1c(CCl)nc2ccccc21
Product: Cn1c(CCC#C[Si](C)(C)C)nc2ccccc21
Yield: 58.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 67(D), from trimethyl(prop-1-ynyl)silane (283 mg, 2.52 mmol) and 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole (380 mg, 2.10 mmol). The crude product was purified over prepacked 25 g silicagel column (DCM/MeOH from 100/0 to 98/2 as eluent) to afford 317 mg of 1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (Yield: 59%) as red solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=O.[CH2:20]=[C:21]([CH3:23])[CH3:22].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]2[CH2:20][C:21]([CH3:23])([CH3:22])[C:7]3[N:6]=[C:5]([C:8]#[N:9])[CH:4]=[CH:3][C:2]=3[NH:1]2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: N#Cc1ccc(N)cn1
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C#N)nc21
Temperature: 85 °C
Reaction time: 18 h
Yield: 12.9 %

Procedure:
To a stirred solution of 5-amino-pyridine-2-carbonitrile (9.3 g, 78.4 mmol) and 3-chloro-4-fluoro-benzaldehyde (12.3 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonitrile (3.2 g, 13.5%) as a light yellow solid: MS (ESI) M+1=316.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10].[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([NH2:10])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cccc(C)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1cc(Br)cc(C)c1N
Temperature: 145 °C
Yield: 21.6 %

Procedure:
To 2-methoxy-6-methyl-phenylamine (10.0 g) dissolved in acetonitrile (200 mL) was added N-bromosuccinimide (14.3 g) and the reaction mixture was heated to 145° C. for 15 minutes in a sealed microwave process vessel. The crude mixture was filtered through Celite, diluted with diethyl ether (200 mL) and washed with sodium hydroxide (2 M, 2×100 mL) and brine (1×100 mL). The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 3.4 g (26%) of the title compound as a black solid. 1H NMR (500 MHz, DMSO-d6): 2.06 (s, 3H), 3.77 (s, 3H), 4.55 (s, 2H), 6.78 (d, 1H), 6.82 (d, 1H).