Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][Br:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCO)cc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: COc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 3-(p-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol) in 250 mL of toluene, cooled to 0° C., was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the addition, the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3×) and brine (3×). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluting with 10% EtOAc/hexane, to obtain 14 g (61%) of 3-(p-methoxyphenyl)-1-propylbromide. 3-(p-Methoxyphenyl)-1-propylmercaptan
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]2[C:11]([CH:12]=[C:13]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:14]=[N:15]2)=[C:10](I)[N:9]=1)=[O:7].[CH3:35][O:36][CH2:37]/[CH:38]=[CH:39]/B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]2[C:11]([CH:12]=[C:13]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:14]=[N:15]2)=[C:10]([CH:39]=[CH:38][CH2:37][O:36][CH3:35])[N:9]=1)=[O:7]
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: COCCNC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC=Cc1nc(C(=O)NCCOC)c(OCc2ccccc2)c2ncc(Cc3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
To Compound 10 (286 mg, 0.5 mmol) and tetrakistriphenyl phosphine palladium (30 mg, 0.026 mmol) was added a dimethylformamide (4 ml) solution of 2-((E)-3-methoxy-propenyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (142 mg, 0.65 mmol), followed by an aqueous solution of 2 moles of potassium carbonate (0.66 ml, 1.32 mmol), and after vacuum deaeration under stirring at room temperature, and replacement with nitrogen, the reaction was heated under stirring in an oil bath at 100° C. After 3 hours, to the reaction mixture were added and dissolved ethyl acetate and water, and was added 10% citric acid (8 ml), and then the mixture was shaken for separation, washed twice with water, dried over sodium sulfate, and subjected to distillation under reduced pressure. The residue was subjected to high flash column chromatography (toluene:acetone (4:1)), and the obtained residue (170 mg) was crystallized from diisopropyl ether, to give 8-benzyloxy-3-(4-fluorobenzyl)-5-(3-methoxypropenyl)[1,6]naphthyridine-7-carboxylic acid (2-methoxyethyl)amide b-11 (135 mg) in 52.3% yield.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[K].[C:6]([NH:11][C:12](=[S:16])[O:13][CH2:14][CH3:15])(OCC)=[O:7].C(N(CC)CC)C>CO>[C:3]([C:2]1[S:16][C:12]([O:13][CH2:14][CH3:15])=[N:11][C:6]=1[OH:7])#[N:4]
Reactant: N#CCCl
Reactant: CCOC(=O)NC(=S)OCC
Agent: [K]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOc1nc(O)c(C#N)s1
Reaction time: 2 h

Procedure:
22.8 g of chloroacetonitrile were added dropwise with stirring at room temperature to a suspension of 61.5 g of the potassium salt of ethyl N-carbethoxy-thiocarbamate [described by Guha et al, Indian Chem. Soc., Vol. 6 (1929), p. 570] in one liter of methanol and after stirring the mixture for 2 hours, 30 g of triethylamine were added thereto. The mixture was stirred for another 48 hours and was then refluxed for 2 hours and filtered. The filtrate was concentrated to dryness and the residue was added to sodium hydroxide solution. The resulting solution was washed with ethyl ether, acidified with hydrochloric acid and extracted with ethyl ether. The extracts were dried and evaporated to dryness and the residue was crystallized from petroleum ether to obtain 26.4 g of 5-cyano-4-hydroxy-2-ethoxy-thiazole melting at 132°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([Sn](C)(C)C)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.Br[C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=1.[Cl-].[Li+]>O1CCOCC1>[C:29]([C:28]1[CH:32]=[CH:33][C:25]([C:16]2[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH2:6][C:7]3[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=3)[CH:15]=2)=[CH:26][CH:27]=1)(=[O:30])[NH2:31]
Reactant: COc1cc(Cc2cnc(N)nc2N)cc([Sn](C)(C)C)c1OC
Reactant: NC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cc(Cc2cnc(N)nc2N)cc(-c2ccc(C(N)=O)cc2)c1OC
Temperature: 0 °C
Yield: 7.1 %

Procedure:
1.0 g of 5-(3,4-dimethoxy-5-trimethylstannyl-benzyl)-pyrimidine-2,4-diamine (Example 1o) and 0.472 g of 4-bromobenzamide are dissolved in 50 ml of dioxan, treated with 0.3 g of lithium chloride and 0.15 g of tetrakis-triphenylphosphine-palladium and held at reflux under argon for 14 hrs. The mixture is poured on to ice-water, extracted with methylene chloride, dried over magnesium sulphate and, after concentration, the residue is chromatographed on silica gel with methylene chloride/methanol 2:1. 64 mg (7%) of 5-(4'-carbamoyl-5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine are isolated as a colourless solid. M.p. 199° (decomposition).
Reaction SMILES: C1N=[CH:4][N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])C=1.[Cl:13][C:14]1[CH:15]=C([CH:20]=[CH:21][C:22]=1[Cl:23])CCN.[NH2:24]C(N)=N>C1COCC1>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:10]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:9][N:8]([C:6]([NH:3][CH3:4])=[O:7])[C:12]([NH2:11])=[NH:24]
Reactant: N=C(N)N
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CNC(=O)N(Cc1ccc(Cl)c(Cl)c1)C(=N)N
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 154.5 %

Procedure:
3.5 g of CDI were added to a solution of 3.0 g of 3,4-dichlorobenzylmethylamine in 110 ml of THF and it was stirred at RT overnight. After addition of 4.6 g of guanidine, the reaction mixture was again stirred overnight and concentrated on a rotary evaporator, and the residue was stirred with 120 ml of water. The precipitate which was deposited during this process was filtered off with suction, dried in vacuo and dissolved in 50 ml of ethyl acetate and 7 ml of methanol. After addition of ethereal hydrochloric acid and suction filtration of the precipitated product, 3.8 g of N-(3,4-dichlorobenzyl)-N-methylaminocarbonylguanidinehydrochloride were obtained;
Reaction SMILES: Cl.[N:2]1([C:7](=[NH:9])[NH2:8])[CH:6]=[CH:5][CH:4]=N1.CCN(C(C)C)C(C)C.[O:19]1CCC(N)[CH2:21][CH2:20]1.CCOCC>CN(C=O)C>[O:19]1[CH2:20][CH2:21][CH:6]([NH:2][C:7]([NH2:8])=[NH:9])[CH2:5][CH2:4]1
Reactant: N=C(N)n1cccn1
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NC1CCOCC1
Reaction time: 72 h
Yield: 78 %

Procedure:
To a stirred solution of 1H-pyrazole-1-carboximidamide hydrochloride (65.2 g, 445 mmol) in DMF (200 mL) at RT under nitrogen was added sequentially DIPEA (103 mL, 593 mmol) and tetrahydro-2H-pyran-4-amine (30 g, 297 mmol; CASRN 38041-19-9) and the reaction was stirred for 3 d. Et2O (100 mL) was added, and the reaction was stirred for 10 min then the reaction was allowed to settle and the ether layer was decanted. This process was repeated 3 times and a solid formed after allowing to settle for 30 min. The solid was filtered off and rinsed with Et2O and dried under high vacuum to afford 35 g, (95% purity, 78% yield) of 1-(tetrahydro-2H-pyran-4-yl)guanidine (24) as a light yellow solid: MS m/z (APCI-pos) M+1=144.1.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH3:10][Si:11]([CH3:14])([CH3:13])Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH3:10][Si:11]([CH3:14])([CH3:13])[O:1][CH2:2][C:3]([CH2:8][O:9][Si:11]([CH3:14])([CH3:13])[CH3:10])([CH2:6][O:7][Si:11]([CH3:14])([CH3:13])[CH3:10])[CH2:4][O:5][Si:11]([CH3:14])([CH3:13])[CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: OCC(CO)(CO)CO
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: C[Si](C)(C)OCC(CO[Si](C)(C)C)(CO[Si](C)(C)C)CO[Si](C)(C)C

Procedure:
1 mole of pentaerythritol, 6 moles of trimethylchlorosilane and 0.004 moles of triethylbenzyl ammonium chloride were reacted at the reflux temperature (54°-86° C.) as in Example 1 and then worked up by distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[N:13][N:14]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1.[C:21](O)(=[O:25])[CH:22]([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[N:13][N:14]([CH:15]4[CH2:20][CH2:19][N:18]([C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1
Reactant: Clc1ccc2ncc3nnn(C4CCNCC4)c3c2n1
Reactant: CC(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)N1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A mixture of 8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine (200 mg, 0.69 mmol), isobutyric acid (67 mg, 0.76 mmol), HATU (315 mg, 0.83 mmol) and DIEA (133 mg, 1.04 mmol) in DMF (5 mL) was stirred at r.t. overnight. Then water (10 mL) was added; the precipitate was collected and dried in vacuo to afford 1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-methylpropan-1-one as a solid (200 mg).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([CH:8]1[CH2:12][C:11]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:10]=2[O:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: c1ccc(CC2Cc3ccccc3O2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1ccc2c(c1)CC(Cc1ccccc1)O2
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A solution of 2-benzyl-2,3-dihydrobenzofuran (1.9 g, 9 mmole) in 25 ml carbon tetrachloride was cooled to 0° C. and a solution of 0.46 ml (9 mmole) bromine in 5 ml carbon tetrachloride was added at 0° C. The mixture was warmed to room temperature, washed with water, sodium bicarbonate solution, and water again. The solvent was then evaporated to afford 2.5 g of crude product which was purified by column chromatography on silica gel, eluting with hexane to afford 1.0 g (38.5%) of the desired compound, m.p. 70°-72° C.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:9]#[N:10].[K+].S(=O)(=O)(O)O>O>[CH:5]1[CH:6]=[CH:7][C:2]([CH:1]([OH:8])[C:9]#[N:10])=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: N#CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 500 ml four-neck round bottom flask was equipped with a magnetic stirring bar, water condenser, addition funnel and drying tube. The glassware was dried and to this was charged 21.2 grams (0.2 mole) benzaldehyde and 19.5 grams (0.3 mole) potassium cyanide dissolved in 70 ml of water. The reaction flask was cooled to 10°-15° C. using a water/ice bath. To this was added 70 ml of 40% sulfuric acid over a 60 minute period. After the addition was complete, the reaction was allowed to warm to room temperature and stir for an additional two hours. At the end of this time the reaction mixture was extracted with carbon tetrachloride (3×75 ml), washed the combined carbon tetrachloride layers with water (2×50 ml), dried the carbon tetrachloride layer with anhydrous magnesium sulfate, filtered and concentrated to yield benzaldehyde cyanohydrin.
Reaction SMILES: [CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4]C1SC=CC=1)[CH3:2].S1C=CC=C1.C([Li])CCC.CCCCCC.CC[Br:32]>O1CCCC1>[CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][Br:32])[CH3:2]
Reactant: CCBr
Reactant: CCCCC(CC)Cc1cccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: CCCCC(CC)CBr
Temperature: -78 °C

Procedure:
In FIG. 2A, an exemplary synthesis of 2-(2-ethylhexyl)thiophene is depicted. As shown in FIG. 2A, a 7.4 mL thiophene was dissolved in 100 mL anhydrous tetrahydrofuran (THF). The solution was then cooled to about −78° C. A 30 mL of 2.5 M n-butyllithium (n-BuLi) in hexane (75 mmol) was added dropwise to the solution. The reaction mixture was warmed to room temperature for about 2 hours, and then cooled to about −15 to about −20° C. 26 mL 2-ethyl bromide was added to the reaction mixture. The reaction mixture was reacted at about 50° C. for about 18 hours, and poured into crushed ice. The organic phase was isolated and washed with water, and extracted with ether three times. After removal of the solvent by rotary evaporator, the residue was distilled under vacuum to get rid of the 2-ethylhexyl bromide. After removal of the 2-ethylhexyl bromide, the residue was purified by elution with hexane by silica gel column chromatography (i.e., about 10 to about 15 cm) to afford 12.6 g 2-(2-ethylhexyl)thiophene as light yellow liquid. The yield was about 85%. The molecular weight was determined by gas chromatography/mass spectrometry (GC-MS) to be 196.3.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24](S(O)(=O)=O)=[CH:23][CH:22]=1>>[N:12]1([CH:2]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:1]([CH3:7])([CH3:6])[CH2:31][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: NC(=O)CCc1ccccc1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(Cc1ccccc1)C(NC(=O)CCc1ccccc1)n1nnc2ccccc21

Procedure:
A suspension of 3-(phenyl)propionamide, the product from Example 18A, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=[CH:9][C:2]1=2.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=C([C:46]2[S:50][C:49]([O:51][C@@H:52]3[CH:59]4[CH2:60][N:55]5[CH2:56][CH:57]([CH2:61][CH:53]3[CH2:54]5)[CH2:58]4)=[N:48]C=2)C=N1.[NH3:62]>>[C:19]1([CH3:29])[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1.[S:1]1[C:2]2[CH:9]=[CH:8][C:7]([C:46]3[S:50][C:49]([O:51][C@@H:52]4[CH:59]5[CH2:60][N:55]6[CH2:56][CH:57]([CH2:61][CH:53]4[CH2:54]6)[CH2:58]5)=[N:48][N:62]=3)=[CH:6][C:3]=2[CH:4]=[CH:5]1
Reactant: c1n[nH]cc1-c1cnc(OC2C3CC4CC2CN(C4)C3)s1
Reactant: N
Reactant: CC1(C)OB(c2ccc3sccc3c2)OC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1cc2cc(-c3nnc(OC4C5CC6CC4CN(C6)C5)s3)ccc2s1

Procedure:
The free base of the title compound was prepared from the product of Example 41B (193 mg, 0.60 mmol) and 2-(benzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (317 mg, 0.74 mmol; Maybridge) according to Method F, and converted to the p-toluenesulfonate salt using the procedure of Method H: 1H NMR (300 MHz, methanol-D4) δ ppm 1.96 (d, J=12.5 Hz, 2H), 2.19 (s, 1H), 2.33 (d, J=13.6 Hz, 2H), 2.36 (s, 3H), 2.64 (s, 2H), 3.52-3.77 (m, 6H), 5.36 (s, 1H), 7.22 (d, J=8.8 Hz, 2H), 7.49 (d, J=5.4 Hz, 1H), 7.67-7.75 (m, 3H), 7.85 (dd, J=8.4, 1.7 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.32 (d, J=1.7 Hz, 1H). MS (DCI/NH3) m/z=370 (M+H)+. Anal. Calcd. for C19H19N3OS2.C7H8O3S: C, 57.65; H, 5.02; N, 7.76. Found: C, 56.45; H, 4.59; N, 7.45.
Reaction SMILES: C([O:9][CH2:10]/[C:11](/[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[OH:9][CH2:10]/[C:11](=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)/[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24]
Reactant: CC(C)(C)OC(=O)/C(=C/CCCCc1ccccc1)COC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)/C(=C/CCCCc1ccccc1)CO
Temperature: 0 °C
Yield: 50.5 %

Procedure:
(E)-2-t-Butoxycarbonyl-7-phenylhept-2-enyl benzoate (5.9 g, 15 mmol) is dissolved in MeOH (75 mL) and cooled to 0° C. K2CO3 (2 g, 15 mmol) is added with stirring and the reaction is allowed to warm to 23° C. After 2 hours the reaction is neutralized with HOAc and the reaction is concentrated to approximately half of its volume. After diluting with ether (500 mL), the solution is washed with water (50 mL) and brine (50 mL). The resulting solution is dried (MgSO4) and concentrated in vacuo. The crude reaction mixture is purified by column chromatography (silica, 25% ether in petroleum ether) to give t-butyl (E)-2-hydroxymethyl-7-phenylhept-2-enoate (2.2 g, 51%): 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.20-7.15 (m, 3H), 6.75 (t, J=7.7 Hz, 1H), 4.28 (d, J=6.8 Hz, 2H), 2.65-2.60 (m, 3H), 2.26 (q, J=7.5 Hz, 2H), 1.71-1.61 (m, 2H), 1.53-1.43 (m, 11H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[N:3][CH:2]=1.[N:8]1CCC[N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]=12.C(#[N:21])C>>[N:1]1[CH:6]=[CH:5][C:4]([O:7][N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[N:12]=[N:21]2)=[N:3][CH:2]=1
Reactant: CC#N
Reactant: Oc1ccncn1
Reactant: C1CCC2=NCCCN2CC1
Product: c1ccc2c(c1)nnn2Oc1ccncn1
Reaction time: 1 h

Procedure:
To a solution of pyrimidin-4-ol (350 mg, 3.6 mmol) and (1H-benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(V) (1.9 g, 4.4 mmol) in 24 mL of acetonitrile was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (820 μL, 5.5 mmol) dropwise at room temperature. After the reaction mixture was stirred for 1 hour, the reaction solvent was removed under reduced pressure. Purification of the residue by flash chromatography (0 to 70% EtOAc/hexanes) provided the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.N1C=CC=CC=1.[CH2:15]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:38][CH:37]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: NCc1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a 0° C. solution of 0.674 g 2-(aminomethyl)pyridine, 20 ml methylene chloride and 1.83 ml pyridine is added, dropwise over 20 minutes, 2.0 g of product from Example 3 dissolved in 25 ml of methylene chloride. The reaction is stirred at 0° C. for 2 hours followed by stirring at room temperature for 17 hours. The reaction mixture is partitioned between chloroform and saturated sodium bicarbonate, washed with water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:75% ethyl acetate/hexane) to give 1.51 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[C:30](O)=[O:31]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][N:24]=5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(O)c1cnccn1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cnccn4)nc3cc21

Procedure:
Pyrazine-2-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and pyrazine-2-carboxylic acid (109 mg, 0.89 mmol). The title compound was obtained as yellow powder (19 mg, 6%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:10]2=[N:9][N:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[Cl:32].CO>CN(C=O)C>[Cl:32][C:26]1[C:27]([Cl:31])=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=[C:10]2[C:15]1=[O:16]
Reactant: O=C1NCCn2c1nnc2-c1cnccn1
Reactant: Clc1cccc(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1c2nnc(-c3cnccn3)n2CCN1Cc1cccc(Cl)c1Cl
Reaction time: 5 h
Yield: 88.8 %

Procedure:
To a slurry of Intermediate 1 (60 mg, 0.18 mmol) and cesium carbonate (237 mg, 0.73 mmol) in DMF (1.4 mL) was added 1-(bromomethyl)-2,3-dichlorobenzene (65 mg, 0.27 mmol). After 5 h, the reaction was quenched with sat aq NH4Cl, poured into brine, and extracted with 20% IPA/CHCl3 (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to give a brown sludge. Trituration with MeOH provided the desired product as a beige powder (60 mg, 88%). MS (ESI): mass calcd. for C16H12Cl2N6O, 374.0; m/z found, 375.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.77 (s, 2H), 7.57 (dd, J=7.9, 1.2 Hz, 1H), 7.49-7.38 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 4.86-4.75 (m, 4H), 3.90-3.81 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH3:23])[CH3:22]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(F)c(F)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
3,4-Difluorophenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.