Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:7][CH:8]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[S:7][CH:8]=1
Reactant: C1=COCCC1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCO)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(CCOC2CCCCO2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of Example 89B (6.3 g, 27.4 mmol) in dichloromethane (100 mL) were added commercially available 3,4-dihydro-2H-pyran (Aldrich) (21 g, 250 mmol) and pyridinium-p-toluenesulfonic acid (Aldrich) (3.5 g, 14.0 mmol). The reaction mixture was stirred for overnight at room temperature and then diluted with dichloromethane, washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford 7.4 g (82%) of the title compound. MS (ESI+) m/z 329 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:19]([C:23]1[NH:24][C:25]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[C:26]([Cl:28])[N:27]=1)[CH2:20][CH2:21][CH3:22].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.[Cl-].[Na+].O>[CH3:18][O:17][C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:24]2[C:25]([CH2:29][O:30][Si:31]([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33])=[C:26]([Cl:28])[N:27]=[C:23]2[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:4][CH:5]=1)=[O:16]
Reactant: CCCCc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 4'-bromomethylbiphenyl-2-carboxylate (2.05 g) in dry THF (10 mL) was added dropwise to a solution of 2-butyl-4-chloro-5-(t-butyldimethylsilyloxymethyl)-1H-imidazole (2.03 g) and NaN(TMS)2 (1.48 g) in dry THF (20 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. It was diluted with brine and the organic layer was collected, dried over MgSO4, and evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc, silica) to separate the two regioisomeric alkylation products. The major isomer, 4'-[[2-butyl-4 chloro-5-(t-butyldimethylsilyloxymethyl) 1H-imidazol-1-yl]methyl][1,1'-biphenyl-2-yl]carboxylic acid methyl ester (1.4 g) was used in the next step and the regiochemistry of this alkylation product was proven by NOE experiments at the stage of the hydrazide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
A mixture of 2-chloro-4,6-dimethoxy-pyrimidine (3.35 g, 19.19 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 24.94 mmol, 1.3 equiv; commercially available) in anhydrous DMF (100 mL) was heated to 100° C. for 48 h. The organic phase was concentrated under reduced pressure and the residue extracted with ethyl acetate (3×50 mL) from a solution of 1 M NaOH (100 mL). The combined organic phases were dried over MgSO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.97 g (30%) of the title compound. MS (ISP): 339.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[C:24]3[C:23]4[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=4[N:17]=[C:16]([NH2:26])[C:15]=3[N:14]=[C:13]2[CH2:27][O:28][CH2:29][CH3:30])=[CH:5][CH:4]=1.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1>>[CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[C:24]3[C:23]4[CH:22]=[CH:21][C:20]([C:39]5[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=5)=[CH:19][C:18]=4[N:17]=[C:16]([NH2:26])[C:15]=3[N:14]=[C:13]2[CH2:27][O:28][CH2:29][CH3:30])=[CH:5][CH:4]=1
Reactant: OB(O)c1cccnc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCC(Cc1ccc(OC)cc1)S(N)(=O)=O
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCC(Cc1ccc(OC)cc1)S(N)(=O)=O
Yield: 53.9 %

Procedure:
4-Methoxybenzyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (1.16 g, 2.0 mmol) and pyridine-3-boronic acid (0.30 g, 2.4 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, at which time additional pyridine-3-boronic acid (0.3 equivalent) was added and the reaction was heated for an additional five hours. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) and then triturated with methanol, isolated by filtration, and dried for 20 hours under high vacuum at 140° C. to provide 0.62 g of 4-methoxybenzyl 4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as a beige powder, mp 230-231.5° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([Br:8])[CH3:7].[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CC(C)=O>[Br:8][CH:6]([CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:13]1[C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]2[C:9]1=[O:19]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Br)CCCCBr
Agent: [K]
Solvent: CC(C)=O
Product: CC(Br)CCCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 1,5-dibromohexane (21.6 g, 0.09 mole) in acetone (75 ml) containing potassium phthalimide (12.3 g, 0.066 mole) was heated at reflux for 24 hr. The mixture was cooled, filtered and concentrated. The excess dibromide was recovered (6.3 g) via distillation at 1.5 mm, 130° internal temperature, and recycled. The total yield of crude product was 20.6 g (74%), mp 48°-51°. This material was used as such in the next step.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(Br)cc1
Reactant: OB(O)c1cc2ccccc2s1
Product: COc1ccc(-c2cc3ccccc3s2)cc1
Yield: 91 %

Procedure:
The title compound was prepared in 91% yield from benzo[b]thiophene-2-boronic acid and 4-bromoanisole by essentially following the procedure detailed Example 1, Part B.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH2:27])([CH:21]2[NH:26][CH2:25][CH:24]=[CH:23][NH:22]2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:28]#[C:29]Br>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[C:21]3=[N:26][CH2:25][CH2:24][CH2:23][N:22]3[C:29]([NH2:28])=[N:27]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CBr
Reactant: NC(c1ccc(OC(F)(F)F)cc1)(c1ccc(F)c(Br)c1)C1NC=CCN1
Solvent: CC#N
Product: NC1=NC(c2ccc(OC(F)(F)F)cc2)(c2ccc(F)c(Br)c2)C2=NCCCN12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36 %

Procedure:
A mixture of 1-(3-bromo-4-fluorophenyl)-1-(tetrahydropyrimidin-2-yl)-1-[4-(trifluoromethoxy)phenyl]methylamine (0.85 g, ˜80% purity, ˜1.52 mmol) and cyanogen bromide (0.81 g, 7.62 mmol) in acetonitrile is stirred at room temperature for 45 min, heated at 100° C. in a sealed tube overnight, cooled to room temperature and concentrated. The resultant residue is purified by flash chromatography (silica, 95:5:0.25 methylene chloride/methanol/concentrated ammonium hydroxide as eluent) to afford the title compound as a tan solid, 0.26 g (36% yield), identified by NMR and mass spectral analyses. 1H NMR (300 MHz, CDCl3) δ 7.74 (dd, J=6.7, 2.3 Hz, 1H), 7.49 (dd, J=6.7, 2.1 Hz, 2H), 7.38 (m, 1H), 7.13 (d, J=8.1 Hz, 2H), 7.03 (t, J=8.5 Hz, 1H), 3.58 (m, 4H), 1.86 (m, 2H); ESI MS m/z 471 [C19H15BrF4N4O+H]+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]([NH2:10])=[NH:9])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:4]=1.[H][H]>CO.[C].[Pd]>[ClH:1].[ClH:1].[NH2:2][C:3]1[N:7]([C:8]([NH2:10])=[NH:9])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:4]=1
Reactant: [H][H]
Reactant: N=C(N)n1nc(-c2ccc([N+](=O)[O-])cc2)cc1N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)n1nc(-c2ccc(N)cc2)cc1N
Yield: 130.3 %

Procedure:
A catalytic amount of 10% palladium-carbon was added to a solution of 0.24 g of 5-amino-3-(4-nitrophenyl)-1H-pyrazole-1-carboxamidine hydrochloride in 40 ml of methanol and stirred for 30 minutes in a hydrogen atmosphere of normal pressure at room temperature. The reaction solution was filtered to remove the insoluble solids therefrom, and 0.5 ml of 4N hydrochloric acid-dioxane were added thereto. The solvents were removed by distillation under reduced pressure, and the resulting residue was recrystallized from ethanol-ether to obtain 0.16 g of 5-amino-3- (4-aminophenyl)-1H-pyrazole-1-carboxamidine dihydrochloride.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:43]([N:45]1[CH2:51][CH2:50][CH2:49][N:48]([C:52](=O)[CH2:53]Cl)[CH2:47][CH2:46]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:53][CH2:52][N:48]2[CH2:49][CH2:50][CH2:51][N:45]([CH3:43])[CH2:46][CH2:47]2)=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)CCl)CC1
Product: CCN(Cc1ccc(OCCN2CCCN(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 44.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-chloroacetyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.6 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[OH:13].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([CH3:12])[CH:6]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c2cc(F)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)nc4ccc(F)cc34)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
6-Fluoro-2-methyl-quinolin-4-ol (237 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (11 mg, yield 7%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:11][C:12]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:13]=1[C:14]([NH:16][C:17]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:33](C(OC(C)(C)C)=O)[CH3:34])[CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20])=[O:15])(=O)C>>[OH:11][C:12]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:13]=1[C:14]([NH:16][C:17]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][CH3:34])[CH:24]=[CH:23][C:18]=1[C:19]([OH:21])=[O:20])=[O:15]
Reactant: COC(=O)c1ccc(-c2ccccc2N(C)C(=O)OC(C)(C)C)cc1NC(=O)c1cc(OC)ccc1OC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cc(OC)ccc2O)c1
Temperature: 52.5 °C
Reaction time: 0.5 h

Procedure:
A trifluoroacetic acid (3.0 mL) solution of the obtained methyl 2-(2-acetoxy-5-methoxybenzamido)-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate was stirred at room temperature for 1 hour and 40 minutes. The solvent was evaporated under reduced pressure, and toluene was added to the residue. The solvent was evaporated under reduced pressure, and dioxane (3.0 mL) and a 4 mol/L aqueous solution of sodium hydroxide (0.25 mL) were added to the obtained residue, followed by stirring at 50 to 55° C. for 1 hour and 30 minutes and then at 55 to 60° C. for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and water added thereto. After adjusting the pH to 7.0 with 1 mol/L hydrochloric acid, the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.025 g of 2-(2-hydroxy-5-methoxybenzamido)-4-(2-(methylamino)phenyl)benzoic acid as a white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[O-])([F:7])[F:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH2:34]>C1COCC1>[F:6][C:5]([F:7])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:4][NH2:1]=[O:34]
Reactant: O
Reactant: [N-]=[N+]=NCC(F)(F)c1cccc[n+]1[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [O-][NH2+]CC(F)(F)c1ccccn1
Reaction time: 1 h
Yield: 96 %

Procedure:
To the solution of 2-(2-azido-1,1-difluoro-ethyl)-pyridine N-oxide (example 60a, 2.7 g, 13.5 mmol) in THF (40 mL) was slowly added triphenylphosphine (3.9 g, 14.9 mmol) at 0° C. After stirred for 1 h, water (5 mL) was added. The reaction mixture was stirred at 55° C. for 2 h and at room temperature for 12 h. After removal of solvent, the crude was puried by flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-20% methanol in methylene chloride in 30 min) to give 2,2-difluoro-2-pyridin-2-yl-ethylamine N-oxide (2.2 g, 96%) as a white solid. LC-MS m/e 175 (MH+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[CH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(N)CCC.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>[O:8]([CH2:9][CH2:10][C:11]#[C:12][C:14]1[CH:20]=[CH:19][CH:18]=[C:16]([NH2:17])[CH:15]=1)[Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: Nc1cccc(Br)c1
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: CC(C)(C)[Si](C)(C)OCCC#Cc1cccc(N)c1

Procedure:
A mixture of 1-(t-butyldimethylsilyloxy)-3-butyne (10 mmol) and m-bromoaniline (10 mmol) in n-butylamine (50 mL) under a nitrogen atmosphere is treated with tetrakis(triphenylphosphine)palladium (0) (0.17 g) and then heated to reflux for 18 hr. After removing the solvent in vacuo, the residue is dissolved in CH2Cl2 and washed with saturated NaHCO3. The combined organic solution is dried over magnesium sulfate, filtered and evaporated to give the above described silyl protected adduct.
Reaction SMILES: [CH3:1][C@H:2]1[C@:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]([OH:23])[C:11]([CH2:24][OH:25])=[CH:10][C@H:9]([C:15]3=[O:16])[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@@H:4]2[CH2:3]1.O.[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=C[CH:28]=1>CC(C)=O>[CH3:1][C@H:2]1[C:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]2[C:11]([CH2:24][O:25][C:27]([CH3:32])([CH3:28])[O:23]2)=[CH:10][CH:9]([C:15]3=[O:16])[CH:5]2[C:6]([CH3:8])([CH3:7])[CH:4]2[CH2:3]1
Reactant: CC1=C[C@]23C(=O)[C@@H](C=C(CO)[C@@H](O)[C@]2(O)[C@H]1O)[C@H]1[C@@H](C[C@H]3C)C1(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1=CC23C(=O)C(C=C4COC(C)(C)O[C@H]4[C@]2(O)[C@H]1O)C1C(C[C@H]3C)C1(C)C

Procedure:
Ingenol is reacted with p-toluenesulphonic acid hydrate and acetone to give ingenol-5,20-acetonide according to the procedure of Opferkuch et al. (1981). Ingenol-5,20-acetonide is converted to the ingenol 3-acylate by treatment with the appropriate acyl chloride and 4-(N,N-dimethylamino)pyridine or pyridine in toluene or benzene, or treatment with the appropriate acid, an alkylpyridinium salt and tributylamine in toluene then treatment with methanolic perchloric acid according to the procedure of Sorg et al. (1982). The ingenol 3-acylate could be converted to the 20-chloro-20-deoxyingenol 3-acylate 5-benzoate by the method of Example 15.
Reaction SMILES: [C:1]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:19]([NH2:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([NH:31][C:14](=[O:15])[CH2:13][CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[C:17]([OH:16])=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)CC(NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 12 h
Yield: 97 %

Procedure:
N-Carbobenzyloxy-L-aspartic anhydride (1 mmol) was dissolved in 50 mL methylene chloride, followed by the addition of 1.05 eq of dodecylamine and 1.1 eq of triethylamine. The reaction was capped to prevent evaporation, and stirred for 12 hours. When no trace of starting material could be detected by thin layer chromatography (TLC) (CH2Cl2, 5% MeOH), the reaction was quenched with 20 mL 1N hydrochloric acid followed by extraction with chloroform (5×). The organic layer was dried over magnesium sulfate, and 7 was obtained as a white solid (yield 97%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[N:5]=[CH:4]1.[CH3:11]O>>[CH3:2][N:3]1[CH2:7][CH:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[CH:4]1
Reactant: CO
Reactant: CN1C=NC(C(=O)O)C1
Agent: Cl
Product: COC(=O)C1CN(C)C=N1

Procedure:
17.0 g of 38C was dissolved in 203 ml of anhydrous methanol and dry hydrogen chloride was bubbled rapidly into the mixture while it was heated to and at reflux for 2 hours. the mixture was cooled, stripped of volatiles, mixed with 300 ml of water, neutralized with solid sodium bicarbonate, made basic to pH=9 with 3N aqueous sodium carbonate solution. The aqueous phase was extracted with methylene chloride, the extract was dried (MgSO4), filtered and stripped of solvent, to give methyl 1-methylimidazoline-4-carboxylate (38D), as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:20])C(Cl)(Cl)Cl)[CH:12]=[C:11]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH3:28].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:20])[N:27]([CH3:28])[CH3:26])[CH:12]=[C:11]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)cn1CC(=O)c1ccc(Cl)cc1
Reactant: CNC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)N(C)C)cn1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
To a solution of methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(trichloroacetyl)-1H-pyrrole-2-carboxylate (97 mg, 0.23 mmol) in THF (2 mL) was added dimethylamine (50 μL, 0.75 mmol). The reaction mixture was stirred at room temperature. After completion (2.5 days, monitored by LCMS) a saturated aqueous solution of ammonium chloride (25 mL) was added and the mixture extracted with CH2Cl2 containing 20% of propan-2-ol (5×25 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to give crude product mixture that was purified using flash chromatography (Biotage SP4, 12 g cartridge; 0-10% MeOH gradient in CH2Cl2) to give methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(dimethylcarbamoyl)-1H-pyrrole-2-carboxylate (45 mg, yield 56%). 1H NMR (400 MHz, d6-acetone): δ 3.12 (br s, 6H), 3.70 (s, 3H), 5.97 (s, 2H), 7.19 (d, 1H, J 2.0 Hz), 7.48 (d, 1H, J 1.9 Hz), 7.62-7.66 (m, 2H), 8.08-8.13 (m, 2H).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17](Cl)=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][C:9]=2[O:20][CH3:21].[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>ClCCl>[CH2:22]([N:24]([CH2:25][CH3:26])[C:17]([CH:12]1[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:20][CH3:21])[N:4]([CH2:3][CH2:2][F:1])[C:16]=2[CH2:15][CH2:14][CH2:13]1)=[O:18])[CH3:23]
Reactant: COc1cccc2c1c1c(n2CCF)CCCC1C(=O)Cl
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CCCc2c1c1c(OC)cccc1n2CCF
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
9-(2-fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carbonyl chloride (18) (371 mg, 1.2 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0° C. diethylamine (177 mg, 2.4 mmol, 250 μL) was then added and the reaction was stirred overnight at RT. The reaction was quenched with 10% aqueous potassium carbonate (2 mL). The dichloromethane layer was collected through a phase separator then concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A): ethyl acetate (B) (50-100% (B), 50 g, 35.2 CV, 40 mL/min) to afford a pale yellow solid. The solid was next triturated with a minimum amount of diethyl ether to afford 240 mg (58%) of 9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethyl amide. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 13.0, 14.6, 19.9, 21.9, 28.0, 36.3, 40.5, 41.9, 43.1 (d, JCF=23 Hz), 54.7, 82.0 (d, JCF=173 Hz), 99.7, 102.1, 108.3, 117.0, 121.5, 135.3, 137.4, 153.3, and 174.8.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:10][O:11][C:12]1[C:13]([CH3:38])=[C:14]([CH3:37])[C:15]2[O:20][C:19]([CH2:22][CH2:23]OS(C3C=CC(C)=CC=3)(=O)=O)([CH3:21])[CH2:18][CH2:17][C:16]=2[C:35]=1[CH3:36].C1(C)C=CC=CC=1>O>[CH3:10][O:11][C:12]1[C:13]([CH3:38])=[C:14]([CH3:37])[C:15]2[O:20][C:19]([CH2:22][CH2:23][N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]3)([CH3:21])[CH2:18][CH2:17][C:16]=2[C:35]=1[CH3:36]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCOS(=O)(=O)c1ccc(C)cc1)O2
Reactant: OCCN1CCNCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCN(CCO)CC1)O2
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution composed of 20 g of N-(2-hydroxyethyl)piperazine, 5 g of 3,4-dihydro-6-methoxy-2-[2-(p-toluenesulfonyloxy)ethyl]-2,5,7,8-tetramethyl-2H-benzopyran and 100 ml of toluene was refluxed for 8 hours in a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. Low-boiling substances were distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 3.66 g of 1-[2-(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)ethyl]-4-(2-hydroxyethyl)piperazine [Compound (35)] having the following physical characteristics.