Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][NH:5][C:4](=[O:9])[N:3]=1.C(O[CH:14]1[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:16]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([CH:31]([F:33])[F:32])[O:15]1)(=O)C.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>CC#N>[C:20]([O:19][C@@H:18]1[C@H:17]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:16]([CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH:31]([F:32])[F:33])[O:15][C@H:14]1[N:5]1[CH:6]=[C:7]([Cl:8])[C:2]([NH2:1])=[N:3][C:4]1=[O:9])(=[O:22])[CH3:21]
Reactant: CC(=O)OC1O[C@@](COCc2ccccc2)(C(F)F)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Reactant: Nc1nc(=O)[nH]cc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](n2cc(Cl)c(N)nc2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
To a solution of 4-amino-5-chloropyrimidin-2(1H)-one 28 (0.336 g, 2.33 mmol) in anhydrous CH3CN (10 mL) was added BSA (0.945 g, 4.64 mmol) portion-wise while maintaining the reaction temperature at 25° C. After the reaction mixture became clear, compound 5 (0.54 g, 1.16 mmol) in CH3CN (2 mL) and SnCl4 (1.2 g, 4.64 mmol) was added into the mixture. The mixture was stirred at 65° C. for 1 h, then cooled and poured into saturated NaHCO3 solution (20 mL). The organic phase was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Purification by flash silica gel chromatography [dichloromethane:methanol (40:1)] gave 29 as a white solid (0.24 g, 31%). LC-MS: (M+H)+=550.1
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.I[CH2:25][CH2:26][OH:27]>>[CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][N:20]([CH2:25][CH2:26][OH:27])[C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1
Reactant: Cc1cccc(C#Cc2nc(C)n(-c3cc[nH]c(=O)c3)c2C)c1
Reactant: OCCI
Product: Cc1cccc(C#Cc2nc(C)n(-c3ccn(CCO)c(=O)c3)c2C)c1

Procedure:
The title compound, light brown solid, MS: m/e=348.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-[2,5-dimethyl-4-m-tolylethynyl-imidazol-1-yl]-1H-pyridin-2-one and 2-iodoethanol.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:10]=[C:9]([OH:11])[C:8](=[O:12])[C:7]([C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:16]=[CH:15][CH:14]=3)=[N:6]2)[CH2:3][CH2:2]1.Cl[CH2:25][CH2:26][N:27]1[C:31]2=[N:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:30]2[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CC(N(C)C)=O>[CH:1]1([CH2:4][N:5]2[CH:10]=[C:9]([O:11][CH2:25][CH2:26][N:27]3[C:31]4=[N:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[N:30]4[CH2:29][CH2:28]3)[C:8](=[O:12])[C:7]([C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:16]=[CH:15][CH:14]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: O=c1c(O)cn(CC2CC2)nc1-c1ccnn1-c1ccccc1
Reactant: ClCCN1CCn2c1nc1ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: O=c1c(OCCN2CCn3c2nc2ccccc23)cn(CC2CC2)nc1-c1ccnn1-c1ccccc1
Temperature: 80 °C
Reaction time: 13 h
Yield: 62.5 %

Procedure:
A suspension of 1-(cyclopropylmethyl)-5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (231 mg), 1-(2-chloroethyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (249 mg), cesium carbonate (428 mg) and sodium iodide (253 mg) in dimethylacetamide (10 mL) was stirred at 80° C. for 13 hr. The reaction mixture was filtered and an insoluble material was separated and washed with ethyl acetate. The filtrate and the washing were combined, and concentrated under reduced pressure to dryness. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) to give the title compound (231 mg) as a white amorphous powder.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1.[CH3:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[CH:22][C:21]=1[F:28]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:26]([C:25]2[CH:24]=[N:23][CH:22]=[C:21]([F:28])[C:20]=2[CH3:19])=[NH:27])[CH:13]=1
Reactant: Cc1c(F)cncc1C#N
Reactant: Nc1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(F)cncc1C(=N)Nc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Potassium bis(trimethylsilyl)amide (1.0 M, 4.1 mL, 0.0041 mol) was added slowly for a period of 5 min to a solution of 4-chloro pyridin-2-amine (0.35 g, 0.00273 mol) in anhydrous tetrahydrofuran (30 mL) at 0° C. and stirred for 15 min at same temperature. Then 4-methyl-5-fluoronicotinonitrile (0.37 g, 0.00273 mol) in tetrahydrofuran (5 mL) was added. The reaction temperature was raised to RT and the reaction mixture was stirred it for 18 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford the title compounds. 1H NMR (400 MHz, CDCl3) δ 10.60 (bs, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.25-8.24 (d, J=4 Hz, 1H), 7.25-7.24 (d, J=4 Hz, 1H), 7.02-7.00 (d, J=4 Hz, 1H), 2.48 (s, 3H), MS (M+1): 265.1.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[K+]>ClCCl.CN1CCCC1=O>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][CH:6]=2)[NH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: CCOC(=O)CN
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(C(F)(F)F)ccc2c1N
Yield: 23.1 %

Procedure:
Under nitrogen, stir and heat a mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile (1.0 g, 5.29 mmol), ethyl glycinate hydrochloride (886 mg, 6.3 mmol), potassium carbonate (1.46 g, 6.3 mmol) and 1-methyl-2-pyrrolidinone (20 mL) at 115–120° C. After six hours add potassium tert-butoxide (700 mg, 6.2 mmol), and stir at ambient temperature for 2 h. Quench into ice/water, extract the aqueous mixture with ether, wash the extract with water and dry it with magnesium sulfate. Filter and concentrate under vacuum to yield the crude product. Chromatograph the crude product on silica gel (10 g, Sepack cartridge) with dichloromethane as eluent to afford 332 mg (23%) of the title compound. Identical on TLC (silica gel, dichloromethane) to the compound disclosed in U.S. Pat. No. 5,189,054.
Reaction SMILES: [OH:1][C:2]1([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[O:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)[CH2:10]2)[CH2:4][CH2:3]1>ClCCCl>[OH:1][C:2]1([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[O:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:10]2)[CH2:4][CH2:3]1
Reactant: COc1ccc(N2CC(CN3CCC(O)(c4ccc5c(c4)OCO5)CC3)OC2=O)cc1
Solvent: ClCCCl
Product: O=C1OC(CN2CCC(O)(c3ccc4c(c3)OCO4)CC2)CN1c1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
A suspension of 3.8 g of 5-[4-hydroxy-4-(3,4-methylenedioxyphenyl)piperidinomethyl]-3-p-methoxyphenyloxazolidin-2-one in 50 ml of 1,2-dichloroethane is added dropwise to a boiling solution of 15.6 g of dimethyl sulphide/boron tribromide complex in 50 ml of 1,2-dichloroethane, the mixture is boiled for another 30 minutes, worked up as usual, to give 5-[4-hydroxy-4-(3,4-methylenedioxyphenyl)piperidinomethyl]-3-p-hydroxyphenyloxazolidin-2-one.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18](C3C=CC=CN=3)C)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:26][C:27]([F:49])([F:48])[C:28]1[N:33]=[CH:32][C:31](CN2CCN(C(OC(C)(C)C)=O)CC2)=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1>CC(O)C.CCN(C(C)C)C(C)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:31]3[CH:32]=[N:33][C:28]([C:27]([F:49])([F:48])[F:26])=[CH:29][CH:30]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(F)(F)F)nc2)CC1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(Br)c(N2CCN(Cc3ccc(C(F)(F)F)nc3)CC2)c1[N+](=O)[O-]

Procedure:
This was prepared using the same procedure as for 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine, but here using tert-butyl 4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperazine-1-carboxylate (1.1 eq, 0.27 mmol, 93 mg), TFA (1 mL) and CH2Cl2 (3 mL), then 5-bromo-4-chloro-3-nitropyridin-2-amine (62 mg, 0.24 mmol) in iPrOH (3 mL) and DIPEA (1 mL). Filtration and washing as previously described gave the product (78 mg, 63% for two steps) as a yellow solid; δH (500 MHz, DMSO-d6) 2.55 (s, br, 4H, piperazine N(CH2)2), 3.07 (s, br, 4H, piperazine N(CH2)2), 3.69 (s, 2H, NCH2), 6.97 (s, br, 2H, NH2), 7.87 (d, J=8.0 Hz, 1H, pyridine H-5), 8.03 (dd, J=8.0, 0.6 Hz, 1H, pyridine H-4), 8.16 (s, 1H, bromopyridine H-6), 8.71 (d, J=0.6 Hz, 1H, pyridine H-2);
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>[Cl-].[Zn+2].[Cl-]>[CH2:25]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]([OH:11])=[CH:2][CH:3]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: Oc1cccc2ccccc12
Reactant: CCCCCCCCCCCCCCO
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCCCCCCCCCCCCc1ccc(O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
In a one liter three-neck flask provided with agitating means were charged and stirred 216 g (1.5 mole) of α-naphthol and 171 g (1.26 mole) of zinc chloride, 278 g (1.26 mole) of tetradecyl alcohol was added dropwise to the flask kept at 160° C. Stirring was continued for 8 hours after the completion of the addition at the same temperature. The reaction product was cooled to room temperature (i.e., 20°-30° C), and then washed with water after the addition of 500 ml of petroleum ether and 500 ml of water with stirring. This washing operation was repeated twice. The petroleum ether layer was separated, which was distilled under a reduced pressure after being dried with anhydrous sodium sulfate. 183 g of 4-tetradecyl-α-naphthol (yield: 42.7%) having boiling range of 188° to 194° C at 0.15 mmHg was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C:12]([OH:14])=O)[C:4]=2[N:3]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(N(C)C)=O>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C:12]([NH:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:14])[C:4]=2[N:3]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1cccc2[nH]c(=O)n(Cc3ccccc3)c12
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: O=C(Cc1cccc2[nH]c(=O)n(Cc3ccccc3)c12)NCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47 %

Procedure:
2-(2-oxo-3-benzylbenzimidazolyl)acetic acid (1.77 mmol, 0.5 g) (example 2) in DMA (5 ml) is charged with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl (2.66 mmol, 0.51 g). Benzylamine (2.48 mmol, 0.27 ml) is added to the suspension, and the mixture is stirred at room temperature for 17 hours. The solution is added dropwise into ice (50 g) and the colorless precipitate is filtered off and dried in vacuo. Recrystallisation from ethyl acetate yields the title product (47%) (R1=CH2—C(O)—NHR5, R5=benzyl, R2=benzyl, n=0).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:25]([OH:27])=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OCC1C=CC=CC=1)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:28]([O:33][CH3:34])(=[O:32])[C:29]([CH3:31])=O>CO.[Pd]>[C:1]([NH:8][C@H:9]([C:25]([OH:27])=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH:29]([C:28]([O:33][CH3:34])=[O:32])[CH3:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)C(C)=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
Dissolve 7.6 g Nα -Boc-Nε -Cbz-L-lysine and 2.04 g methyl pyruvate in 75 ml methanol. Add 2 g 10% palladium on charcoal and hydrogenate at an initial pressure of 40 psig for 3 hours at room temperature. Filter the solution and concentrate the filtrate at aspirator pressure to obtain Nα -Boc-Nε -(1-methoxycarbonylethyl)-L-lysine.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:37](=[O:36])[CH2:38][OH:39])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)CO)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f6) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:16][C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]([O:21]C)=[O:20])[CH:13]=2)[CH2:8]1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:16][C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]([OH:21])=[O:20])[CH:13]=2)[CH2:8]1
Reactant: COC(=O)c1ccccc1Nc1ccc2c(c1)CC(NCc1ccc(Cl)c(Cl)c1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccccc1Nc1ccc2c(c1)CC(NCc1ccc(Cl)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
Methyl 2-[2-(3,4-dichloro-benzylamino)-indan-5-ylamino]-benzoate (0.98 g) was dissolved in 20 mL 1:1 THF/MeOH, and this solution was treated with 9 mL 50% NaOH and stirred at room temperature for 24 hours. When the starting material was no longer observed by mass spec, the mixture was concentrated to remove the MeOH, extracted with diethyl ether, and the precipitate was collected by filtration and dried in vacuo overnight to give 2-[2-(3,4-dichlorobenzylamino)-indane-5-ylamino]-benzoic acid (0.09 g, 10% yield). MS (APCI) m/z 427.1 (M++1). CHN for (C23H20Cl2N2O2.1.85HCl) calc: C, 55.83, H, 4.45, N, 5.66; found: C, 55.45, H, 4.22, N, 5.50.
Reaction SMILES: [F:1][C:2]([F:32])([C:28]([F:31])([F:30])[F:29])[C:3]([F:27])([F:26])[C:4]([F:25])([F:24])[O:5][C:6]([F:23])([F:22])[C:7]([F:21])([F:20])[O:8][C:9]([F:19])([F:18])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[CH2:33]([O:39][C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)=[N:44][CH:45]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.C1(C)C=CC=CC=1>[CH2:33]([O:39][C:40]1[CH:45]=[N:44][C:43]([C:46]2[CH:47]=[CH:48][C:49]([O:52][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:21])([F:20])[C:6]([F:23])([F:22])[O:5][C:4]([F:25])([F:24])[C:3]([F:27])([F:26])[C:2]([F:32])([F:1])[C:28]([F:31])([F:30])[F:29])([F:19])[F:18])=[CH:50][CH:51]=2)=[N:42][CH:41]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
A 500 mL flask was charged with 5-(2-(2 -(nonafluorobutoxy)tetrafluoroethoxy)-2,2 -difluoroethoxy)-l-bromopentane (18.6 g, 32 mmol; prepared from 1,5-dibromopentane and 2-(2 -(nonafluorobutoxy)tetrafluoroethoxy)-2,2 -difluoroethanol), 5-hexyloxy-2-(4 -hydroxyphenyl)pyrimidine (8.0 g, 29.4 mmol), potassium carbonate (5.4 g, 39 mmol), and acetonitrile (200 mL), and the resulting mixture was stirred and refluxed overnight under nitrogen. Toluene (150 mL) and water (150 mL) were added to the refluxed mixture. The resulting toluene layer was collected and residual water removed by distillation using a Dean-Stark apparatus. The toluene layer was then filtered through a pad of silica gel and the toluene removed under reduced pressure. The crude product was further purified by distillation using a Kugelrohr apparatus (b.p. 210°- 25° C. at 0.3 torr)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:11].[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[CH3:11][N:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[CH2:5][C:4]1[CH:12]=[CH:13][CH:14]=[C:2]([O:1][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1
Reactant: CN1CCCC1Cc1cccc(O)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1CCCC1Cc1cccc(OC(=O)C(C)(C)C)c1
Temperature: 0 °C

Procedure:
Stir 380 mg of 2-(3-hydroxybenzyl)-1-methylpyrrolidine at 100° for 2.5 hours with 480 mg of pivaloyl chloride in 5 ml of absolute pyridine. Pour the resulting reaction mixture into 50 ml of ice water. Then add 20 ml of saturated sodium carbonate solution thereto before extracting it with diethyl ether. Dry the ether extract over sodium sulfate, distil off the solvent and distil the residue under a high vacuum to obtain 320 mg (58% of theory) of the title compound as colorless liquid of b.p. 95° to 100° at 0.002 mm of Hg.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC(=O)[NH:14][C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[N:19]=1)([CH3:17])[CH3:16])(C)(C)C>>[ClH:1].[NH2:14][C:15]([C:18]1[N:19]=[C:20]([C:24]#[N:25])[CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(C#N)n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(N)c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
Add 4N HCl in dioxane (17 mL, 68 mmol) to [1-(6-cyano-pyridin-2-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (1.2 g, 5 mmol). Stir the solution at room temperature for 10 minutes and observe the formation of a white solid. Stir the reaction at room temperature for 4 hours. Evaporate the solvent to give 6-(1-amino-1-methyl-ethyl)-pyridine-2-carbonitrile hydrochloride salt as a white solid (880 mg, 97% yield).
Reaction SMILES: [CH:1]1([N:7]([CH:30]([CH3:32])[CH3:31])[C:8](=[O:29])[C:9]2[CH:14]=[CH:13][C:12]([CH:15](O)[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.S(=O)(=O)(O)O.[Pd].C(OCC)(=O)C>[CH:1]1([N:7]([CH:30]([CH3:32])[CH3:31])[C:8](=[O:29])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(Cc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC

Procedure:
The compound prepared in Example 14 (800 mg, 1.81 mmol) in ethyl alcohol (20 mL) containing concentrated sulfuric acid (4 drops) was hydrogenated at 60 psi and room temperature using 5% Pd/C as catalyst. The catalyst was filtered and the filtrate concentrated in vacuo to give the crude product as an oil. The crude product was dissolved in ethyl acetate and washed twice with aqueous NaHCO3 solution and then with saturated aqueous NaCl solution. After drying (Na2SO4), the organic layer was filtered and concentrated in vacuo to give the title compound.
Reaction SMILES: ClC1C=CC(P(Cl)(Cl)=O)=CC=1.[NH:12]1C=NN=N1.[C:17]([O:20][C@H:21]1[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@:24]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH:34]([F:36])[F:35])[O:23][C@H:22]1[N:46]1[CH:51]=[CH:50][C:49](=O)[NH:48][C:47]1=[O:53])(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:20][C@H:21]1[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@:24]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH:34]([F:35])[F:36])[O:23][C@H:22]1[N:46]1[CH:51]=[CH:50][C:49]([NH2:12])=[N:48][C:47]1=[O:53])(=[O:19])[CH3:18]
Reactant: c1nnn[nH]1
Reactant: CC(=O)O[C@@H]1[C@H](n2ccc(=O)[nH]c2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Agent: O=P(Cl)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](n2ccc(N)nc2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 176.3 %

Procedure:
4-Chlorophenylphosphonic dichloride (0.4 g, 0.81 mmol) was added to a cooled (0° C.) solution of 1-H-tetrazole (0.056 g, 0.81 mmol) and 35 (0.113 g, 0.22 mmol) in dry pyridine (5 mL). The reaction mixture was left to stir under a nitrogen atmosphere at 20° C. for 3 h and then evaporated to dryness under reduced pressure. The residue was dissolved in dioxane and NH3.H2O (5 mL) was added. After stirring for 5 h at 20° C., the reaction mixture was evaporated to dryness under reduced pressure to afford 36 (0.2 g, crude).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:23][CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:22]=1)[CH3:2].C([O-])(=O)C.[NH4+:37].[OH-].[K+]>>[CH2:26]([O:25][CH2:24][CH2:23][N:6]1[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:37])[C:8]=2[N:22]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOCc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCc1ccccc1
Temperature: 156 °C
Yield: 40.2 %

Procedure:
2-(Ethoxymethyl)-1-[2-(benzyloxy)ethyl]-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (4.33 g, 10.03 mmol) was placed in a glass reaction flask, and then ammonium acetate (45 g) was added. The flask was sealed with a teflon screw cap and heated to 156° C. for 44 hours. The reaction was determined to be complete by HPLC analysis, and the desired product's molecular weight was confirmed by LC/MS. The resulting solution was basified with 1 N potassium hydroxide to a pH of about 14. The basic solution was extracted with dichloromethane (5×), and the organic layers were combined, washed with water (3×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was triturated with diethyl ether. After the resulting solids were filtered off and dried, they were recrystallized from ethyl acetate/diethyl ether and again dried. NMR analysis or the recrystallized solids indicated impurities. The recrystallized solids were dissolved in ethanol. Hydrochloric acid (10 mL, 1 N) was added to the ethanol solution, and the resulting salt was filtered off and dissolved in water. The resulting aqueous solution was basified with 1 N potassium hydroxide to a pH of about 14 and extracted with dichloromethane (4×). The organic layers were combined, washed with water (2×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a white solid. The white solid was dried to provide 1.4285 g of 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 107.3–108.2° C.