Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:46])[CH:6]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:42])[CH:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:20]([CH2:43][O:44][CH3:45])[CH2:19]1)[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.Cl>C1COCC1.O>[C:38]([O:37][C:35]([NH:34][CH:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:24]([N:21]1[CH2:22][CH2:23][N:18]([CH:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[C:5]([OH:46])=[O:4])[CH2:19][CH:20]1[CH2:43][O:44][CH3:45])=[O:42])=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCC1CN(C(Cc2ccc3ccccc3c2)C(=O)O)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 100 %

Procedure:
LiOH (0.71 g, 29.7 mmol) is added to the cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazine-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 63, (3.6 g, 5.9 mmol) in THF/H2O (2/1, 60 mL). The reaction mixture is stirred for overnight. The reaction mixture is cooled in ice bath and pH is adjusted to 3 with 1M HCl. The aqueous layer is extracted with EtOAc (3×100 mL) and dried over Na2SO4. The solution is concentrated in vacuo to afford 3.7 g 100% yield) of the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[C:5]([CH3:28])[CH:4]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:4][C:5]=3[CH3:28])=[O:27])[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(F)cn2)cc1=O
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCCC2)ccc1C(=O)Cn1ccc(OCc2ccc(F)cn2)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-fluoro-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 2b, 111 mg, 0.25 mmol) in DMF (2 mL) is added pyrrolidine (63 μL, 0.75 mmol). The reaction mixture is stirred for 60 min at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: C([O:3][P:4]([CH:10]([OH:28])[CH:11]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH2:12][NH:13]C(OC(C)(C)C)=O)([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])C>Cl>[ClH:27].[NH2:13][CH2:12][CH:11]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:10]([P:4]([CH2:6][CH2:7][CH2:8][CH3:9])(=[O:3])[OH:5])[OH:28]
Reactant: CCCCP(=O)(OCC)C(O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Product: CCCCP(=O)(O)C(O)C(CN)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.35 g of ethyl 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxy-propyl(n-butyl)phosphinic acid in 10 ml of 5.0M aqueous hydrochloric acid is heated to reflux--for 24 hours. The reaction is cooled to room temperature and washed with 3×50 ml dichloromethane and 1×50 ml ether. After evaporation of the aqueous layer the residue is co-evaporated with water (3×50 ml) and absolute ethanol (3×50 ml) and dried in high vacuum to afford 3-amino-2-(4-chlorophenyl)-1-hydroxy-propyl(n-butyl)phosphinic acid hydrochloride.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[ClH:21].[NH3:22]>C(O)C>[ClH:21].[F:1][C:2]([F:19])([F:20])[CH:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]([NH2:22])=[NH:16])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: N
Reactant: CCCCCCC(Oc1ccc(C#N)cc1)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCCCCCC(Oc1ccc(C(=N)N)cc1)C(F)(F)F

Procedure:
Into 20 ml of dry ethanol containing 3.76 g of oa p-(1-trifluoromethyl-heptyloxy)-benzonitrile, about 1 g of dry hydrogen chloride was introduced under stirring at a temperature below 10° C. After stirring at room temperature for 3 days, solvent was distilled off to obtain any oily product. To this, were added slowly 20 ml of dry ethanol containing about 2 g of ammonia under cooling with ice, followed by stirring at room temperature for 3 days. Ethanol and ammonia were removed to obtain 3.40 g of oily oa p-(1-trifluoromethyl-heptyloxy)-benzamidine hydrochloride. This oily hydrochloride was solidified by trituration in hexane to use the following reaction.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([NH:35]N)=[CH:27][CH:26]=1>>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:35]([C:28]4[C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]=[CH:26][CH:27]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Reactant: NNc1ccnc2ccccc12
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4ccccc34)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and quinolin-4-yl-hydrazine according to the method described for example 43. MS: M=444.3 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2].OS(O)(=O)=O.[CH3:22]O>>[CH3:22][O:15][C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To a solution of (2,4-dinitro-phenyl)-acetic acid (5 g) in MeOH (100 mL) was added concentrated H2SO4 (1 mL) and the resulting solution was heated at reflux for overnight. After removing solvent in vacuum, the residue was partitioned between EtOAc and aqueous NaHCO3 (sat.). The organic solution was concentrated in vacuum to give the desired compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH3:17])=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH3:17])=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1cnccc1C(=O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1cnccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(3-methyl-pyridin-4-yl)-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.32 (s, 9H), 2.19 (s, 3H),7.04 (d, 1H, J=1.4 Hz), 7.21 (d, 1H, J=5.2 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.52 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.77-7.83 (m, 3H), 8.64 (d, 1H, J=5.2 Hz), 8.71 (s, 1H), 10.75 (s, 1H). MS: m/z 443.0 (M++1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1>>[F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(N)no1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Product: Cc1cc(NC(=O)c2c(C(F)(F)F)nc3c(C(F)(F)F)cccc3c2O)no1
Yield: 48.6 %

Procedure:
Using the procedure of Example 2, 27.2 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride and 6.38 g of 3-amino-5-methyl-isoxazole were reacted to obtain 12.8 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(5-methyl-isoxazol-3-yl)-3-quinoline-carboxamide melting at 216° C.
Reaction SMILES: Cl[C:2]1C(Cl)=CC(C(Cl)(Cl)Cl)=C[N:3]=1.[Cl:13][C:14]1[C:19](Cl)=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.[C-]#N.[K+]>CS(C)=O>[Cl:13][C:14]1[C:19]([C:2]#[N:3])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)cnc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3Chloro-2-fluoro-5-(trifluoromethyl)pyridine (obtained as a by-product from the fluorine exchange reaction when converting 2,3-dichloro-5-trichloromethyl pyridine to 2,3-dichloro-5-(trifluoromethyl)pyridine) (40.0 g, 0.2 mole) was put into 270 ml of dimethyl sulfoxide and stirred while potassium cyanide (14.4 g, 0.221 mole) was spooned in over a 20-minute period. The mixture was then stirred for another 20 minutes. The temperature was held between 23° C. and 28° C. throughout the reaction. The mixture was poured into 600 ml of ice water and the product was extracted into hexane. The hexane was removed on a rotary evaporator. The product was treated with activated charcoal and distilled on a Vigreaux-Claisen still at 108°-110° C. at 30 mm Hg to yield 31.45 g of colorless oil with an analysis of, in percent by weight:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:34]>>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:50][CH2:49][CH:48]([NH:47][C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:53][CH2:52]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1cc(OC)c(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)cc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(2,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl) pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([CH3:16])=[CH:4][N:3]=1.[CH3:17][N:18]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>C(Cl)Cl.CO>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:16])=[CH:4][N:3]=[C:2]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([N:18]([CH3:17])[CH:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][CH:23]=3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Cc1cnc(Cl)nc1-c1ccc(F)c(Cl)c1
Reactant: CN1CCC(N(C)c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Nc2ccc(N(C)C3CCN(C)CC3)cc2)nc1-c1ccc(F)c(Cl)c1
Yield: 25 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-4-fluorophenyl)-5-methylpyrimidine and N1-methyl-N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine in 25% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 7.69 (dd, 1H, J=7.2, 1.7 Hz), 7.49 (m, 1H), 7.41 (d, 2H, J=8.9 Hz), 7.20 (d, 1H, 8.5 Hz), 6.79 (d, 2H, J=8.5 Hz), 3.49 (m, 1H), 3.00 (d, 2H, J=10.6 Hz), 2.74 (s, 3H), 2.34 (s, 3H), 2.21 (s, 3H), 2.11 (m, 2H), 1.89 (m, 2H), 1.72 (d, 2H, J=11.6 Hz); MS (ESI): 440.3 [M+H]+, 220.8 [M+2H]2+.
Reaction SMILES: [Br:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].C([N:9](CC)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.NC1C=CC=CC=1.Cl>C(Cl)Cl>[Br:1][C:2](=[CH2:6])[C:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: CCN(CC)c1ccccc1
Reactant: C=C(Br)C(=O)Cl
Agent: Cl
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: C=C(Br)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A vigorously stirred solution of 4.5 grams (0.027 mole) of 2-bromopropenoyl chloride (Step B product) in 150 ml of dried methylene chloride was cooled to 5°±5°. To this was added dropwise 4.0 grams (0.027 mole) of N,N-diethylaniline at such a rate that the reaction mixture temperature did not exceed 10°. Upon completion of addition, 2.5 grams (0.027 mole) of aniline was added dropwise while continuing to maintain the reaction mixture temperature below 10°. The reaction mixture was allowed to warm to ambient temperature where it was stirred for two hours. After dilution with 100 ml of aqueous 1N hydrochloric acid, the reaction mixture was poured into a separatory funnel. The organic layer was separated and extracted with 50 ml of aqueous 1N hydrochloric acid, then with 100 ml of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual solid. The solid was dissolved in methylene chloride and decolorized with silica gel. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual solid. The solid was recrystallized from hexane to give 4.0 grams of 2-bromo-N-phenyl-2-propenamide; mp 90.5°-92.5°.
Reaction SMILES: [CH3:1]I.[CH:3]1([C:6]2[CH:7]=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:10][C:11]=2[OH:12])[CH2:5][CH2:4]1>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH:3]1([C:6]2[CH:7]=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:10][C:11]=2[O:12][CH3:1])[CH2:4][CH2:5]1
Reactant: CI
Reactant: CCOC(=O)c1ccc(C2CC2)c(O)n1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C2CC2)c(OC)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Silver carbonate (70 g) and methyl iodide (11.2 mL) were added to a solution of ethyl 5-cyclopropyl-6-hydroxypyridine-2-carboxylate (12.4 g) in chloroform (250 mL), and the mixture was stirred at 60° C. for eight hours. The reaction solution was filtered through celite, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give ethyl 5-cyclopropyl-6-methoxypyridine-2-carboxylate (13.05 g, 99%) as a colorless oil.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[N:10]=[N:11][C:12]([O:15][CH2:16][C:17]2[N:18]([CH3:29])[N:19]=[N:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:13][CH:14]=1)=[O:8])C>O.C1COCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[N:20]=[N:19][N:18]([CH3:29])[C:17]=2[CH2:16][O:15][C:12]2[N:11]=[N:10][C:9]([C:7]([OH:8])=[O:6])=[CH:14][CH:13]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
A solution of lithium hydroxide monohydrate (111 mg, 3.09 mmol) in water (5 mL) was added dropwise to a suspension of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (471 mg, 1.32 mmol) in THF (5 mL). The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (430 mg, 99%) as a white solid after trituration with ethyl acetate. MS: m/e=328.3 [M−H]−.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].CS(Cl)(=O)=O.[CH2:24](O)[CH2:25][CH2:26][OH:27]>>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:26]([OH:27])[CH2:25][CH3:24]
Reactant: OCCCCCCCCCCCCCCCCF
Reactant: OCCCO
Agent: CS(=O)(=O)Cl
Product: CCC(O)OCCCCCCCCCCCCCCCCF

Procedure:
A general procedure for the preparation of terminal fluorinated alkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated in Scheme 7, below. Fluoroalkoxyalkyl esters of acyclic nucleoside phosphonates such as 3-(16-fluoro-hexadecyloxy)propyl cidofovir (16-F-HDP-CDV) 49 and 3-(16-fluoro-hexadecyloxy)propyl (S)-HPMPA 50 (16-F-HDP-(S)-HPMPA) can be prepared using this process. Briefly, with reference to Scheme 7, the Grignard reagent prepared from 1-bromo-4-fluorobutane and magnesium is reacted with 12-bromododecanol 44 to obtain 16-fluorohexadecanol 45. Reaction of 45 with methanesulfonyl chloride followed by reaction with 1,3-propanediol provides 16-fluorohexadecyloxy-1-propanol 46. Coupling of 46 with cyclic cidofovir or cyclic (S)-HPMPA as described generally in Example 2 (step a), provides the cyclic esters (47 and 48, respectively) which can then be converted to the desired compounds (49 and 50, respectively) using the general method set forth in Example 2 (step b).
Reaction SMILES: C(=O)(O)[O-].[K+].[C:6]1([CH2:12][C:13](Cl)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH2:24][CH2:23][CH2:22]2>>[C:6]1([CH2:12][C:13]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[O:28][CH3:29])[CH2:24][CH2:23][CH2:22]3)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc2c(cc1CCN)CCC2
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Product: COc1cc2c(cc1CCNC(=O)Cc1ccccc1)CCC2

Procedure:
Using the procedure of Example 1, but with potassium bicarbonate replacing triethylamine, phenylacetyl chloride was reacted with 5-aminoethyl-6-methoxyindan to produce the desired product. After recrystallization from ether it had a melting point of 135° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]1[CH:20]=[C:21]([O:25][CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH3:32])[CH:22]=[N:23][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]([O:25][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[CH3:32])[CH:22]=[N:23][CH:24]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 50.6 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)phenylboronic acid (0.55 g, 2.0 mmol, Lancaster Chem Co.) and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (300 mg, 1.1 mmol) in toluene (5.0 mL) was added Pd(0) (25 mg) and Na2CO3 (1 mL of a 2 M solution), and the mixture was heated at reflux. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel to afford 225 mg of the title compound. MS (CI/NH3) m/z 405 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.83 (m, 3H), 2.08 (m, 1H), 2.36 (m, 1H), 2.54 (s, 3H), 2.78 (m, 1H), 3.17 (m, 1H), 4.10 (m, 2H), 7.42 (m, 1H), 7.92 (s, 1H), 8.00 (s, 2H), 8.42 (m, 1H), 7.92 (s, 1H), 8.00 (s, 2H), 8.42 (m, 1H), 8.48 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]([CH3:15])[CH2:7][C:6]2=[O:16].N1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH:8]([CH3:15])[CH2:7][C:6]2=[O:16]
Reactant: CCCCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a cooled mixture of 1.15 g. (5.17 mmol) of the quinoline product of Example 4, 751 mg. (10.15 mmol) of dry pyridine and 5.5 ml. of methylene chloride stirred under a nitrogen atmosphere was added dropwise 1.03 g. (7.60 mmol) of butyl chloroformate in 1 ml. methylene chloride over 10 min. at a rate to maintain a 10°-15° temperature. After the addition was complete the bath was removed, the reaction stirred at room temperature for 45 min., and poured onto 25 ml. saturated sodium bicarbonate solution. The organic phase was collected and washed with 25 ml. of saturated sodium bicarbonate solution, 50 ml. saturated sodium chloride solution, dried over magnesium sulfate, then gravity filtered and evaporated to a viscous amber oil. Evaporative distillation at 110° C (0.05 mm) gave 1.4 g. of a very viscous amber oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1.[C:18]1(=[O:28])[C@@H:26]2[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=O)[O:19]1.Cl.C([O-])(O)=O.[Na+]>C(#N)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:7]3[CH:6]=[CH:5][C:4]([OH:17])=[CH:3][C:2]=3[N:1]=[C:20]2[C@H:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@H:26]2[C:18]([OH:28])=[O:19])=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Nc1cc(O)ccc1NCc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(O)ccc2n1Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
3-Amino-4-((4-bromobenzyl)amino)phenol (7.8 g, 27 mmol) and cis-hexahydroisobenzofuran-1,3-dione (4.1 g, 27 mmol) were dissolved in acetonitrile (200 mL) and the mixture heated to 80° C. After 18 h, HCl (50 mL, 6 N) was added and the resulting mixture stirred at 60° C. for 16 h. The mixture was then cooled to RT and the pH was adjusted to ˜pH 7 with sat.NaHCO3. The aqueous was then extracted with EtOAc (3×200 mL). The combined organics were washed with water (200 mL), dried with Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.93 (s, 1H), 7.47 (d, J=8.4, 2H), 7.06 (dd, J=8.6, 2.7, 3H), 6.89 (d, J=2.1, 1H), 6.60 (dd, J=8.6, 2.2, 1H), 5.52-5.26 (m, 2H), 3.63 (d, J=4.4, 1H), 2.70 (d, J=10.7, 1H), 2.55 (d, J=8.9, 1H), 1.81 (d, J=8.9, 2H), 1.61 (dd, J=32.5, 21.3, 3H), 1.34 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[C:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH:20]=1>CCOC(C)=O.CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]1
Reactant: CC(C)C(=O)Nc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Nc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1F
Yield: 84.6 %

Procedure:
A solution of tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (2.40 g, 6.31 mmol) and 10% Pd/C (500 mg) in EtOAc (40.0 mL) and MeOH (10.0 mL) was hydrogenated (200 psi) at room temperature overnight. The reaction mixture was filtered through celite and washed with ethanol (3×10 mL). The combined extracts were concentrated in vacuo to afford 2.04 g (5.34 mmol, 85%) of tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-1-piperidinecarboxylate: ESMS m/e: 383.2 (M+H)+.