Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25].[OH-].[Na+].[Na+].[I-].Br[CH2:31][CH2:32][OH:33]>C(O)(C)C.C(O)=O>[OH:33][CH2:32][CH2:31][O:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Reactant: OCCBr
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=CO
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCO
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (100 mg) (8.9 mg, 0.025 mmol) in isopropanol (1 mL) is added 2 N aq. NaOH (100 μL), NaI (1 mg, 0.007 mmol) and 2-bromo-ethanol (12.5 mg, 0.1 mmol). The reaction mixture is heated to 90° C. and shaken for 8 h before it is cooled to rt. Formic acid (0.2 mL) is added and the reaction mixture is separated by prep. HPLC to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzylamide (5.4 mg) as a colourless lyophilisate. LC-MS: tR=1.00 min, [M+1]+=400.26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[C:18]([Cl:27])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]=[N:22][CH:21]=[CH:20]4)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[S:28]([N:31]=CN(C)C)(=[O:30])=[O:29].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[C:18]([Cl:27])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]=[N:22][CH:21]=[CH:20]4)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[S:28]([NH2:31])(=[O:30])=[O:29]
Reactant: CN(C)C=NS(=O)(=O)c1cc(CN[C@H]2CC[C@@H](Oc3ccc4cnccc4c3Cl)CC2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1cc(CNC2CCC(Oc3ccc4cnccc4c3Cl)CC2)ccc1Cl
Temperature: 65 °C
Reaction time: 5 h
Yield: 48.4 %

Procedure:
53 mg 2-Chloro-5-{cis-[4-(5-chloro-isoquinolin-6-yloxy)-cyclohexylamino]-methyl}-N-dimethylaminomethylene-benzenesulfonamide (74) were dissolved in 5 ml ethanol. 2 ml 2N NaOH were added and the mixture was heated to 65° C. After 5 h, the solvent was removed i. vac., the residue was dissolved in H2O and neutralized by adding 1 N HCl. The precipitate was filtered and dried, to yield 23 mg of the title compound as hydrochloride. Rt=0.89 min (Method #1). Detected mass: 480.2/484.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]#[N:11])[CH:3]=1.[N:12]([Si](C)(C)C)=[N+:13]=[N-:14].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1.C([Sn](=O)CCCC)CCC>[Cl:9][C:6]1[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=[C:4]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[N:5]=1
Reactant: N#Cc1cc(Cl)c(Cl)c(Cl)n1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Clc1cc(-c2nnn[nH]2)nc(Cl)c1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
A mixture of 4,5,6-trichloropyridine-2-carbonitrile (4.77 g, 23.0 mmol), azidotrimethylsilane (6.1 mL, 46.0 mmol) and dibutyltin oxide (0.57 g, 2.3 mmol) in toluene (75 mL) was heated to 90° C. After 3 hours, the reaction mixture was heated to reflux. After 7 hours, azidotrimethylsilane (0.5 mL, 3.8 mmol) and dibutyltin oxide (100 mg, 0.4 mmol) were added to drive the reaction to completion. After a short time, the volatiles were removed, and then the residue was taken up in methanol (50 mL) and stirred briefly at 25° C. The volatiles were removed and the residue was partitioned between saturated aq. NaHCO3 (200 mL), ethyl acetate (200 mL) and diethyl ether (100 mL). The layers were carefully separated in order to retain the insoluble white material in the aqueous fraction. The aqueous fraction then was acidified to pH 2 with concentrated HCl while stirring vigorously. The white precipitate was collected, washed with water and dried to provide 2,3,4-trichloro-6-(1H-tetrazol-5-yl)pyridine (5.4 g, 21.6 mmol), mp 197-198° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[S:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[O:13]=[C:10]1[NH:9][C:8]2[CH:14]=[C:4]([CH2:3][CH2:2][O:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:5]=[CH:6][C:7]=2[S:12][CH2:11]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CSc2ccc(CCO)cc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc2c(c1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
A solution of (h) (0.34 g, 1.7 mmol) and triethylamine (0.25 ml, 0.19 g, 1.8 mmol) in dichloromethane (5 ml) was cooled to −15° C. and treated dropwise with methanesulfonyl chloride (0.14 ml, 1.75 mmol). The ice bath was removed and the mixture stirred 15 hours at room temperature. The organic phase was separated, washed with water, dried over magnesium sulfate and evaporated. The crude product was chromatographed on silica gel eluting with ethyl acetate/heptane (2/1) to give a white solid (0.36 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:20]=1[CH2:21]O>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:21][C:20]3[C:19]([F:18])=[CH:26][C:25]([F:27])=[CH:24][C:23]=3[F:28])=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1
Reactant: OCc1c(F)cc(F)cc1F
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cc(F)cc3F)cc2)C1

Procedure:
In an analogous manner to that described in Example 28b), the alkylation of the (R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 28a)] with 2,4,6-trifluorobenzylalcohol yields the (R)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester as a white solid. MS: m/e=380 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:7]=12.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:7]=12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1c(C)n(C2CCCCC2)c2c(Cl)nncc12
Reactant: OCc1ccccc1
Product: Cc1c(C)n(C2CCCCC2)c2c(OCc3ccccc3)nncc12
Yield: 92.8 %

Procedure:
The title compound was prepared as a white powder in 92.8% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-cyclohexyl-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [NH:1]([C:13]([CH3:15])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:16](O)(=O)[CH:17]=C.N(C(C)=O)[C@H](C(O)=O)CC1C=CC=CC=1>C(O)C.Cl>[NH:1]([C:13]([CH3:15])=[O:14])[C@H:2]([C:10]([O:12][CH2:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=CC(=O)O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(C)=O

Procedure:
The synthesis of N-Ac-L-Phe-acrylic acid is shown below in Scheme B. To a solution of N-Ac-L-Phe (5.0 g, 24.1 mmol) in 120 ml of ethanol was added a few drops of concentrated HCl. The reaction mixture was refluxed overnight, then concentrated under reduced pressure. The residual solid was dissolved in ethyl acetate, washed twice with dilute NaHCO3, then once with water. The organic phase was dried over MgSO4, concentrated under reduced pressure, and dried under vacuum, to give N-Ac-Phe-OEt (7) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]2[CH:17]=[C:18]([NH:19][C:2]3[N:7]=[C:6]([NH:19][C:18]4[CH:20]=[CH:21][CH:22]=[C:16]([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH:17]=4)[C:5]([F:9])=[CH:4][N:3]=3)[CH:20]=[CH:21][CH:22]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(-c2ccccc2)c1
Product: Fc1cnc(Nc2cccc(-c3ccccc3)c2)nc1Nc1cccc(-c2ccccc2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-phenylaniline were reacted to yield N2,N4-bis[(3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.02 (d, 1H, J=5.1 Hz), 7.82 (t, 1H, J=1.5 Hz), 7.67 (t, 1H, J=1.8 Hz), 7.58 (dd, 1H, J=1.2 and 7.2 Hz), 7.42-7.24 (m, 15H); LCMS: ret. time: 32.06 min.; purity: 94%; MS (m/e): 433 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[CH:22](=O)[C:23]1[C:24]([O:29][CH3:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30]
Reactant: COc1ccccc1C=O
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: COc1ccccc1C=CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared by heating a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and o-anisaldehyde (77 ul, 0.633 mmol) similar to Example 1 and isolated as a yellow solid (107 mg, 39%). 1H NMR (CDCl3): 8.03 (d, J=15.9 Hz, 1H), 7.61 (dd, J=1.4, 7.7 Hz, 1H), 7.44 (d, J=16.2 Hz, 1H), 7.40-7.34 (m, 1H), 7.25 (d, J=3.3 Hz, 1H), 7.09 (dd, J=3.0, 8.7 Hz, 1H), 7.00-6.94 (m, 2H), 6.92 (d, J=9.3 Hz, 1H), 4.42-4.32 (m, 4H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[NH:11][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:27])C(=O)C1>C1COCC1>[Cl:27][C:8]1[N:7]([CH2:6][C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:15]2[C:14](=[O:16])[NH:13][C:12](=[O:17])[NH:11][C:10]=2[N:9]=1
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccc(Cl)cc2)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2c(nc(Cl)n2Cc2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Yield: 18.1 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (2.2 g, 7.97 mmol) in THF (30 mL) was added NCS (1.1 g, 8.27 mmol) at 0° C. in portions. Then the resulting mixture was stirred at room temperature until it became a clear solution. The reaction was immediately quenched with ice-water and concentrated. The residue was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to give a crude product. This material was purified by silica gel chromatography eluting with DCM/methanol (50:1 to 20:1) to give 8-chloro-7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (450 mg, 18.2% yield) as white solid. LCMS retention time 1.071; LCMS MH+-58 311.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[O:21][CH:22]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=1
Reactant: Fc1ccc(C(OCCCCCl)c2ccc(F)cc2)cc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(OC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCNCC1
Reaction time: 72 h
Yield: 30 %

Procedure:
Piperazine (4.31 g, 50 mmol) was dissolved in 40 mL of anhydrous DMF and stirred with K2CO3 powder (2.76 g, 20 mmol) and KI (100 mg, 0.6 mmol) for 0.5 h. To this turbid solution, 1-[bis(4-fluorophenyl)methoxy]-4-chlorobutane (2, 1.55 g, 5 mmol) in 10 mL of DMF was added slowly. The reaction mixture was stirred for 72 h at 60°-70°. The turbid reaction mixture was poured into 200 mL of ethyl acetate, washed with sat. NaCl solution (60 mL×5), dried over MgSO4 and evaporated to dryness. The crude oil was applied to a silica gel column for purification. Elution with CHCl3:MeOH (93:7) afforded the desired mono-alkylated product 3 (540 mg, 1.5 mmol, 30%) as a slightly yellow oil. 1H NMR (CDCl3): δ 1.55-1.69 (4H, m), 2.31 (2H, t, J=7.5), 2.39 (4H, br s), 2.88 (4H, t, J=4.8), 3.43 (2H, t, J=6.0), 5.28 (1H, s), 6.98-7.02 (4H, m), 7.25-7.29 (4H, m). mp (bis oxalate salt): 215°-218° C. Anal. C25H30N2O9F2) C, H, N.
Reaction SMILES: [CH3:1][CH:2]1[O:16][C:5]2=[CH:6][C:7]3[CH2:8][C:9](=[O:15])[N:10]([CH2:13][CH3:14])[C:11]=3[CH:12]=[C:4]2[CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:8]2[C:7]3[CH:6]=[C:5]4[O:16][CH:2]([CH3:1])[CH2:3][C:4]4=[CH:12][C:11]=3[N:10]([CH2:13][CH3:14])[C:9]2=[O:15])=[O:26])=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCN1C(=O)Cc2cc3c(cc21)CC(C)O3
Product: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2)c2cc3c(cc21)CC(C)O3
Yield: 45 %

Procedure:
Following the procedure of Example 1 and employing 326 mg. (1.5 mmoles) of 2-methyl-5-ethyl-6-oxo-2,3,6,7-tetrahydrofuro[2,3-f]indole and 0.24 ml. (2.1 mmoles) of 4-fluorophenylisocyanate, 240 mg. (45% yield), m.p. 196°-197° C. of the desired product was obtained.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([N:17]([CH3:28])[C@H:18]([C:20]([C@:22]([CH3:27])([OH:26])[C:23]([OH:25])=O)=[O:21])[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[CH2:10]([N:17]([CH3:28])[C@H:18]([C:20]([C@:22]([CH3:27])([OH:26])[C:23]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:25])=[O:21])[CH3:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C1CCNCC1
Reactant: C[C@@H](C(=O)[C@](C)(O)C(=O)O)N(C)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)[C@](C)(O)C(=O)N1CCCCC1)N(C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
5.4 g (41.4 mmol) of N,N-diisopropylethylamine (Hünig's base) and 5.3 g (20.7 mmol) of bis(2-oxo-3-oxazolidinyl)-phosphonium acid chloride (BOP-Cl) are added at 0° C. to a solution of 5.0 g (18.8 mmol) of N-benzyl-N-methyl-L-alanyl-D-lactic acid and 1.6 g (20.7 mmol) of piperidine in 150 ml of methylene chloride, and the mixture is stirred at 0° C. for two hours and then at room temperature for 18 hours. The residual crude product is chromatographed on a silica gel column (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane:ethyl acetate (3:1). 3.5 g (55.8% of theory) of N-benzyl-N-methyl-L-alanyl-D-lactic acid piperidide are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: Nc1ccccc1C=O
Reactant: COc1cccc(F)c1CCC#N
Product: COc1cccc(F)c1Cc1cc2ccccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-aminobenzaldehyde and 3-(2-fluoro-6-methoxyphenyl)propionitrile.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:17](OC)(=[O:20])[C:18]#[CH:19]>C(O)C>[O:20]=[C:17]1[CH:18]=[CH:19][N:6]2[C:2]([S:3][C:4]3[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][C:5]=32)=[N:1]1
Reactant: C#CC(=O)OC
Reactant: CCOC(=O)Cc1ccc2nc(N)sc2c1
Solvent: CCO
Product: CCOC(=O)Cc1ccc2c(c1)sc1nc(=O)ccn12
Yield: 47.2 %

Procedure:
A stirred mixture of 5 g of ethyl 2-aminobenzothiazole-6-acetate [prepared according to Sawhney et al., Ind J. Chem., Vol. 16B p. 605 (1978)], 1.95 g of methyl propiolate and 30 ml of ethanol was heated under reflux for 2 hours and the mixture was allowed to cool. The crude product was collected and then recrystallized from n-butyl alcohol to obtain 2.88 g of ethyl 2-oxo-2H-pyrimido[2,1-b]benzothiazole-8-acetate as yellow needles (48% yield).
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].[CH2:6]([O:8][C:9](=[O:16])[C:10]([C:12]([F:15])([F:14])[F:13])=[O:11])[CH3:7].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:6]([O:8][C:9](=[O:16])[C:10]([OH:11])([C:12]([F:13])([F:15])[F:14])[CH:2]=[C:3]([CH3:5])[CH3:4])[CH3:7]
Reactant: C=C(C)CBr
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(C=C(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 73 %

Procedure:
A suspension of 0.27 mol Mn and 0.01 mol ZnCl2 in 105 ml THF is heated to reflux. 0.01 mol 3-bromo-2-methyl-1-propene is added to the boiling mixture and after 30 minutes a solution of 0.11 mmol ethyl-trifluoropyruvate and 0.18 mol 2-bromo-2-methyl-1-propene in 90 ml THF is dropped to the reaction mixture within 2.5 hours. After 3 hours under reflux the mixture is stirred for 19 hours at room temperature. The reaction mixture is poured on 90 ml of a saturated NH4Cl and ice mixture. After vigorous stirring for 30 minutes the mixture is extracted four times with 110 ml of MTBE each. The combined organic extracts are washed with 30 ml of brine, dried over magnesiumsulfate and concentrated in vacuo. The residue is destined under reduced pressure. ethyl-2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is obtained in 73% yield.
Reaction SMILES: [F:1][CH:2]([CH3:18])[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][OH:17].CS([O-])(=O)=O.[CH2:24](O)[CH2:25][CH2:26][OH:27]>>[F:1][CH:2]([CH3:18])[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][O:17][CH2:24][CH2:25][CH2:26][OH:27]
Reactant: CC(F)CCCCCCCCCCCCCCO
Reactant: OCCCO
Agent: CS(=O)(=O)[O-]
Product: CC(F)CCCCCCCCCCCCCCOCCCO

Procedure:
A general procedure for the preparation of penultimate fluorinated alkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated in Scheme 6, below. Fluoroalkoxyalkyl esters of acyclic nucleoside phosphonates such as 3-(15-fluorohexadecyloxy)propyl cidofovir 42 (15-F-HDP-CDV) and 3-(15-fluorohexadecyloxy)propyl (S)-HPMPA 43 (15-F-HDP-(S)-HPMPA) can be prepared using this process. Briefly, with reference to Scheme 6, commercially available 2-bromopropanoic acid 35 is reduced to the alcohol with borane:THF complex solution to provide 2-bromo-1-propanol 36. Fluorination of 36 is achieved with 1,1,2-trifluoro-2-chloroethyldiethylamine, a mild and safe reagent to convert 1-hydroxy-2-halogenoalkanes into the corresponding rearranged fluoride 37. Conversion of 37 into a Grignard reagent followed by reaction with 13-bromo-tridecanol in the presence of the catalyst provides 15-fluorohexadecanol 38. Conversion of alcohol 38 into the methanesulfonate derivative, followed by reaction with 1,3-propanediol provides 3-(15-fluorohexadecyloxy)propan-1-ol 39. Reaction of 39 with cyclic cidofovir or cyclic (S)-HPMPA as described generally in Example 2 (step a), provides the cyclic esters (40 and 41, respectively) which can then be converted to the desired compounds (42 and 43, respectively) using the general method set forth in Example 2 (step b).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[S:16][CH:17]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:18]([O:20][C@H:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:39])[F:40])=[C:33]([O:41][CH2:42][CH:43]3[CH2:44][CH2:45]3)[CH:32]=2)[CH2:28][C:27]2[C:26]([Cl:46])=[CH:25][N+:24]([O-:47])=[CH:23][C:22]=2[Cl:21])=[O:19])[S:16][CH:17]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1csc(C(=O)O)c1)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1csc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a solution of 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-thiophene-2-carboxylic acid (Int. 44) (100 mg, 0.311 mmol) in DCM (5 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (131 mg, 0.311 mmol), EDC (179 mg, 0.934 mmol) and DMAP (19.01 mg, 0.156 mmol) were added, and reaction was stirred at RT overnight. The mixture was diluted with DCM (10 ml) and washed with 1N HCl; the aqueous phase was extracted with EtOAc and the combined organic layers were dried over sodium sulfate. The solvent was removed under vacuum and the crude was purified by flash chromatography on silica gel (DCM/MeOH=98/2) affording (S)-4-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)thiophene-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (Int. 45) (72 mg, 0.100 mmol, MS/ESI+722.9 [MH]+).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc(Cl)c1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.1 g) and 3-chlorobenzenesulphonyl chloride (0.13 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].BrC#[N:35].O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]3[CH2:21][CH2:22][N:23]([C:26]#[N:35])[CH2:24][CH2:25]3)=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
To a stirred mixture, under N2 of 6-fluoro-1-phenylsulfonyl-3-(4-methyl-1-piperazinyl)-1H-indazole (30.0 g, 0.86 mol) of Example 31c, K2CO3 (4.7 g, 0.086 mol) and dimethyl sulfoxide (DMSO) [250 ml] was added, dropwise, BrCN (9.1 g, 0.086 mol) dissolved in DMSO (50 ml). The reaction was stirred at ambient temperature for 2 hours and water was added. The resultant solid was collected and taken up in CH2Cl2, and after washing the organic layer with H2O, drying (K2CO3) and concentrating there remained 25.3 g of the target compound. A sample (5.0 g) was removed and recrystallized from ethyl acetate (twice) to afford 2.3 g (35%) of 4-(6-fluoro-1-phenylsulfonyl-1H-indazol-3-yl)-1-piperazine carbonitrile m.p. 178°-180° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>O1CCOCC1>[Br:1][C:2]1[C:7]([NH:21][CH2:20][CH2:19][O:18][CH3:17])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: COCCN
Solvent: C1COCCO1
Product: COCCNc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and 2-methoxyethylamine in dioxane. ES-MS m/e (%): 315 (M{81Br}+H+, 100), 313 (M{79Br}+H+, 80).