Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10](OCC)(OCC)(OCC)[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(OCCCCCCCC)(=O)C1C(=CC=CC=1)C(OCCCCCCCC)=O>[CH3:10][C:11]12[O:7][CH2:6][C:3]([CH2:8][OH:9])([CH2:4][O:5]1)[CH2:2][O:1]2
Reactant: CCOC(C)(OCC)OCC
Reactant: OCC(CO)(CO)CO
Agent: CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: CC12OCC(CO)(CO1)CO2
Yield: 85 %

Procedure:
Pentaerythritol (13.6 g, 0.1 mol), triethyl orthoacetate (16.22 g, 0.1 mol, 18.3 mL), pyridine p-toluenesulfonate (PPTS) (0.5 g, 2 mmol) and 100 mL of dioctyl phthalate were mixed in a 250 mL, round-bottom flask fitted with a regular distillation apparatus. The mixture was heated to 130°-140° C. and ethanol was slowly distilled. When the amount of ethanol was close to the theoretical value the pressure was reduced to <0.1 torr and the product was distilled in vacuo. The white product which distilled crystallized in the condenser to give 13.6-14.9 g of MHTBO. Yield: 85-93%. The compound can be recrystallized from toluene but can be used directly. Mp: 110°-112° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][F:6].[Mg].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[F:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: FCCCCBr
Reactant: OCCCCCCCCCCCCBr
Agent: [Mg]
Product: 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: CS(C)=O.[CH:5]1([CH:11]([OH:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CCN(CC)CC>C(Cl)Cl>[C:14]1([CH:12]([C:11]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:20])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(c1ccccc1)C(O)C1CCCCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C(=O)C1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.48 h
Yield: 85.4 %

Procedure:
DMSO (118 mL, 1.6674 mol) was added dropwise to a solution of 126.42 g (0.579 mol) of 1-cyclohexyl-2-phenylpropanol in 1737 mL of CH2Cl2 (cooled in a wet ice acetone bath). After 29 min, 147.93 g (1.0422 mol) of P2O5 was added. After 11 min, the cooling bath was removed. An aliquot quenched with Et3N showed complete reaction within 3 h at RT. The reaction mixture was cooled in a wet ice acetone bath. Et3N (282 mL, 2.0265 mol) was added dropwise to the cooled reaction mixture over a 30 min period. The cooling bath was removed and the mixture was stirred overnight at RT. The reaction mixture was quenched by dropwise addition of 500 mL of 3 N HCl (aq) (pH=0). After shaking in separatory funnel, the aqueous phase was removed. The organic phase was washed with 500 mL of 3 N HCl (aq) (pH=0), washed twice with 1 L of 10% K2CO3 (aq) (pH=12;12), washed three times with 500 mL of NaOCl (aq) solution, washed with 1L of water, washed with 1 L of 25% NaCl (aq), dried over MgSO4, gravity filtered and concentrated under vacuum with dry ice trap to collect Me2S. An amber oil of the title compound (107.01 g, 85.437%) was obtained;
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=S)[NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3]>C(O)C.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Yield: 7.2 %

Procedure:
A solution of 69.90 g of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-thioxo-4-thiazolidinone in 4 liters of ethanol was hydrogenated at 500 pounds per square inch (psi) in the presence of 200 g of 5% palladium on carbon overnight at 100° C. The reaction mixture was filtered and evaporated to dryness. In sections, the material was dissolved in 1 volume of hot ethyl acetate, diluted with 2 volumes of hexane, filtered, and loaded onto a silica gel chromatography column. Elution with 35% ethyl acetate in hexane provided various fractions which were combined according to the purities of the respective compounds. A total of 4.6 g of Compound B were isolated by chromatography. Fractions which were predominantly Compound B were crystallized from ethyl acetate/hexane providing a total yield of Compound B of 13.79 g. Rechromatography of fractions containing impure Compound C on silica eluting with 25% ethyl acetate in hexane provided 9.82 g of Compound C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][CH2:29][NH:30]3)=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:33].N1C=CC=CC=1>ClCCl>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][CH2:29][N:30]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:33]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Chlorobenzenesulphonyl chloride (71 mg, 0.3 mmol, 1.1 equiv.) was added to a mixture of crude 2-chloro-4-[(2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester (100 mg, 0.3 mmol, 1 equiv.) and pyridine (0.2 mL, 2.4 mmol, 8 equiv.) in dichloromethane (2 ml) and the mixture was stirred at room temperature for 16 hours. The solvent was removed under a stream of N2 and the residue purified by column chromatography (SiO2, dichloromethane). The fractions were combined to afford crude 2-chloro-4-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, 101 mg. This material was taken onto the next step without further purification. LC @215 nm; Rt 2.52: 84%, m/z (ES+): 505 (M+H+.).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH:2]1[O:4][CH2:3]1.[C:11](OC)(=[O:14])[CH:12]=[CH2:13]>>[CH2:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]1[O:4][CH2:3]1)=[O:14]
Reactant: C=CC(=O)OC
Reactant: OCCCCOCC1CO1
Product: C=CC(=O)OCCCCOCC1CO1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
In each case 20 mMol of 4-hydroxybutyl glycidyl ether (2.92 g) were stirred with 80 mMol of methyl acrylate (6.89 g), 100 mg of Novozym® 435 and 4.0 g of 5 Å molecular sieve were stirred at 20 or 40° C. for 2, 4, 6, 8 or 24 h. Thereafter, the enzyme was filtered off and the excess of methyl acrylate was removed on a rotary evaporator. A colorless acrylate was obtained with 93% (at 20° C.) or 94% (at 40° C.) yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10].NC1C=C(F)C=CC=1[C:19](O)=[O:20].[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[C:2]([NH:1][C:19]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:20])[CH:7]=1
Reactant: Nc1nccs1
Reactant: Nc1cc(F)ccc1C(=O)c1cccs1
Reactant: Nc1cc(F)ccc1C(=O)O
Product: O=C(Nc1nccs1)Nc1cc(F)ccc1C(=O)c1cccs1
Yield: 65 %

Procedure:
(2-Amino-4-fluoro-phenyl)-thiophen-2-yl-methanone was (618 g, 28%) was prepared from 2-amino-4-fluoro-benzoic acid (1.55 g, 10 mmol) following the general procedure S. N-[5-Fluoro-2-(thiophene-2-carbonyl)-phenyl]-N′-(thiazol-2-yl)urea (113 mg, 65%) was prepared from (2-amino-4-fluoro-phenyl)-thiophen-2-yl-methanone (110 mg, 0.5 mmol) and 2-aminothiazole (0.060 g, 0.6 mmol) following the general procedure D.
Reaction SMILES: [C:1]1([S:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:16]([S:18](Cl)(=[O:20])=[O:19])=[CH2:17]>O.C(#N)C>[CH:16]([S:18](=[O:20])(=[O:19])[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])=[CH2:17]
Reactant: O=S(O)c1cccc2ccccc12
Reactant: C=CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: C=CS(=O)(=O)S(=O)(=O)c1cccc2ccccc12
Yield: 24.9 %

Procedure:
15 ml of water was added to 9.6 g of 1-naphthalene sulfinic acid and a solution of 2 g of sodium hydroxide in 5 ml of water was added to the mixture. To the solution there was added a solution of 6.3 g of vinylsulfonyl chloride in 20 ml of acetonitrile at room temperature with stirring and the mixture was stirred at room temperature for additional 24 hours. The reaction solution was poured into 300 ml of water, the resulting precipitates were recovered through filtration and recrystallized from a mixed solvent of benzene and ethanol to give 3.5 g of vinyl-1-naphthyldisulfone.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([O:15]C)=[O:14])=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:6]1(=[O:24])=[O:23])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-].Cl>O1CCOCC1.O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:6]1(=[O:24])=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC(C)(C)N1C(=O)C(NCC(=O)O)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
Methyl [(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]acetate (1.28 g, 3.64 mmol) was dispersed in a mixture of dioxane (20 mL), MeOH (20 mL) and water (20 mL). Aqueous LiOH (1M, 0.218 g, 9.10 mmol) was added and the reaction mixture was stirred at rt for 2 h. Aqueous HCl was carefully added to the reaction mixture to give the pH˜1 and the resulting mixture was extracted with DCM. The organic phases were combined, dried over Na2SO4, filtered, evaporated and the crude residue was purified by preparative HPLC giving the title compound (0.51 g, 41%). 1H-NMR (CD3OD, 500 MHz): δ 7.52-7.48 (m, 2H), 7.46-7.42 (m, 3H), 5.41 (brs, 8H) 1.95 (s, 2H), 1.71 (s, 9H); 13C-NMR (CD3OD, 125 MHz): δ 178.4, 174.8, 160.8, 136.5, 132.8, 130.4, 129.5, 126.6, 107.4, 62.1, 48.3, 27.9, 22.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH2:11].[CH:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14].O.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:13]=[CH2:14])=[N:6][C:5]=1[NH2:11]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Cl)nc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: C=Cc1ccc(C(=O)OC)c(N)n1
Temperature: 130 °C
Yield: 66.5 %

Procedure:
2-Amino-6-chloro-nicotinic acid methyl ester (2.95 g, 15.8 mmol), vinyl tri-n-butyltin (5.01 g, 15.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.83 g, 1.58 mmol) were suspended in xylene (15 mL), and heated for 1 hour at 130° C. The reaction mixture was allowed to room temperature, water and ethyl acetate were added thereto, this mixture was filtered through Celite pad, then, the filtrate thereof was partitioned. The organic layer was separated, the solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography to obtain the title compound (1.87 g, 10.5 mmol, 66%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[CH:8][C:7]2=[O:17])[CH2:3][CH2:2]1.N1C=CC=CC=1.S(OC)(O[C:28](SC)([S:31][CH3:32])[S:29][CH3:30])(=O)=O>O1CCOCC1>[CH3:30][S:29][C:28]([S:31][CH3:32])=[C:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([NH:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:7]1=[O:17]
Reactant: COS(=O)(=O)OC(SC)(SC)SC
Reactant: O=c1cc(O)c2ccccc2n1NCC1CC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CSC(SC)=C1C(=O)c2ccccc2N(NCC2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To the suspension of the product of Example 353A (984.4 mg, 4.28 mmol) in 1,4-dioxane (40 mL) was added pyridine (2.8 mL, 34.6 mmol) and tris(methylthio)methyl methyl sulfate (prepared using the procedures in Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi) (2.26 g, 8.55 mmol) at room temperature. The suspension was put in a preheated oil bath at 55° C. and stirred for 15 minutes. To the solution was added another portion of tris(methylthio)methyl methyl sulfate (2.26 g, 8.55 mmol) and the mixture was stirred at 55° C. for 15 minutes and cooled to room temperature. The mixture was concentrated in vacuo and the residue was diluted with dichloromethane and loaded on a silica gel column and eluted with dichloromethane, 2% ethyl acetate/dichloromethane and then 5% ethyl acetate/dichloromethane to give the title compound (852.1 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (m, 2 H) 0.42 (m, 2 H) 0.98 (m, 1 H) 2.61 (s, 6 H) 2.73 (t, J=6.43 Hz, 2 H) 6.05 (t, J=5.88 Hz, 1 H) 7.15 (m, 1 H) 7.64 (m, 1 H) 7.76 (d, J=8.09 Hz, 1 H) 7.98 (m, 1 H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.C([O-])([O-])=O.[K+].[K+].[C:19]([O:23][C:24](=[O:49])[CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35][S:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])=[CH:34][C:29]=2[N:28]=[C:27]1[CH2:46][CH2:47][CH3:48])([CH3:22])([CH3:21])[CH3:20]>CC#N.CCOC(C)=O.O>[C:19]([O:23][C:24](=[O:49])[CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][C:33]([N:35]([S:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)(=[O:37])=[O:38])[CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)=[CH:34][C:29]=2[N:28]=[C:27]1[CH2:46][CH2:47][CH3:48])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1nc2cc(N(Cc3cccc(C(F)(F)F)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Trifluoromethylbenzyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH3:15])=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O>[CH3:15][C:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=2)[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)c1ccc(-n2ccnc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nccn1-c1ccc(C(=O)O)cc1
Temperature: -15 °C

Procedure:
To a stirring solution of 4-(2-methyl-imidazol-1-yl)-benzoic acid methyl ester (250 mg) in MeOH (2 mL) add 10 M NaOH aqueous solution (2.3 mL) and stir the reaction at rt for 20 h. Dilute with water (25 mL) and cool to −15° C. Quench with careful dropwise addition of conc. HCl (2.2 mL) over 5 min to a final pH of 1-2. Wash the suspension with EtOAc (50 mL). Concentrate the aqueous layer to a solid, and further dry in vacuo under P2O5 to remove all moisture. Triturate the solid in MeOH and filter to remove inorganic salts, washing with MeOH. Concentrate the filtrate, triturate the residue in EtOAc/hexane, and filter, washing with hexane. Suspend the solid in 10% MeOH/EtOAc (20 mL) and stir/sonicate. Syringe filter the suspension to remove inorganics solids, concentrate the organic to a solid residue, and repeat this procedure. Triturate the organic residue in EtOAc/hexane and filter/dry the solid to afford the desired product 4-(2-methyl-imidazol-1-yl)-benzoic acid as a solid in 93% yield (238 mg, 1.06 mmol).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:13][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)c1ccc(CC#N)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1ccc(C(C)C#N)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
In a 250 mL flask, 4-isopropylphenylacetonitrile 8.00 g (50.2 mmol) was dissolved in tetrahydrofuran (150 mL) under a nitrogen atmosphere. The solution was cooled to −78° C. and lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 52.8 mL (52.8 mmol) added. The resulting mixture was stirred at −78° C. for 1 hour. To this reaction mixture was added iodomethane 3.29 mL (52.8 mmol). The resulting mixture was slowly allowed to warm to ambient temperature over 16 hours then quenched with 0.2M hydrochloric acid and extracted twice with diethyl ether. The organic fractions were combined, dried (MgSO4) and concentrated under vacuo. Chromatography (SiO2, 20% ethyl acetate/hexanes) gave 6.32 g (73%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:12][C:5]1[C:6]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[CH2:21][CH2:22]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: c1cncc(CN2CCNCC2)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Cl)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.030 g, 0.14 mmol) and isopropanol (3.0 ml) was added 1-[(3-pyridyl)-methyl)-piperazine (0.028 g, 0.16 mmol) followed by diisopropylethylamine (0.03 ml, 0.18 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature, and diluted with isopropanol (2.5 ml). The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.036 g, 75%); 1H-NMR (500 MHz, DMSO-d6) 3.06 (br t, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2pyridyl), 6.95 (s, 2H, NH2), 7.36 (dd, J=7.8, 5.4 Hz, 1H, pyridine 5-H), 7.73 (dt, J=7.8, 1.8 Hz, 1H, pyridine 4-H), 8.07 (s, 1H, 6-H), 8.47 (dd, J=4.8, 1.6 Hz, 1H, pyridine 6-H), 8.51 (d, J=1.7 Hz, 1H, pyridine 2-H);
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29]Br.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(F)=C(F)C=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([F:34])=[C:26]([F:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(F)c(F)c3)c(-c3ccc(Cl)cc3)c2CC1
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1F

Procedure:
The title compound (0.002 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.07 g) using 3,4-difluorobenzyl bromide (0.4 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(3,4-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12; found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.41-7.38 (m, 2H), 7.36-7.33 (m, 2H), 7.22-7.20 (m, 1H), 7.07-7.02 (m, 1H), 6.96-6.92 (m, 1H), 5.26 (s, 2H), 3.06-3.02 (m, 4H), 2.94-2.91 (m, 2H), 2.87-2.84 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:42]=[C:43]=[O:44])=[O:41])=[CH:35][CH:34]=1>O1CCCC1>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:43]([NH:42][C:40](=[O:41])[CH2:39][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[O:44])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4F)ccn3)CC2)CC1
Reaction time: 72 h
Yield: 7.1 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (71 mg) in tetrahydrofuran (2.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.65 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=97:3) to provide the titled compound (7.1 mg, 7.1%) as white powder.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5]C(C)(C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH-:41])=[CH:35][CH:34]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:5])[OH:10].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH-:41])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1ccc(CC[NH-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
Fmoc-Asp(OtBu)-2-(4-methoxyphenyl)ethyl amide (5.44 g; 10 mmoles) was treated with 50% TFA/CH2Cl2 for 90 minutes at room temperature. The solvent was evaporated and the residue was triturated with ethyl ether/petroleum ether. The precipitate was dried and used without further purification.