Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[N:22]=[C:23]=[O:24]>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[NH:22][C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)=[O:24]
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C=Nc1ccc2ccccc2c1
Product: O=C(Nc1ccc2ccccc2c1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 2-naphthyl isocyanate. m/z (ES+) 314 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl.O>[C:37]([Si:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[O:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH2:1])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(CN)CO
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(CN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution at 0° C. of 0.500 g (4.85 mmol) of 3-amino-2,2-dimethylpropanol (CAS 26734-09-8) in 12 ml of dichloromethane are added 0.059 g (0.48 mmol) of dimethylaminopyridine and 1.35 ml (9.7 mmol) of triethylamine. 1.60 g (5.82 mmol) of tert-butyldiphenylsilyl chloride dissolved in 5 ml of dichloromethane are then added dropwise. The mixture is stirred for 30 minutes at 0° C. and then for 2 hours at room temperature. 20 ml of water are then added. The organic phase is separated out by settling, washed with water and then with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give an oil, which is chromatographed on a column of aminopropyl silica gel, eluting with a mixture of 0 to 10% methanol in dichloromethane, to give 1.20 g of 3-(tert-butyldiphenyl-silanoxy)-2,2-dimethylpropylamine in the form of a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=2[C:24]([F:27])([F:26])[F:25])[C:10]1=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:71][C:72]1[CH:78]=[CH:77][C:75]([NH2:76])=[CH:74][C:73]=1[NH:79][C:80]1[N:85]=[C:84]([C:86]2[CH:87]=[N:88][CH:89]=[N:90][CH:91]=2)[CH:83]=[CH:82][N:81]=1>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:76][C:75]3[CH:77]=[CH:78][C:72]([CH3:71])=[C:73]([NH:79][C:80]4[N:85]=[C:84]([C:86]5[CH:91]=[N:90][CH:89]=[N:88][CH:87]=5)[CH:83]=[CH:82][N:81]=4)[CH:74]=3)=[O:21])=[CH:17][C:16]=2[C:24]([F:25])([F:27])[F:26])[C:10]1=[O:28])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)C1=O
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncnc2)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(CN3CC[C@H](NC(=O)OC(C)(C)C)C3=O)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cncnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Eight hundred mg of 4-[(S)-3-(t-butoxycarbonylamino)-2-oxopyrrolidin-1-ylmethyl]-3-trifluoromethylbenzoic acid (Reference Example 17) was dissolved in 7 ml of anhydrous N,N-dimethylformamide, and 0.67 ml of N,N-diisopropyl-N-ethylamine and 1.00 g of 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) were added in turn, followed by stirring at room temperature for 30 minutes. 4-Methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (Reference Example 18) was added and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed in turn with an aqueous saturated sodium hydrogen carbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 453 mg of the objective compound as a pale yellow amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](Cl)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
880 mg of 4-methoxyphenol was dissolved in 10 ml of N,N-dimethylformamide. 790 mg of potassium t-butoxide was added thereto. Then, 1.7 g of 4-benzyloxy-2-nitro-chlorobenzene was added thereto. The mixture was stirred for 1 hour at 110°-120° C. The reaction mixture was introduced into a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: toluene) to obtain 1.92 g of 5-benzyloxy-2-(4-methoxyphenoxy)nitrobenzene.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12]C=O)[CH2:10][C:9]2=[CH:15][CH:16]=[CH:17][C:7]3=[C:8]2[N:3]1[CH2:4][CH2:5][CH2:6]3.C(O)C.CCOCC.[ClH:26]>>[ClH:26].[O:1]=[C:2]1[CH:11]([NH2:12])[CH2:10][C:9]2=[CH:15][CH:16]=[CH:17][C:7]3=[C:8]2[N:3]1[CH2:4][CH2:5][CH2:6]3
Reactant: O=CNC1Cc2cccc3c2N(CCC3)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: NC1Cc2cccc3c2N(CCC3)C1=O

Procedure:
A solution of N-(2,3,6,7-tetrahydro-3-oxo- 1H,5H-benzo(ij)quinolizin-2-yl)-formamide (0.8 g, 3.4 retool) in ethanolic hydrogen chloride (10 mL of 4.2 M) was heated at 50° C. for 2 hours. The ethanol was cooled, an equal volume of ether was added, and the precipitate was filtered off and washed with ether to give 0.78 g of 2,3,6,7-tetrahydro-3-oxo-1H,5H-benzo(ij) quinolizin-2-amine hydrochloride, mp 216°-221° C. The product was recrystallized for analysis; mp 219°-222° C. Anal. Calc'd for C12H14N2O·HCl: C, 60.37; H, 6.33; Cl, 14.85; N, 11.74. Found: C, 59.89; H, 6.42; Cl, 15.41; N, 11.68.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[OH:10].[I:12]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([I:12])[CH:7]=[N:6][C:5]=1[OH:10]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cccnc1O
Solvent: ClCCl
Product: COC(=O)c1cc(I)cnc1O
Yield: 82.3 %

Procedure:
To a solution of 2-hydroxynicotinic acid methyl ester (3-067-02) (20 g) in methylene chloride (500 mL) was added N-iodosuccinimide (NIS, 38 g) at room temperature, and the reaction mixture was heated under reflux for 16 h, and evaporated. To the residue was added ethyl acetate (200 mL) and the reaction mixture was heated under reflux for 2 h. The insoluble solid was filtered to give 2-hydroxy-5-iodonicotinic acid methyl ester (3-067-03) (30 g, 81%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:3])[CH3:2].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>CN(C=O)C.CC(OC)(C)C>[CH2:16]([O:15][C:6]1[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([C:1](=[O:3])[CH2:2][CH3:28])[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]=12)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(=O)CC)CCN(C)C2=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.60 g, 1.62 mmol; Example 7, step 7) in anhydrous DMF (17 mL), a solution of lithium bis(trimethylsilyl)amide (1.94 mL, 1.94 mmol) in MTBE was added. The mixture was stirred at −78° C. for 15 minutes, treated with iodomethane (0.12 mL, 1.94 mmol), allowed to slowly warm up to room temperature, and stirred at the temperature overnight. The product mixture was concentrated under vacuum. The residue was partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to preparation HPLC on C-18 stationary phase eluting with a gradient of methanol in water in the presence of ammonium acetate (1 g/L). Collection and concentration of appropriate fractions provided the title compound. The corresponding bis-methylated ketone was also isolated and was used for the preparation of Examples 60 & 61.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH2:9]([NH2:13])[CH2:10][CH2:11][NH2:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][CH2:11][CH2:10][CH2:9][NH2:13])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1ccc(Cl)nn1
Yield: 66 %

Procedure:
A mixture of 3,6-dichloropyridazine (0.168 mol), 1,3-propanediamine (0.84 mol) and sodium carbonate (0.17 mol) in ethanol (500 ml) was stirred and refluxed overnight. The reaction mixture was filtered over dicalite. The filtrate was evaporated. The residue was crystallized from acetonitrile. The crystals were filtered off and dried, yielding 20.7 g of N-(6-chloro-3-pyridazinyl)-1,3-propanediamine; mp. 124.9° C. (interm. 1-c).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([C:19](OC3CCCC(=O)C=3)=[O:20])[C:10]2=[O:29])=[CH:5][CH:4]=1.C(N(CC)CC)C.C[C:38]([CH3:42])([OH:41])[C:39]#N.[C:43](O)(=O)[CH2:44][C:45](CC(O)=O)(C(O)=O)[OH:46]>ClCCl>[OH:46][C:45]1[CH2:44][CH2:43][CH2:42][C:38](=[O:41])[C:39]=1[C:19]([C:11]1[C:10](=[O:29])[N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[CH:16][N:17]=2)=[O:20]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COc1ccc(-n2c(=O)c(C(=O)OC3=CC(=O)CCC3)cc3cccnc32)cn1
Reactant: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2c(=O)c(C(=O)C3=C(O)CCCC3=O)cc3cccnc32)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
1.78 g (4.5 mmol) of 3-oxo-1-cyclohexenyl 1-(6-methoxy-3-pyridyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in dichloromethane (50 mL), and 0.77 mL (5.5 mmol) of triethylamine and 0.43 g (5.0 mmol) of acetone cyanohydrin were added to the above solution. The resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into an aqueous solution of citric acid, and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried, and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:1 to 7:3), and thus 0.37 g (yield: 21%) of the title compound was obtained as orange-colored crystals.
Reaction SMILES: [O:1]1[CH:3]2[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]12.Br[Mg][CH2:19][CH:20]=[CH2:21]>O1CCCC1>[CH2:21]([CH:2]1[CH:3]([OH:1])[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)[CH:20]=[CH2:19]
Reactant: C=CC[Mg]Br
Reactant: c1ccc2c(c1)Cc1ccccc1C1OC21
Solvent: C1CCOC1
Product: C=CCC1c2ccccc2Cc2ccccc2C1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
1a,10b-dihydro-6H-dibenzo[3,4:6,7]cyclohept[1,2-b]oxirene (1 g) was dissolved in 15 ml tetrahydrofuran and cooled to 0° C., under N2 atmosphere. Bromo-2-propenyl-magnesium (5,2 ml, 1M in tetrahydrofuran) was added dropwise to the mixture and the mixture was stirred at room temperature and then at 60° C. for two hours. The mixture was cooled to room temperature and quenched with 10% NH4Cl and water, dried and the solvent was evaporated, yielding 0.5 g (48%) of 10,11-dihydro-11-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-10-ol (interm. 4).
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[C:15]([CH3:23])=[CH:14][N:13]=2)[O:7]C1C1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2]>Cl>[OH:7][CH:8]([CH2:9][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[C:15]([CH3:23])=[CH:14][N:13]=1
Reactant: Cc1cnc(OCC2CN(C(C)(C)C)C(c3ccccc3)O2)c2cc(Cl)ccc12
Agent: Cl
Product: Cc1cnc(OCC(O)CNC(C)(C)C)c2cc(Cl)ccc12

Procedure:
1 g of 1-(3-tert.-Butyl-2-phenyl-5-oxazolidinyl-methoxy)-7-chloro-4-methylisoquinoline is heated to 80° in 10 ml of 1N hydrochloric acid for 10 minutes. The reaction mixture is extracted with ether. The ethereal phase is discarded and the aqueous phase worked up to yield the title compound in free base form. M.p. 116°-117°.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])[CH:3]=[O:4].[CH2:16](O)[CH2:17][CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:1][CH:2]([CH:3]1[O:19][CH2:18][CH2:17][CH2:16][O:4]1)[CH:5]=[CH:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15]
Reactant: CC(C=O)=CCC1=C(C)CCCC1(C)C
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(C=CC(C)C2OCCCO2)C(C)(C)CCC1

Procedure:
103 g (0.5 mol) of 2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenal, 38 g (0.5 mol) of 1,3-propanediol and 1 g of p-toluenesulfonic acid are heated with 200 g of toluene for 2.5 hours in a water separator. After cooling, the mixture is washed with soda solution and dried over sodium sulfate. 3 g of sodium carbonate are added and the mixture is distilled on a 30 cm packed column. At 122-126° C./1.6-0.82 mbar this yields 81 g of product comprising 66% of 2-[1-methyl-3-(2,6,6-trimethyl-1-cyclohexen-1-yl)allyl]-1,3-dioxane and also containing other isomers with double bonds.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2].Cl[C:13]1[N:18]=[N:17][C:16]([C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([N:3]([C:13]1[N:18]=[N:17][C:16]([C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2]
Reactant: NC(=O)c1ccc(Cl)nn1
Reactant: CCNCc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1N)c1ccc(C(N)=O)nn1
Reaction time: 24 h
Yield: 39.2 %

Procedure:
N-Ethyl-N-(2-aminobenzyl)amine (707 mg, 4.7 mmol) in DMF (11 ml) was treated with 6-chloropyridazin-3-amide (4.7 mmol) followed by diisopropylethylamine (15.4 mol) and the reaction stirred at 140° under argon for 24 hours. The reaction was evaporated in vacuo (cold-finger) and the residue partitioned between water and ethyl acetate. The combined organic extracts were dried and evaporated to give a brown gum. The gum was purified by medium pressure chromatography to give 6-(N-ethyl-N-(2-aminobenzyl)amino)-pyridazine-3-carboxamide (500 mg, 30%).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][O:28][C:29]1[CH:52]=[CH:51][C:32]([CH2:33][O:34][C:35]([NH:37][C:38]2[N:46]=[CH:45][N:44]=[C:43]3[C:39]=2[N:40]=[CH:41][N:42]3[CH2:47][C:48](O)=[O:49])=[O:36])=[CH:31][CH:30]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:48](=[O:49])[CH2:47][N:42]2[CH:41]=[N:40][C:39]3[C:43]2=[N:44][CH:45]=[N:46][C:38]=3[NH:37][C:35]([O:34][CH2:33][C:32]2[CH:51]=[CH:52][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[O:36])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)cc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(4-methoxybenzyloxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.60 (bs, 1H), 8.59 (d, 1H), 8.34 (m, 2H), 8.27 (m, 1H), 7.72 (m, 2H), 7.38 (d, 2H), 6.94 (d, 2H), 5.40 (s, 1.2H), 5.28 (s, 0.8H), 5.14 (s, 2H), 4.56 (s, 0.8H), 4.28 (m, 2.4H), 4.09 (t, 2H), 3.87 (t, 0.8H), 3.75 (s, 3M).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Na].[F:8][C:9]([F:19])([F:18])[C:10]([F:17])([F:16])[C:11](OCC)=[O:12]>C(OCC)C>[F:16][C:10]([F:17])([C:9]([F:19])([F:18])[F:8])[C:11]([CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])=[O:12]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: CCOC(C)=O
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)CC(=O)C(F)(F)C(F)(F)F
Yield: 18.4 %

Procedure:
Ethyl acetate (20.26 g, 0.23 mole) and sodium metal (2.3 g, 0.10 g-atom) was added to ethyl pentafluoropropionate (20.26 g, 0.23 mole) and the mixture was refluxed with stirring until sodium metal was dissolved. After sodium metal was dissolved, dry diethyl ether (100 ml) was added and the solution was further reacted under reflux overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and the resulting residue was made acidic with 50 ml of 15% sulfuric acid, while it was cool. The solution was extracted with diethyl ether and the ether layer was dried with anhydrous sodium sulfate. Diethyl ether was then distilled off by distilling at atmospheric pressure using a fractionating column packed with Raschig ring and the resulting residue was further distilled under reduced pressure to give 9.90 g (42.3%) of the title compound as a colorless liquid, b.p. 77°-78° C./80 mmHg. The structure of this compound was confirmed by IR and NMR.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([CH2:25][O:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5])=[O:27])[CH3:30]
Reactant: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(OCC(F)(F)F)cc1C(=O)NCc1ccccn1

Procedure:
Using the general method of Example I Part A, 9.8 g (0.03 mole) of 2-hydroxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide was reacted with 7.0 g (0.042 mole) of ethyl bromoacetate to give 7.6 g of ivory powdery -(ethoxycarbonylmethoxy)-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide, m.p. 109°-111° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:13]=1[F:12])=[O:6]
Reactant: O=C(O)c1c(I)ccnc1Cl
Reactant: Nc1ccc(F)cc1F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1F)c1c(I)ccnc1Cl
Reaction time: 63 h
Yield: 54.5 %

Procedure:
To a homogeneous mixture of 2-chloro-4-iodonicotinic acid (CB Research & Development, Inc., 0.58 g, 2.0 mmol) and 2,4-difluoroaniline (Aldrich, 0.21 mL, 2.0 mmol) in anhydrous DMF (7 mL) was added PyBroP (Novabiochem, 1.4 g, 3.1 mmol) followed by DIPEA (1.1 mL, 6.6 mmol). The mixture was stirred for 63 hours, and then partitioned between chloroform and 10% LiCl (aq). After the aqueous layer was extracted with chloroform, the combined organic layers were washed twice with 10% LiCl (aq), dried over anhydrous MgSO4, and then concentrated in vacuo. Purification of the residue by flash column chromatography (SiO2, eluting with 1:1 hexane/EtOAc) afforded the desired compound (0.43 g, 53%). MS(ESI+) m/z 395 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH:14]2[O:16][CH2:15]2)[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: ClCC1CO1
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1c(Cl)cc(OCC2CO2)cc1Cl
Reaction time: 3 h

Procedure:
To a stirred solution of 2,6-dichloro-4-hydroxybenzaldehyde (3.0 gm 0.0167 m) in 1.5N sodium hydroxide (25 m) at 50° is added epichlorohydrin (4.4 gm, 0.048 m). After stirring at 50° for 3 hours, the solution is cooled and extracted with chloroform. The chloroform is dried over anhydrous sodium sulfate, filtered and concentrated to 2,6-dichloro4-(2,3-epoxypropoxy)-benzaldehyde (3 g) which is used without further purification.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][CH:18]1[CH2:19][CH2:20][CH:21]2[CH:26]=[N:27][OH:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:18]1[CH2:19][CH2:20][C@H:21]2[C:26]([Cl:8])=[N:27][OH:28])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1N2CC(CCC2C=NO)N1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1N2C[C@@H](CC[C@H]2C(Cl)=NO)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
NCS (295 mg, 2.2 mmol) was added to a solution of 6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbaldehyde oxime (560 mg, 2.0 mmol) in dry DCM (15 mL) at rt. Pyridine (one drop) was then added, and the reaction mixture was stirred at rt for 18 hrs. The solution was evaporated to afford (2S,5R)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbimidoyl chloride, which was directly used in the next step. ESI-MS (EI+, m/z): 274 [M-Cl]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=3[CH3:46])[N:37]=[CH:38][C:31]=12>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=3[CH3:46])[N:37]=[CH:38][C:31]=12)[C:24]([O:26][CH3:27])=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(F)cccc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(F)c1C

Procedure:
Prepared using a procedure analogous to that described for Intermediate AE2 using (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) and 4-chloro-1-(3-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AF5). 1H NMR (400 MHz, DMSO) d 0.94 (9H, s), 1.96 (3H, d), 3.81-3.63 (7H, m), 4.09-4.02 (1H, m), 4.13 (1H, m), 5.89 (1H, m), 7.50-7.30 (9H, m), 7.63 (4H, m), 8.49 (1H, s), 8.59 (1H, s). m/z (ES+) (M+H)+=629; HPLC tR=3.43 min.