Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:33]=[C:32]([F:40])[C:31]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:47]([C:45]3[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:31]4[C:32]([F:40])=[CH:33][C:34]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:35][C:30]=4[F:29])[N:46]=3)=[O:48])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(S(C)(=O)=O)cc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (15.0 mg, 0.0384 mmol), 6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridine-2-carboxylic acid (15.3 mg, 0.0461 mmol), HATU (36.5 mg, 0.0960 mmol) in DMF (0.09 mL) and DIPEA (14.9 mg, 0.115 mmol) was stirred at room temperature for 16 h. The mixture was filtered, concentrated under reduced pressure and purified by preparative LC-MS (method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a colorless gum (11.0 mg, 41%). LCMS calc. for C33H37F3N5O7S (M+H)+: m/z=704.2. Found: 704.2.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][C:26]=1[Cl:33])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][C:26]=1[Cl:33])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cc(CBr)ccc1OCc1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1-benzyloxy-4-bromomethyl-2-chloro-benzene (CAB02128, 1.56 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) was added. The mixture was transferred into a separation funnel and washed with water (two times 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.38 g (66°/e). 1H-NMR (400 MHz, d6-DMSO) δ=4.99 (s, 2H), 5.17 (s, 2H), 6.76 (d, J=9.0 Hz, 2H), 7.16 (d, J=8.6 Hz, 1H), 7.20 (dd, J=8.6, 2.2 Hz, 1H), 7.32-7.47 (m, 6H), 7.76 (d, J=9.0 Hz, 2H), 8.81 (s, 2H). LRMS (FAB+): 416.1 (100, [M+H]+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:21](=[O:30])[CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:21](=[O:30])[CH:20]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: NCc1ccn(-c2ccsc2)c(=O)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccn(-c2ccsc2)c(=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (97 mg, 0.30 mmol), 4-aminomethyl-1-thiophen-3-yl-1H-pyridin-2-one (61 mg, 0.30 mmol), and triethylamine (77 μL, 0.59 mmol) in N,N-dimethylformamide (2 mL) is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure, and the residue is triturated with acetonitrile to provide (4Z)-6-iodo-4-[({[2-oxo-1-(3-thienyl)-1,2-dihydropyridin-4-yl]methyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione as a mauve powder (65 mg, 43%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](O)=[O:14])([O-:3])=[O:2].B.CO>O1CCCC1>[N+:1]([C:4]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][OH:14])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(CO)cccc1CO
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 2-nitro-1,3-benzenedicarboxylic acid (12.7 g, 0.06 mole) in tetrahydrofuran (60 ml) is cooled to 0° C. and 1N borane:tetrahydrofuran (300 ml, 0.3 mole) is added dropwise over one hour. The mixture is allowed to warm slowly to 25° C. and is stirred for 36 hours. Methanol (50 ml) is added slowly, the mixture is filtered and evaporated. The residue is dissolved in ethyl acetate (100 ml) and washed with water (25 ml), dried (MgSO4), filtered, and evaporated to yield a yellow solid. This is further purified by flash chromatography over silica (elution with 1:1 hexane:ethyl acetate) to afford after concentration pure 2-nitro-1,3-benzenedimethanol, mp 100°-101° C.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>C1(C)C(C)=CC=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:3]([C:5]2[NH:6][S:7](=[O:20])(=[O:21])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:4])[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Solvent: Cc1ccccc1C
Product: O=C(Nc1cccc(Cl)c1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1

Procedure:
A mixture consisting of 1 gm (3.3 millimols) of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide, 0.5 gm (4 millimols) of 3-chloroaniline and 200 ml of anhydrous xylene was refluxed for 25 hours in a Soxhlet apparatus equippedwith a 4-A-molecular sieve. Upon cooling, the desired product crystallized out. Yield: 0.9 gm (68% of theory); m.p. 262° C (decomp.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:11]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-n2ccc3ccccc32)cc1
Yield: 20.2 %

Procedure:
A mixture of 17.57 g (0.15 mole) of indole, 23.55 g (0.15 mole) of bromobenzene, 21 g of anhydrous potassium carbonate, 0.75 g of CuO, and 30 mL of DMF was stirred and heated under reflux for 43 hours. The cooled mixture was diluted with 200 mL of H2O and extracted with 150 mL of ether. The extract was washed with H2O (2×50 mL) and 50 mL of brine and dried over MgSO4. The oil was chromatographed on the solvent left 35.7 g of brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 15-22 were combined giving 5.86 g (20%) of 1-phenylindole as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[Br:13].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[N:9]2[CH3:14])=[CH:4][C:3]=1[Br:13]
Reactant: Nc1cc2c(cc1Br)CCC(=O)N2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)CCc2cc(Br)c(N)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 89.5 %

Procedure:
7-Amino-6-bromo-3,4-dihydro-1H-quinolin-2-one 280 mg (1.16 mmol) was dissolved in 8 ml THF and cooled to 0° C. KHMDS (2.56 ml, 1.27 mmol, 0.5 M in toluene) was then added dropwise, followed by dropwise addition of 80 ml (1.27 mmol) CH3I. The mixture was stirred for 12 hours, then partitioned between ethyl acetate and brine. The organic layer was dried over MgSO4 filtered and concentrated under reduced pressure. Purification by column chromatography, eluting with 75% ethyl acetate/hexanes, provided 265 mg of 7-amino-6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([OH:7])=[O:6].[N+](=[CH2:18])=[N-]>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: C=[N+]=[N-]
Reactant: CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Product: CON=C(C(=O)OC)c1ccc(O)c(Cl)c1

Procedure:
2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.) and diazomethane (1.5 g.) were reacted and the product was purified by column chromatography according to a similar manner to that of Preparation (5-3) (b) to give crystals of methyl 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetate (syn isomer) (3.0 g.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C[N:17](C)[CH2:18][CH2:19][CH2:20]N=C=NCC.C(N(CC)CC)C.C(N)C#C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:17][CH2:18][C:19]#[CH:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: C#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.2 %

Procedure:
To a mixture of 4-tert-butoxycarbonylaminobutyric acid (5 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.66 g) and triethylamine (7.47 g) in dichloromethane (80 mL) at rt was added 2-propynylamine (1.49 g). After being stirred at rt for 3 h, the mixture was diluted with dichloromethane (80 mL) and washed with 0.5 M HCl (aqueous, 2×), saturated NaHCO)3 (1×) and water (1×). The dichloromethane was dried over sodium sulfate, filtered and evaporated to afford (3-Prop-2-ynylcarbamoyl-propyl)-carbamic acid tert-butyl ester (1.67 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]1.[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([CH:30]2[CH2:33][CH2:32][CH2:31]2)[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]3)[CH2:28][CH2:29]2)[CH:21]=[C:20]([CH:30]2[CH2:33][CH2:32][CH2:31]2)[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: O=c1cnn(CCCCCl)c(=O)[nH]1
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCn3ncc(=O)[nH]c3=O)CC2)n1

Procedure:
2-{4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-2H-[1,2,4]triazine-3,5-dione was prepared from 2-(4-chloro-butyl)-2H-[1,2,4]triazine-3,5-dione and 2-tert-butyl-4-piperazin-1-yl-6-cyclobutylpyrimidine by analogy to the process described in example 1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:21]2[CH:37]=[CH:36][C:24]([O:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:23][CH:22]=2)[C:17]([NH:19][OH:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Cl>ClCCl.CCOCC>[NH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:36]=[CH:37][C:21]([C@@H:16]([NH:15][S:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=2)(=[O:14])=[O:13])[C:17]([NH:19][OH:20])=[O:18])=[CH:22][CH:23]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)NO)c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)NO)c2ccc(OCCN)cc2)cc1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Through a solution of 0.354 g (0.664 mmol) of the product of Example 199, tert-butyl 2-{4-[(1R)-1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydroxyamino)-2-oxoethyl]phenoxy}ethylcarbamate, in 10 mL of dichloromethane was bubbled hydrogen chloride gas for 10 minutes. The reaction was stoppered and let sit at room temperature for 30 minutes. The reaction was then diluted with 15 mL of ether and the resulting white precipitate was collected by filtration and dried in vacuo to give 0.283 g of (2R)-2-[4-(2-Aminoethoxy)phenyl]-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxyethanamide as a white solid. Electrospray Mass Spec 434.3 (M+H)+
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.[Al](Br)(Br)Br>CCCCCC.C(Br)Br.[Al](Br)(Br)Br>[CH2:1]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: C=CCCCCCCCC
Agent: Br[Al](Br)Br
Solvent: BrCBr
Solvent: CCCCCC
Product: CCCCCCCCCCC12CC3CC(CC(C3)C1)C2

Procedure:
Decyl adamantane was prepared by reacting 140 g 1-decene, 54.4 gram adamantane in 100 cc n-hexane solvent and using 3 mmoles 1.0M AlBr3 in CH2Br2 or AlBr3 catalyst at 15°-50° C. reaction temperature. The product was isolated by quench the catalyst with dilute acid and aqueous work-up followed by distillation at 155° C. and 0.2 mm-Hg using a Kugelrohr to remove any C20 -material. The C30 + fraction was obtained in 80% yeild. It was hydrogenated at 200° C. and 500 psi H2 using 1 wt. % Ni/SiO2 catalyst.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 4-piperidin-4-yl-morpholine using standard reductive amination conditions. The resulting crude solid was triturated with methanol to give 2-chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as an off white solid (50% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was purified by mass directed chromatography to give 336 as an off white solid (21% yield). NMR (CDCl3, 400 MHz), 1.60-1.67 (2H, m),1.86 (2H, d, J=12.2), 2.14 (2H, t, J=10.6), 2.17-2.23 (1H, m), 2.57-2.59 (4H, m), 3.05 (2H, d, J=11.7), 3.73-3.75 (4H, m), 3.83 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=497
Reaction SMILES: CON(C)[C:4](=[O:24])[CH:5]([N:13]1[C:17]2=[N:18][CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]2[CH:15]=[N:14]1)[CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:26]([Mg]Br)=[CH2:27].Cl>O1CCCC1>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[N:13]([CH:5]([CH2:6][CH:7]3[CH2:8][CH2:9][O:10][CH2:11][CH2:12]3)[C:4](=[O:24])[CH:26]=[CH2:27])[N:14]=[CH:15][C:16]=12
Reactant: COc1ccnc2c1cnn2C(CC1CCOCC1)C(=O)N(C)OC
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)n1ncc2c(OC)ccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of N-methoxy-2-(4-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (0.37 g) in dry tetrahydrofuran (15 mL) was slowly added vinylmagnesium bromide (1.0M tetrahydrofuran solution: 7.8 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added again vinylmagnesium bromide (1.0M tetrahydrofuran solution: 2.6 mL) at 0° C., and the mixture was stirred for 1 hr under ice-cooling. The reaction solution was poured into an ice-cooled 6M hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.178 g, yield 53%) as a pale-pink oil from the fraction eluted with ethyl acetate-hexane (6:4, volume ratio). MS: 316 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[H-].[Na+].[C:14]([O:18][C:19]([NH:21][C@@H:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:23]I)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:23][CH:9]([C:10]#[N:11])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[C:25]([O:27][CH3:28])=[O:26])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CCc1cccc(F)c1F
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(CC(C#N)c1cccc(F)c1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2,3-difluorophenyl)acetonitrile (18.6 g, 122 mmol) in N,N-dimethylformamide (243 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (4.37 g, 109 mmol). After 20 min, methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (20.0 g, 60.8 mmol) was added, and the resulting mixture stirred 50 min. Saturated aqueous sodium bicarbonate was added, and the mixture was warmed to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate) gave the title compound. MS: m/z=377.3 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][CH2:21][O:22][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CCO[Si](C)(C)C(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)C(CCO)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.53 g (3.20 mmol) of (rac)-4-[3-(tert-butyl-dimethyl-silanyloxy)-1-methoxycarbonyl-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester (evaporated twice with toluene) in 25 ml of dichloromethane was treated at 0° C. with 3.20 ml (3.20 mmol, 1 M in dichloromethane) of boron trichloride and kept 1 h at this temperature. The solution was stirred 17 h at room temperature and then extracted with cold sat. aq. sodium hydrogencarbonate solution and ethyl acetate (3×). The organic phases were washed with sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated to give 1.34 g (quantitative) of the title compound as yellow viscous oil. MS: 365.1 (MH+).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](=N)[O:4][C@H:5]1[S:22][CH2:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9].OC1C=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[CH2:21][S:22][C@H:5]1[O:4][C:3]1[CH:28]=[CH:29][C:30]([C:33](=[O:35])[CH3:34])=[CH:31][CH:2]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)SC[C@H]1OC(C)=O
Reactant: CC(=O)c1ccc(O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C(C)=O)cc1
Yield: 47 %

Procedure:
If the procedure described in Preparation LXXXI is followed starting from 380 mg (0.882.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate, 100 mg (73.5.10-3 mol) of 1-(4-hydroxyphenyl)ethanone and 1.47 ml of a 0.1M solution of boron trifluoride etherate in methylene chloride, 140 mg (yield: 47%) of the expected product are obtained after crystallization from ether.
Reaction SMILES: [ClH:1].O[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]>>[Cl:1][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: Cl
Reactant: O=C1c2ccccc2C(=O)N1CO
Product: O=C1c2ccccc2C(=O)N1CCl

Procedure:
reacting said mixture at a temperature of from about 45° to about 75° C at a pressure of from about 0 psig to about 50 psig which intimately contacting said reacting mixture with anhydrous HCl at a rate of from approximately 15 to approximately 65 pounds HCl per hour per pound-mole of N-hydroxymethyl phthalimide used to form the mixture in step (a), to maintain the concentration of said aqueous HCl at 35 to 40 wt.%, to form N-chloromethyl phthalimide in a first aqueous-organic mixture;
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6]C)=O.[NH2:18][C:19]([CH2:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[O:22]>C1(C)C(C)=CC=CC=1>[CH2:25]([C:19]1[NH:18][C:2]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:3][C:4](=[O:6])[C:20]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:26]
Reactant: CCC(N)=CC(=O)OC
Reactant: COC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1C
Product: CCc1[nH]c(-c2ccc(C(F)(F)F)cc2)cc(=O)c1C(=O)OC

Procedure:
1.00 g (3.84 mmol) of methyl 3-oxo-3-[4-(trifluoromethyl)phenyl]propanoate and 546 mg (4.23 mmol) of methyl 3-aminopent-2-enoate [Pena et al., J. Am. Chem. Soc. 124., 14552-14553 (2002)] were taken up in 4 ml of xylene, 1.50 g molecular sieve (4 Å) which had been dried by heating were added and the mixture was reacted at reflux temperature overnight. The molecular sieve was removed by filtration and washed with methanol/chloroform (1/1). The combined organic phases were concentrated on a rotary evaporator and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 10:90→90:10). This gave 270 mg (21% of theory) of the target compound.