Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([CH2:7][C:8]1[CH:9]=[C:10]([S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH:2]=[CH2:3].[Cl:20][C:21]1[CH:22]=[C:23]([NH2:30])[C:24](=[CH:28][CH:29]=1)[C:25](O)=[O:26].C1N=CN(C(N2C=NC=C2)=O)C=1.O>C1COCC1>[CH2:1]([O:4][C:5]([CH2:7][C:8]1[CH:9]=[C:10]([S:14]([N:17]2[C:25](=[O:26])[C:24]3[C:23](=[CH:22][C:21]([Cl:20])=[CH:29][CH:28]=3)[NH:30][C:18]2=[O:19])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: C=CCOC(=O)Cc1cccc(S(=O)(=O)N=C=O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)Cc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Following the Synthesis Method (A), 3.27 g (11.6 mmol) of 3-allyloxycarbonylmethylbenzenesulfonyl isocyanate was dissolved in 100 ml of anhydrous THF, then 1.98 g (11.5 mmol) of 4-chloroanthranilic acid was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled with ice water, then 1.87 g (11.5 mmol) of CDI was added and the resultant mixture was stirred under ice cooling for 30 minutes. An excess amount of water was poured into the reaction solution, then the mixture was extracted with ethyl acetate. The organic layer was washed, dried, and concentrated to obtain a crude product. This was crystallized with a small amount of ethyl acetate to obtain 2.0 g (yield 40%) of 3-(3-allyloxycarbonylmethylbenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione. The allyl product thus obtained was dissolved in 100 ml of a formic acid-THF (1:9) mixture and 700 mg of triphenylphosphine was added. The reactor was shaded from light and under nitrogen atmosphere, then 700 mg of tetrakis(triphenylphosphine)palladium (0) was added and the resultant mixture was stirred while shaded at room temperature overnight. The reaction solution was concentrated in vacuo and the solid obtained was washed with methylene chloride to obtain 1.47 g (yield 81%) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.76 (2H, s), 7.13 (1H, s), 7.24 (1H, d), 7.61-7.69 (2H, m), 7.86 (1H, d), 8.05 (2H, s), 12.50 (1H, br).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.C(Cl)(=O)C([Cl:15])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][Cl:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1ccc(Cl)nc1Cl
Yield: 113.1 %

Procedure:
A solution of 2,6-dichloronicotinic acid (3.84 g), oxalyl chloride (2.0 g), and 1 drop of dimethylformamide in dichloromethane (25 ml), was stirred at room temperature for 18 hours. The solution was concentrated in vacuo to give 3.50 g of 2,6-dichloronicotinyl chloride which was added portionwise in dichloromethane (25 ml) to an ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (2.15 g) and diisopropylethylamine (2.03 g) in dichloromethane (50 ml). The mixture was stirred at room temperature for 18 hours and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield 2.65 g of the title as a an amorphous solid. m.p. 115-130° C. MS, m/z: 358.1 (M+H)+.
Reaction SMILES: C(O[C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:11][C:10]=1[O:22][CH3:23])(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.C1(OC(=O)[NH:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:51][CH:50]=2)C=CC=CC=1>C(Cl)Cl>[C:55]([C:52]1[CH:51]=[CH:50][C:49]([CH2:48][NH:47][C:6](=[O:24])[NH:7][CH2:8][C:9]2[C:10]([O:22][CH3:23])=[CH:11][C:12]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])=[C:13]([CH:15]=[CH2:16])[CH:14]=2)=[CH:54][CH:53]=1)([CH3:58])([CH3:56])[CH3:57]
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)c(OC)cc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(CNC(=O)Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C=Cc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)c(OC)cc1NS(C)(=O)=O
Temperature: 0 °C
Yield: 6.2 %

Procedure:
To a ice-cooled solution of (4-methanesulfonylamino-2-methoxy-5-vinyl-benzyl)-carbamic acid tert-butyl ester (220 mg, 0.73 mmol) in methylene chloride was treated with trifluoroacetic acid (100 mg, 0.88 mmol)) for 1 hr, and then concentrated under reduced pressure. The part of crude residue (100 mg, 0.27 mmol) was suspended in methylene chloride and treated with triethylamine followed by (4-tert-butyl-benzyl)-carbamic acid phenyl ester (92 mg, 0.32 mmol). The resulting mixture was heated with reflux for 3 days and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate=1/2) to yield a white solid (8.8 mg, 7.0%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:19]([CH3:30])[CH2:18]3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].B>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:19]([CH3:30])[CH2:18]3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: C[C@H]1CN(Cc2cccc(-c3ccc(F)c(C#N)c3)c2)CCN1C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2cccc(-c3ccc(F)c(CN)c3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
A solution of 1,1-dimethylethyl (2S)-4-[(3′-cyano-4′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (2.29 g, 5.59 mmol) in THF (50 mL) was flushed with Ar. Borane (19 mL, 1M in THF, 19 mmol) was slowly added and the reaction was allowed to stir at room temperature for 12 hours. The reaction was quenched slowly with water, diluted with water (175 mL) and then extracted with EtOAc (2×250 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was placed onto a SPE silica cartridge (20 g) using 50% hexane/50% EtOAc, and then eluted with the following sequence: 50% hexane/50% EtOAc, 10% MeOH/90% DCM, 30% MeOH/70% DCM. The product fractions were combined and concentrated to give the title compound (1.48 g, 64.1%). EI-MS m/z 414(M−H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22](C2C=CN=CC=2)[NH:21][C:20]1=[O:35].N1C2C(=CC=CC=2)CC1=O>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C:19]2([NH2:18])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:21]([CH3:22])[C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NC(c2ccncc2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: O=C1Cc2ccccc2N1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(C)c2ccccc21

Procedure:
Following General Procedure I above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1-methyl-2-indolinone monohydrochloride (Example 5-B), the title compound, as a ˜1:1 diastereomeric mixture at C3 of the indolinone, was prepared as a white solid having a decomposition point of 215-220° C. Purification was by flash chromatography eluting with 3:1 CH2Cl2/EtOAc gradient to straight EtOAc followed by recrystalization from CHCl3. Rf=0.16 and 0.22 (EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:24][C:25]([NH2:29])([C:27]#[CH:28])[CH3:26].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.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:29][C:25]([CH3:26])([C:27]#[CH:28])[CH3:24])=[O:23])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.6 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (70 mg, 0.225 mmol), 2-methylbut-3-yn-2-amine (28 mg, 0.338 mmol), HATU (171 mg, 0.45 mmol) and DIEA (58 mg, 0.45 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Then the mixture was poured into water and filtered to give the crude product. The crude compound was then washed with MeOH to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(2-methylbut-3-yn-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (20 mg, 23.5%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][N+:21]([O-])=O)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].[ClH:28].C(OCC)(=O)C>O1CCCC1.C(OCC)(=O)C.O>[ClH:28].[CH:7]1([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][C:14]=2[O:24][CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1cc(C=C[N+](=O)[O-])ccc1OC1CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CCN)ccc1OC1CCCC1
Yield: 71 %

Procedure:
A slurry under nitrogen of lithium aluminium hydride (3.05 g, 80.34 mmoles) in dry tetrahydrofuran (30 ml), was dropwise added under stirring with a solution of 1-cyclopentyloxy-2-methoxy-4-(2-nitro-vinyl)-benzene (7.05 g, 26.78 mmoles), obtained as described in example 7, in dry tetrahydrofuran (100 ml). At the end of the addition the mixture was refluxed for 2 hours, then cooled in ice and slowly added with water (3.05 ml), 15% NaOH (3.05 ml) and water again (9.15 ml). Off the cooling bath, the stiring was kept on for another hour, then the solid was filtered off and the solution was concentrated to small volume, diluted with ethyl acetate, washed with water, anhydrified over Na2SO4 and dried to give an oil which was dissolved in ethyl acetate (100 ml) and acidified with HCl/ethyl acetate. The product crystallized, thus was filtered and dried under vacuum at 50° C. to give 5.14 g of the title product (yield: 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.[Cl:16][C:17]1[C:22]([Cl:23])=[C:21]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:37])[C@:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32]>CN(C)C1C=CN=CC=1.CCOC(C)=O>[Cl:16][C:17]1[C:22]([Cl:23])=[C:21]([S:24]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:26])=[O:25])[CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:37])[C@:30]([OH:36])([CH3:35])[C:31]([F:32])([F:33])[F:34]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl)C(F)(F)F
Reactant: COc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(NS(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Cl)cc1
Yield: 46 %

Procedure:
To a stirred solution of p-anisidine (74 mg, 0.6 mmol), pyridine (0.14 ml, 1.0 mmol) and 4-dimethylaminopyridine (10 mg) in EtOAc (10 ml) was added a solution of (R)-N-[2,3-dichloro-4-(chlorosulphonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (200 mg, 0.5 mmol) (Method 1) in EtOAc (10 ml). The resultant mixture was stirred at ambient temperature overnight, washed with 1 M aqueous hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on a Bond Elut column (using 10% EtOAc in DCM as eluent) to give the title compound as a foam (114 mg, 0.23 mmol); NMR: 1.6 (s, 3H), 3.6 (s, 3H), 6.8 (d, 2H), 7.0 (d, 2H), 7.95 (d, 1H), 8.1 (d, 1H); m/z 485.
Reaction SMILES: Cl(O)(=O)(=O)=O.[Br:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[CH:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18]>C(OC(C)(C)C)(=O)C>[Br:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[CH:16]([O:21][C:15]([CH3:7])([CH3:10])[CH3:14])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(O)c1sc2ncccc2c1Br
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1sc2ncccc2c1Br
Reaction time: 1 h
Yield: 50 %

Procedure:
Under a nitrogen atmosphere, perchloric acid (70%, 750 μL) was added at −10° C. to a solution of methyl 2-{3-bromothieno[2,3-b]pyridin-2-yl}-2-hydroxyacetate (14f) (180 mg, 0.6 mmol) in tertbutyl acetate (5 mL). After 1 hour, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 90/10) to afford the desired product (14g) as a white solid (55 mg, 0.15 mmol, 26%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH2:20][C@@H:19]1[C:32]([O:34]C)=[O:33].[ClH:36]>CO.O.ClCCl.CO>[ClH:36].[ClH:36].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH2:20][C@@H:19]1[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCSc4cccs4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C

Procedure:
0.5 cm3 of 5N aqueous sodium hydroxide was added to a stirred solution of 0.34 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-ylthio)ethyl]piperidine-3-carboxylate in 3 cm3 of methanol and then the mixture was heated at a temperature in the region of 60° C. for 20 hours. After evaporating the solvents under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained was taken up in 5 cm3 of water and then acidified by addition of 1 cm3 of 35% hydrochloric acid. The mixture was again evaporated under reduced pressure under the same conditions as above; the residue obtained was taken up in 5 cm3 of a dichloromethane/methanol (90/10 by volume) mixture. The insoluble material was filtered off and then the solvent was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.35 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-ylthio)ethyl]piperidine-3-carboxylic acid dihydrochloride was obtained in the form of a solid with a beige color which melts with softening in the region of 150° C.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]1[CH2:6][N:5]([C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=45)[CH:20]=[CH:19][N:18]=3)=[C:9]([O:32][CH3:33])[CH:8]=2)[CH2:4]1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:34][N:2]([CH3:1])[CH:3]1[CH2:4][N:5]([C:7]2[CH:8]=[C:9]([O:32][CH3:33])[C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=45)[CH:20]=[CH:19][N:18]=3)=[CH:11][C:12]=2[NH2:13])[CH2:6]1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Yield: 75.1 %

Procedure:
A mixture of N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 157, 355 mg, 0.77 mmol), iron (258 mg, 4.63 mmol), NH4Cl (30.9 mg, 0.58 mmol), ethanol (12.6 mL) and water (4.2 mL) was heated at reflux for 1.5 h. After cooling the mixture was concentrated in vacuo. The resulting residue was triturated in 10% CH3OH in CH2Cl2 (20 mL) for 15 minutes and the mixture was then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (20 mL) and then filtered. The combined filtrates were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (249 mg, 75%) as a brown solid after trituration with diethyl ether; 1H NMR: 2.12 (6H, s), 3.02-3.09 (1H, m), 3.47 (2H, t), 3.71 (3H, s), 3.98 (2H, t), 4.04 (2H, br s), 6.28 (1H, s), 7.05 (1H, td), 7.09 (1H, s), 7.16 (1H, d), 7.36-7.41 (1H, m), 7.93 (1H, s), 8.27 (1H, d), 8.48 (1H, d), 8.74 (1H, s), 8.77 (1H, d); m/z: ES+ MH+ 431.35.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:14]([OH:16])[CH3:15]>>[ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12](=[NH:13])[O:16][CH2:14][CH3:15])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)Cc1ccc([N+](=O)[O-])cc1
Yield: 47 %

Procedure:
Hydrogen chloride gas was passed through a solution of 4-nitrophenyl acetonitrile (5.0 g, 30.8 mmol) in ethanol (400 mL) until saturation, keeping the temperature between 0-5° C. The solvent was removed under reduced pressure at 15° C. to give a residue which on trituration with diethyl ether gave a solid. The solid was filtered under a nitrogen atmosphere and washed thoroughly with diethyl ether. Drying under vacuum afforded ethyl 2-(4-nitrophenyl)-acetimidate hydrochloride (3.5 g, 47%) which was hygroscopic in nature.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[N:24]=[CH:23][C:22]=3[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:50])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:50])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[N:24]=[CH:23][C:22]=3[C:21]([CH3:37])([CH3:36])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccccc4F)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccccc4F)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 108.9 %

Procedure:
To a stirred solution of (2R,5R)-4-{2-[6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.572 g, 0.97 mmol) and triethylamine (0.22 mL, 0.157 g, 1.55 mmol) in DCM (10 mL) at −10° C. under nitrogen was added a solution of methanesulfonyl chloride (0.09 mL, 0.133 g, 1.2 mmol) in DCM (5 mL). Mixture was stirred at 20° C. for 18 h then partitioned between saturated aqueous NaHCO3 (50 mL) and DCM (3×30 mL) and combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound (0.576 g) as an oil, used without further purification. MS: [M+H]+=545.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:18]=[C:19]([NH2:20])[CH:21]=[CH:22][CH:23]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: CC(C)(C)c1cc2ncc(C#Cc3cccc(N)c3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=291.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 3-ethynylaniline.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].O[Li].O.O>CO>[C:17]([O:16][C:14]([NH:13][CH2:12][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC12CCCC2
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1(C(=O)O)CC12CCCC2
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of 1-(tert-butoxycarbonylaminomethyl)-spiro[2.4]heptane-1-carboxylic acid methyl ester (16.5 g, 58.2 mmol) in methanol (100 mL) was added LiOH—H2O (4.9 g, 116 mmol) and water (15 mL). After 3 hours, additional methanol (50 mL) and water (15 mL) was added and reflux was continued for 6 hours total. The solvent was removed under reduced pressure. The residue was dissolved in water (200 mL) and washed with ether (200 mL). The aqueous solution was cooled in an ice bath and methylene chloride (200 mL) was added. With stirring, 4N HCl was added dropwise until pH=2-3. The layers were separated and the aqueous layer was extracted with methylene chloride (2×300 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was dissolved in hexane and evaporated to give 12.6 g (80%) of 1-(tert-butoxycarbonylaminomethyl)-spiro[2.4]heptane-1-carboxylic acid as a white foamy solid: 1H NMR (300 MHz, CDCl3) δ 1.08 (d, J=5.0 Hz, 1H), 1.44 (s, 9H), 1.45 (m, 2H), 1.55-1.8 (m, 6H), 1.92 (m, 1H), 3.35 (dd, J=6.0, 14.0 Hz, 1H), 3.44 (dd, J=6.0, 14.0 Hz, 1H), 5.28 (br t, 1H); MS (APCI) m/z=170 [M+H-100(Boc)]+.
Reaction SMILES: [CH2:1]([N:8]([C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C@H:9]([CH3:18])[CH2:10][C:11](OC(C)(C)C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH2:1]([N:8]([C@@H:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:20])[C@H:9]([CH3:18])[CH2:10][CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CC(=O)OC(C)(C)C)N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](CCO)N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
tert-Butyl(3R)-3-{benzyl[(1R)-1-phenylethyl]amino}butanoate (6.2 g, 17.6 mmol) was dissolved in THF (100 mL). The 1 L-flask was purged with N2 and cooled to 0° C. Lithium aluminum hydride (2.7 g, 69.8 mmol) was slowly added over 5 minutes. The reaction was allowed to stir at 0° C. for 1 hour, and then heated to 60° C. for 1 hour. The reaction was cooled to room temperature and diluted with Et2O (500 mL). This solution was quenched with a mixture of celite:Na2SO4 10H2O (1:1) added over 15 minutes. The solution was then filtered and the mother liquor condensed to yield 3.9 g (13.8 mmol, 78%) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:3].[CH:12]1[C:18]([NH2:19])=[N:17][C:15](=[O:16])[N:14]([C@@H:20]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C:21]2([F:29])[F:28])[CH:13]=1.Cl>>[F:29][C:21]1([F:28])[C@H:22]([OH:27])[C@@H:23]([CH2:25][OH:26])[O:24][C@H:20]1[N:14]1[CH:13]=[CH:12][C:18]([NH:19][C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:3])=[N:17][C:15]1=[O:16]
Reactant: CCCCCCCOC(=O)Cl
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: Cl
Product: CCCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 93 %

Procedure:
Using Method A and heptyl chloroformate, gemcitabine hydrochloride was converted to 43 (white solid, 93% yield): 1H NMR (200 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.24-8.28 (d, 1H), 7.12-7.16 (d, 1H), 6.33-6.37 (d, 1H), 6.16-6.24 (t, 1H), 5.31-5.36 (t, 1H), 4.19-4.33 (m, 1H), 4.10-4.17 (t, 2H), 3.63-3.94 (m, 3H), 1.60-1.66 (t, 2H), 1.29-1.31 (t, 8H), 0.86-0.92 (t, 3H).