Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:25]([C:28]([C:38](=[O:40])[CH3:39])=[CH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)(=[O:27])[CH3:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:25]([CH:28]([C:38](=[O:40])[CH3:39])[CH:29]([C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)[CH:3]([C:2]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=1)=[O:1])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])(=[O:27])[CH3:26]
Reactant: O=C(CC(=O)OCc1ccccc1)Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)C(C(C)=O)C(c1ccc(C#N)cc1)C(C(=O)Nc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of benzyl 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate (6.7 g, 19.2 mmol) (Example 3A) and 4-(2-acetyl-3-oxobut-1-en-1-yl)benzonitrile (4.2 g, 19.2 mmol) (Example 4A) in tetrahydrofuran (140 ml) is added tetrabutylammonium fluoride (9.9 ml of a 1 M solution in tetrahydrofuran). The reaction is stirred for 2 hours at room temperature, then concentrated in vacuo and chromatographed over silica gel 60 with cyclohexane/ethyl acetate mixtures as eluent. The product is isolated as a mixture of diastereomers.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH:10]([CH:11]([O:22][C:23](=[O:25])[CH3:24])[CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:9][C:8]([C:26]([O:28][CH3:29])=[O:27])=[CH:7][CH:6]1[N:30]=[N+]=[N-])(=[O:3])[CH3:2].O.[Cl-].[NH4+]>C(Cl)Cl.[Zn]>[C:1]([NH:4][CH:5]1[CH:10]([CH:11]([O:22][C:23](=[O:25])[CH3:24])[CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:9][C:8]([C:26]([O:28][CH3:29])=[O:27])=[CH:7][CH:6]1[NH2:30])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=CC(N=[N+]=[N-])C(NC(C)=O)C(C(OC(C)=O)C(COC(C)=O)OC(C)=O)O1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1=CC(N)C(NC(C)=O)C(C(OC(C)=O)C(COC(C)=O)OC(C)=O)O1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a reaction vessel, 55 g of methyl 5-acetamido-4-azido-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate, 500 ml of denatured alcohol and 100 ml of water was added under stirring at room temperature. To the reaction mass 14 g ammonium chloride and 18 g zinc dust was added. The reaction mixture was stirred at 20° C.-30° C. for 30 minutes. On completion of reaction, the reaction mass was cooled to 10° C. and then filtered through hyflo. The filtrate was concentrated under vacuum to obtain a solid product which was then dissolved in about 200 ml of methylene dichloride. The organic layer was filtered and concentrated to yield 52 g of solid title compound, dried under vacuum (yield—94%, HPLC purity—96%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]1)=[O:16])[CH:9]=[CH:8]2)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]1)=[O:16])[CH:9]=[CH:8]2
Reactant: COC(=O)C1CCN(C(=O)c2ccc3cc(OC(C)=O)ccc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
A mixture of methyl 1-(6-acetoxy-2-naphthoyl)piperidine-4-carboxylate (1 g, 2.814 mmol, 1.0 eq), K2CO3 (1.94 g, 14.07 mmol, 5.0 eq) in MeOH (20 mL) was stirred at room temperature for 2 h. The reaction was filtered. The filtrate was concentrated and the residue was purified by prep-HPLC (MeOH: 0.05% TFA/H2O=0-95%) to afford methyl 1-(6-hydroxy-2-naphthoyl)piperidine-4-carboxylate as a white solid (350 mg, yield: 40%). ESI-MS: 314.0 (M+H)+. 1HNMR (400 MHz, DMSO-d6) δ: 9.94 (s, 1H), 7.86-7.84 (m, 2H), 7.73 (d, 1H), 7.38 (d, 1H), 7.16-7.12 (m, 2H), 3.63 (s, 3H), 3.16-2.97 (m, 2H), 2.69-2.63 (m, 3H), 1.96-1.79 (m, 2H), 1.61-1.51 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:10](=O)([O-])[O-:11].[K+].[K+].C(=O)=O>O>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2=[N:8][C:10](=[O:11])[N:1]=[C:2]2[CH:3]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(c1)=NC(=O)N=2
Temperature: 230 °C
Yield: 473.8 %

Procedure:
24.4 g (0.2 mol) of 3,4-diaminotoluene, 18 g of water and 5.5 g (0.04 mol) of potassium carbonate were introduced into a 200 ml reactor. After sealing, CO2 was injected up to a pressure of 35 bar. The mixture was then heated to 230° C., and this temperature maintained for 12 hours. During the heating period, the pressure rose to up to 80 bar. After the reaction was completed, the mixture was cooled, the excess CO2 pressure was let down, and the aqueous slurry of crystals was removed. The aqueous catalyst solution was separated off through a filter, the solid was washed with water until it no longer contained carbonate, and was dried. 27.7 g (93.7% of theory) of 5-methylbenzimidazolone of m.p. = 301-303° C. were isolated.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:21]([OH:23])=O)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2].[NH3:34]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:21]([NH2:34])=[O:23])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(=O)O)ccc3N3CCOCC3)CC2)c(F)c1
Reactant: N
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(N)=O)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step2 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-morpholin-4-yl-benzoic acid and ammonia (10%, white solid, MS (m/e): 455.2 (M+H, 100%)
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([O:22][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:10]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(OCC)c2ccccc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(=O)OCC)c(OCc2ccccc2)c2ccccc2c1OCC
Yield: 98 %

Procedure:
Benzyl bromide (1.32 ml, 11.1 mmol) was added to a stirred solution of diethyl 1-(ethyloxy)-4-hydroxy-2,3-naphthalenedicarboxylate (2.45 g, 7.38 mmol) and potassium carbonate (1.53 g, 11.1 mmol) in acetone (50 ml). The reaction mixture was refluxed for 1 hour under an atmosphere of argon. The resulting mixture was evaporated and the residue was partitioned between 2× ethylacetate and brine. The combined organics were washed with water and dried over magnesium sulphate. The clear oil was purified by chromatography on silica gel, eluting with ethyl acetate (0-40%) in hexane to give the title compound as clear oil (3.05 g, 7.23 mmol). LC/MS: Rt=3.77, [MH]+ 423.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].ClCCl.C(N(CC)CC)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:61]([CH3:60])(=[O:63])=[O:62])[CH2:46][CH2:45]3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCNCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: -15 °C
Yield: 94.4 %

Procedure:
A 1 L 3-neck round-bottomed flask equipped with a thermometer was charged with 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (25.1 g, 37.7 mmol) in dichloromethane (500 mL, 37.7 mmol). The suspension was stirred at −15° C. and treated with dropwise with triethylamine (52.4 mL, 377 mmol). The resulting solution was treated with methanesulfonyl chloride (8.92 mL, 113 mmol) and stirred at 0° C. for 1 h. The resulting mixture was sonicated and the solid was filtered, washed with water and dried in vacuo to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (26.5 g, 35.6 mmol, 94% yield). m/z (ESI, positive ion) m/z 744 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6].[C:18]([Cl:21])(=O)[CH3:19].O1CCOCC1.Cl>O1CCOCC1>[ClH:21].[CH3:18][C:19]1[N:11]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(C(=O)O)ccc1NC1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 93.1 %

Procedure:
3-Amino-4-((tetrahydropyran-4-yl)amino)benzoic acid (see Working Example 4-2) (90 g, 0.38 mol) was dissolved in dioxane (900 mL), and after cooling to 10° C., a solution of acetyl chloride (35.0 g, 0.45 mol) in dioxane (900 mL) was added dropwise over the course of 35 minutes. After heating to reflux with stirring for 2.5 h, another solution of acetyl chloride (15.8 g, 0.20 mol) in dioxane (200 mL) was added to the reaction solution, and this was further heated to reflux with stirring for 3 hours. Next, a 4N HCl dioxane solution (100 mL) was added, and after heating to reflux with stirring for 8 h, this was allowed to cool to room temperature, the solid obtained was filtered off and washed with hexane to yield the title compound (105 g, quant.) as a light purple solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O.[I:10]I.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:10])[CH:3]=1
Reactant: II
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a solution of 4-chlorophenol in THF (75 mL), and H2O (75 mL) was added a mixture of crushed iodine (78.7 mmol, 20 g) and sodium bicarbonate (78.7 mmol, 6.6 g). The reaction mixture was stirred at room temperature overnight, then quenched with sufficient 5% sodium thiosulfate solution to turn the color of the reaction mixture from deep violet to light yellow and extracted with ether (2×200 mL). The ether layer was collected, washed with H2O, and the washed ether layer was dried, filtered and the filtrate was evaporated to a crude product, which was purified by distillation to obtain 4-chloro-2-iodo phenol (7%, 1.3 g); mp 79° C.-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:22][O:23][NH:24][CH3:25].C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:24]([O:23][CH3:22])[CH3:25])=[O:6]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To 2-bromoisonicotinic acid, (25.2 g, 124 mmol), HOBt (20.2 g, 149 mmol) and O,N-dimethyl-hydroxylamine hydrochloride (14.6 g, 149 mmol) in DMF (150 mL) at 0° C., was added diisopropylethyalamine (26.0 mL, 149 mmol). EDC (28.6 g, 149 mmol) was then added and the mixture stirred at room temperature for 1 hour. The mixture was then poured into ice cold water (500 mL) and the resulting solution extracted with EtOAc (3×150 mL). The combined organic fraction was were washed with water (2×200 mL), 0.5 M HCl (200 mL), sat. NaHCO3 solution, brine (200 mL) and then dried (MgSO4). The solvent was evaporated in vacuo to give 2-bromo-N-methoxy-N-methyl-isonicotinamide (23 g, 75%)
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[C:14]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])([CH3:17])([CH3:16])[CH3:15]>C(O)C>[C:14]([C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)[CH:22]=[CH:23][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1ccc2nc(Cl)cnc2c1
Reactant: CC(C)(C)c1cccc(N)c1
Solvent: CCO
Product: COc1ccc2nc(Nc3cccc(C(C)(C)C)c3)cnc2c1
Temperature: 80 °C

Procedure:
A solution containing 2-chloro-6-methoxyquinoxaline (synthesized as described in J. Chem. Soc. Perkin Trans 2001, 978-984) (1 eq), 3-t-butylaniline (2 eq) in ethanol was heated at 80° C. overnight. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave the desired product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([I:21])[CH:20]=1)[C:15]([NH2:17])=[O:16]>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([C:15]2[O:16][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[N:17]=2)[CH:18]=[C:19]([I:21])[CH:20]=1
Reactant: NC(=O)c1cc(Br)cc(I)c1
Reactant: O=C(CBr)c1ccccn1
Solvent: Cc1ccccc1
Product: Brc1cc(I)cc(-c2nc(-c3ccccn3)co2)c1
Yield: 0.5 %

Procedure:
A solution of 2-bromoacetylpyridine (1.0 g, 5 mmol) in toluene (5 mL) was treated with 3-bromo-5-iodobenzamide (2.0 g, 6 mmol) and the mixture heated at reflux for 60 hours. The mixture was then cooled and the solvent was removed in vacuo. Silica gel chromatography using a gradient of hexane to ethyl acetate afforded 10 mg (1%) of 2-(3-bromo-5-iodophenyl)-4-(pyridin-2-yl)-1,3-oxazole: 1H-NMR (CDCl3), δ ppm: 8.62 (d, 1H), 8.42 (m, 1H), 8.38 (s, 1H), 8.24 (m, 1H), 8.00 (t, 1H), 7.95 (d, 1H), 7.8 (m, 1H), 7.27 (m, 1H).
Reaction SMILES: C(N1CCN([C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)CC1)C1C=CC=CC=1.ClC(O[CH:28]=[CH2:29])=O>>[N:15]1([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[N:22]=[CH:23][CH:14]=[N:15]3)[CH2:29][CH2:28][NH:22][CH2:23][CH2:14]1
Reactant: c1ccc(CN2CCN(c3cnc4ccccc4n3)CC2)cc1
Reactant: C=COC(=O)Cl
Product: c1cc(N2CCNCC2)c2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 127.3 %

Procedure:
To a room temperature solution of 1-benzyl-4-(quinoxalin-yl)-piperazine (1.0 g, 3.3 mmol) in anhydrous CH2C2 under nitrogen was added vinyl chloroformate (0.34 mL, 3.9 mmol) drop wise. The reaction mixture was heated at reflux 2 hours. The reaction was cooled, concentrated to dryness and concentrated HCl (25 mL) and 1,4-dioxane (25 mL) were added. The resulting solution was stirred at ambient temperature overnight. The solution was basified with 2.5 N NaOH (300 mL) and extracted into EtOAc (3×200 mL). The organic layers were combined, dried over Na2SO4, concentrated and chromatographed (10% MeOH/CH2Cl2/NH4OH) to give 450 mg (64%) of an orange solid: mp 106-108° C.: MS (+) ESI m/e 215 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:4]1[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][C@@:5]1([C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[F:32])[CH3:22])[CH:2]=C.C(=O)(O)[O-:34].[Na+].O=O.[BH4-].[Na+]>C(Cl)Cl.CO>[F:32][C:24]1[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=1[C@:5]1([CH3:22])[C@H:4]([CH2:1][CH2:2][OH:34])[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6]1
Reactant: C=CC[C@H]1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Reactant: O=C([O-])O
Agent: O=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)[C@H](CCO)S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl ((5R,6S)-6-allyl-5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (250 mg, 0.532 mmol) (cis-isomer from Step 1) in DCM (4 ml) and MeOH (1.3 ml), was added sodium bicarbonate (89 mg, 1.065 mmol) and the mixture was cooled to −78° C. The resulting mixture was ozonolized for about 10 min or until analysis showed no starting material present. The stream of oxygen was passed through the solution for 5 min, then solid sodium borohydride (40.3 mg, 1.065 mmol) was added to the mixture. The flask was removed from the bath and allowed to reach RT and stirred for 30 min. The reaction was quenched with saturated NH4Cl solution (caution: there is evolution of gas), diluted with water to dissolve solids and extracted into EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to afford tert-butyl ((5R,6S)-5-(2-fluoro-5-nitrophenyl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:2]3[N:3]=[C:4]([NH2:11])[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:21]=2)[CH:17]=[N:18]1
Reactant: Nc1nc(Cl)nc2[nH]ccc12
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Nc1nc(Nc2ccc3cn[nH]c3c2)nc2[nH]ccc12
Temperature: 115 °C
Yield: 12.8 %

Procedure:
To a mixture of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-amine (0.06 g, 0.353 mmol) in nBuOH (0.7 mL) was added 6-aminoindazole (0.094 g, 0.70 mmol) and TMSCl (0.023 mL, 0.175 mmol). After heating at 115° C. for 8 h, it was cooled and purified by prep HPLC to give N2-(1H-indazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine (0.012 g, MS calcd for C13H11N7 265.3. found 266.1; UV 216.9, 308.0 nm).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[C:11]([O:12][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CON(C)C(=O)c1ncccc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccnc1C(=O)N(C)OC
Yield: 28.2 %

Procedure:
3-Hydroxy-pyridine-2-carboxylic acid methoxy-methyl-amide (5.21 g, 28.60 mmol), N,N-dimethylformamide (500 ml), potassium carbonate (15.91 g), and methyl iodide (3.6 ml, 57.70 mmol) were stirred for 18 hours at room temperature. The reaction was concentrated. Water and ethyl acetate was added. The organic layer was separated, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (0-70% [10% methanol in ethyl acetate] in hexanes) to give 1.58 g (28%) of 3-methoxy-pyridine-2-carboxylic acid methoxy-methyl-amide. 1H NMR (250 MHz, CDCl3) δ 8.20-8.11 (m, 1H), 7.32-7.18 (m, 2H), 3.83 (s, 3H), 3.51 (s, 3H), 3.35 (s, 3H); MS: m/z 310.6+197.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]3)[CH2:31][CH2:30]2)[CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[CH:21][C:20]=2[O:19][CH3:18])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and tert-butyl 4-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (INTERMEDIATE 8).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH2:19]([O:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[S:28][C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(COc2cccs2)cc1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(OCc4ccccc4)s3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-benzyloxy-thiophene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH:10]([O:13][CH2:14][C:15](N)=[NH:16])([CH3:12])[CH3:11].C(OCC)(=O)C>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH:10]([CH3:12])[CH3:11])[N:16]=1
Reactant: CC(C)OCC(=N)N
Reactant: N#Cc1nccnc1N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)OCc1nc(N)c2nccnc2n1

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 8.8 g (0.073 mole) of 3-amino-2-pyrazinecarbonitrile and 13.0 g (0.11 mole) of 2-isopropoxyacetamidine in 295 ml of absolute ethanol. Refluxing time: 4 hours. Yld: 4.5 g (28%), m.p. 139°-141° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:7]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N1CCCCC1
Product: CN1CCN(c2cc(N3CCCCC3)c([N+](=O)[O-])cc2Cl)CC1
Yield: 83.6 %

Procedure:
The procedure of Example 5, step (b) was followed using 968 mg (3.52 mmol) of 1-(4,5-dichloro-2-nitro-phenyl)-piperidine (as prepared in the previous step) and 1.95 mL (17.6 mmol) of 1-methylpiperazine. Crystallization from hexane afforded 997 mg (84%) of the title compound as a yellow-tan solid: Mass spectrum (ESI, m/z): Calcd. for C16H23ClN4O2, 339.2 (M+H), found 339.1.