Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1.Cl.[CH3:29][O:30][NH2:31].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:29][O:30][NH:31][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: CON
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), O-methyl-hydroxylamine hydrochloride (15 mg, 0.17 mmol), triethylamine(58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 21.6 mg (67%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.23 (1H, s), 8.71 (1H, d, J=2.2), 8.05 (4H, m), 7.51 (5H, m), 7.25 (1H, s), 7.10 (1H, d, J=7.7 Hz), 6.91 (1H, m), 5.98 (1H, m), 4.31 (1H, d, J=14.3), 7.20 (1H, d, J=7.3),4.42 (2H, d, J=3.2). ESIMS (M+H+): 412.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[O:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C(O)=O.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:12]2[O:11][N:10]=[C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[CH:2][CH:3]=3)[CH:13]=2)=[CH:16][CH:17]=1
Reactant: Nc1ncc(Cl)cc1-c1cc(Cc2ccc(COc3ccccn3)cc2)on1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)on1
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 2 %

Procedure:
To a solution of 5-chloro-3-(5-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-3-yl)-pyridin-2-ylamine (37 mg, 94 μmol) described in Manufacturing Example 30-1-3 in N-methyl-2-pyrrolidinone (2 mL) were added formic acid (5.3 μL, 0.14 mmol), N,N-diisopropylethylamine (49 μL, 0.28 mmol) and bis(tri-tert-butylphosphine)palladium (0) (9.6 mg, 19 μmol) at room temperature, which was stirred under nitrogen atmosphere for 1 hour and 25 minutes at 100° C. Water and ethyl acetate were added to the reaction solution at room temperature, which was then filtered through a Celite pad. The filtrate was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid), and then further purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (0.66 mg, 2.0%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@H:4]1[CH2:9][O:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:15]=[C:14]([C:16]2([S:19]([CH3:22])(=[NH:21])=[O:20])[CH2:18][CH2:17]2)[N:13]=[C:12]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[N:29](S(C4C=CC(C)=CC=4)(=O)=O)[CH:30]=[CH:31][C:24]=23)[N:11]=1.O.Cl>COCCOC>[CH3:3][C@@H:4]1[CH2:9][O:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:15]=[C:14]([C:16]2([S:19]([CH3:22])(=[NH:21])=[O:20])[CH2:18][CH2:17]2)[N:13]=[C:12]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][CH:30]=[CH:31][C:24]=23)[N:11]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4nc(N5CCOC[C@H]5C)cc(C5(S(C)(=N)=O)CC5)n4)ccnc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: C[C@@H]1COCCN1c1cc(C2(S(C)(=N)=O)CC2)nc(-c2ccnc3[nH]ccc23)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
Sodium hydroxide, 2M aqueous solution (9.95 ml, 19.90 mmol) was added to (3R)-3-methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (6.44 g, 11.37 mmol) in DME (100 ml)/water (25.00 ml). The resulting solution was stirred at 50° C. for 18 hours. Further NaOH, 2M aqueous solution (18 ml, 36.00 mmol) was added and the mixture was stirred at 50° C. for a further 3 days. The reaction mixture was acidified with 2M HCl (˜22 ml) to pH5. The reaction mixture was evaporated and the residue was dissolved in DCM (250 ml) and washed with water (200 ml). The organic layer was dried over MgSO4, filtered and then evaporated to approximately 50 ml in volume. The solution was purified by flash chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. Pure fractions were evaporated to afford 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (2.440 g, 52%); 1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.42 (1H, dd), 1.47-1.58 (2H, m), 1.68-1.80 (1H, m), 3.10 (3H, s), 3.24-3.31 (1H, m), 3.51 (1H, t), 3.66 (1H, dd), 3.80 (1H, d), 3.83-3.88 (1H, m), 4.00 (1H, dd), 4.20 (1H, s), 4.57 (1H, s), 6.99 (1H, d), 7.22 (1H, dd), 7.53-7.63 (1H, m), 7.94 (1H, d), 8.34 (1H, t), 11.80 (1H, s); m/z: (ES+) MH+, 413.47.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[CH3:15][O:16][C:17](=[O:50])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][C@H:24]1[C:28](=[O:29])[CH2:27][C@@H:26]([OH:30])[C@@H:25]1[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH:36]([O:40]CC1C=CC(OC)=CC=1)[CH2:35][CH2:34]2.O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:15][O:16][C:17](=[O:50])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][C@H:24]1[C:28](=[O:29])[CH2:27][C@@H:26]([OH:30])[C@@H:25]1[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH:36]([OH:40])[CH2:35][CH2:34]2
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1c1ccc2c(c1)CCC2OCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1c1ccc2c(c1)CCC2O
Reaction time: 0.92 h
Yield: 434.7 %

Procedure:
DDQ (41 mg, 0.18 mmol) was added to a mixture of 15-5 (11 mg, 0.021 mmol) in dichloromethane (3.5 mL)/water (175 μL). After 55 min., saturated NaHCO3 solution was added and the resulting mixture was extracted with dichloromethane (3×50 mL). The combined dichloromethane solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (50%→60% ethyl acetate/hexanes) gave 15-6 (34 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:30][C:25]1[CH:24]=[C:23]([CH2:22][N:3]2[C:4]3[CH:10]=[C:9]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=3[N:6]=[C:2]2[CH3:1])[CH:28]=[CH:27][C:26]=1[CH3:29]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Reactant: Cc1ccc(CCl)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1ccc(C)c(C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate prepared as described in Example 26, step d (0.22 g, 0.799 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added in 4-(chloromethyl)-1,2-dimethylbenzene (0.185 g, 1.199 mmol) and potassium carbonate (0.331 g, 2.397 mmol). The resulting reaction mixture was stirred at 80° C. for 3 h. It was cooled to room temperature and poured into water (30 mL). The mixture was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL) and concentrated. The crude material was subjected to normal phase purification (0˜40% EtOAc/Hexane) then (0˜1% MeOH/DCM) to give the product (0.24 g, 76%). MS(ES+) m/e 394.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[OH:11][CH:12]([CH3:16])[C:13](=O)[CH3:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[OH:11][CH:12]([CH3:16])[CH:13]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)[CH3:14]
Reactant: CC(=O)C(C)O
Reactant: COC(=O)c1csc(N)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1csc(NC(C)C(C)O)n1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Methyl 2-aminothiazole-4-carboxylate (1.0, 6.32 mmol), 3-hydroxy-2-butanone (1.045 ml, 12.01 mmol) and acetic acid (2.278 g, 37.9 mmol) were dissolved in 1,2-dichloroethane. Sodium triacetoxy borohydride (3.75 g, 17.70 mmol) was added and the reaction mixture was stirred overnight. Sodium triacetoxy borohydride (3.1 g) was added in two portions and the reaction mixture was stirred over two nights. 1M NaHCO3 was added slowly and mixture was extracted twice with DCM. DCM phase was dried and evaporated to afford 68.1% of the title product. m/z [230.3+1].
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][CH:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:29]([CH:28]([OH:27])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(C(O)c3ccccc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (2RS)-hydroxy(phenyl)ethanoic acid, the title compound was obtained in 73% purity by HPLC. MS(ESI+): m/z=469.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C@@H:6]([NH:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[C:13]([CH3:20])[N:12]=1)[CH2:7][CH2:8][CH3:9])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C@@H:6]([NH:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:20])[N:12]=1)[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCC[C@@H](CC(=O)OCC)Nc1nc(C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCC[C@@H](CC(=O)OCC)Nc1nc(C)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 109 %

Procedure:
To a slurry of (S)-3-(6-methyl-3-nitro-pyridin-2-ylamino)-hexanoic acid ethyl ester (358 mg, 1.21 mmol) in MeOH (10 mL) was added Pd/C (150 mg). The reaction mixture was de-gassed using house vacuum and saturated with H2. The reaction mixture was stirred at room temperature for 3 hours. The mixture was filtered through a celite and the filtrate was concentrated to afford 350 mg (100%) of the desired product as pale yellow oil. The resulting residue was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]([S:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:7])[C:3](=[O:6])[CH2:4][CH3:5].[Br-:13].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>C(Cl)Cl>[Br:13][CH:4]([CH3:5])[C:3](=[O:6])[C:2]([S:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:1])[CH3:7]
Reactant: [Br-]
Reactant: CCC(=O)C(C)(C)SCC(=O)O
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(Br)C(=O)C(C)(C)SCC(=O)O
Reaction time: 0.25 h

Procedure:
To a solution of [(1,1-dimethyl-2-oxobutyl)thio]acetic acid (0.3 g, 1.58 mmol) in CH2Cl2 (10 ml) was added phenyltrimethylammonium tribromide (0.62 g, 1.65 mmol) at 0° C. After stirring for 15 min, the solution was allowed to come to room temperature and stirring was continued for 1 h. Water (30 ml) was added and the aqueous layer was extracted with diethyl ether (15 ml). The combined organic layers were washed with brine (25 ml), dried over Na2SO4, filtered and concentrated in vacuo. The remaining oil was purified by flash chromatography (ethyl acetate-petroleum ether 1:1 containing 0.1% glacial acetic acid). Yield: 0.39 mg (91%). 1H-NMR (400 MHz, CDCl3): δ=1.15, 1.64 (2×s, 6H, C(CH3)2), 1.81 (d, 3H, J=7.0 Hz), 3.14, 3.21 (2×d, 2H, J=6.8 Hz), 5.07 (q, 1H, J=7.0 Hz) ppm. C8H13BrO3S (269.16, 267.98), HRMS: calcd (M+Na)+ 290.9661, found 290.9669.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.C[CH:21]([OH:23])[CH3:22]>>[CH:6]1([NH:5][C:21](=[O:23])[C:22]2[CH:17]=[CH:18][CH:19]=[CH:14][C:4]=2[NH:3][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[C:4]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:3]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Reactant: CC(C)O
Product: COc1ccc2nc(-c3cccnc3)nc(Nc3ccccc3C(=O)NC3CCCCC3)c2c1

Procedure:
To the crude amide was added the solution of 4-chloro-6-methoxy-2-pyridin-3-yl-quinazoline (20 μmol) in 2-propanol (200 μL). The mixture was refluxed for 8 h. After evaporation, the residue was dissolved in 5% TFA/MeOH-DMF (1:1) and purified by PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[NH:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:27]=3)[CH2:15][CH2:16][C:17]3[CH:25]=[C:21]([NH:22][C:23]=1[N:24]=2)[CH:20]=[CH:19][C:18]=3[NH2:26].[C:28](Cl)(=[O:36])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[NH:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:27]=3)[CH2:15][CH2:16][C:17]3[CH:25]=[C:21]([NH:22][C:23]=1[N:24]=2)[CH:20]=[CH:19][C:18]=3[NH:26][C:28](=[O:36])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine trihydrochloride (100.0 mg, 0.223 mmol) in pyridine (1 mL) was added carbonochloridic acid, phenyl ester (42.0 μL, 0.335 mmol). The reaction solution was stirred at room temperature overnight. The reaction solution was concentrated and diluted with water. The resulting precipitate was filtered and dried under vacuum to give the desired product (100 mg, 88%). LCMS for C24H20ClN6O2 (M+H)+: m/z=459.2.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>C(#N)C>[F:24][C:22]1[CH:21]=[CH:20][C:19]2[CH:15]([NH:14][C:11]3[O:12][CH2:13][C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])[CH:26]=[CH:25][C:9]=4[N:10]=3)[CH2:16][O:17][C:18]=2[CH:23]=1
Reactant: CC(C)(O)CN
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Solvent: CC#N
Product: CC(C)(O)CNCC(=O)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Yield: 100 %

Procedure:
Prepared from rac-2-chloro-N-[2-(6-fluoro-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 42 step A) (50 mg, 0.133 mmol, HPLC 1.056 min) and 1-amino-2-methyl-propan-2-ol (237 mg, 2.66 mmol) in acetonitrile (3 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (57 mg, 100%, HPLC 0.473 min 100%), MS (ISP) m/e=429.3 [(M+H)+].
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[F:25].[Br:26]C(Cl)(Cl)C(Br)(Cl)Cl>C1COCC1>[Br:26][C:18]1[C:17]([F:25])=[C:16]([Cl:15])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c(F)c1Br
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a cooled (−78° C.) solution of DIEA (4.9 mL, 48 mmol) in THF was added drop wise n-BuLi (132 mL, 2.3 eq, 2.5 M solution). The mixture was stirred at −30° C. for 30 min. Again the reaction mixture was cooled to −78° C., and a solution of 4-chloro-3-fluorobenzoic acid (25 g, 143 mmol) in THF was added over 1 h. The reaction was stirred at −78° C. overnight. The next day a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (87 g, 267 mmol) in THF was added and the reaction was stirred at −78° C. for further 2 h and then rt for 4 h. The reaction mixture was quenched with H2O, organic layer was separated and aqueous layer washed with Et2O. Aqueous layer acidified with 1.5N HCl and extracted in EtOAc (2×200 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford Intermediate 12A (30 g, 83.3% yield). MS (ESI) m/z: 252.6 (M−H)+.
Reaction SMILES: [I-].[CH:2]([O:5][C:6]1[C:7]([N+:20]([O-])=O)=[CH:8][C:9]([CH3:19])=[C:10]([C:12]2[CH:17]=[CH:16][N+:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)([CH3:4])[CH3:3].[BH4-].[Na+].C(O)(C(F)(F)F)=O>CO.O=[Pt]=O>[CH:2]([O:5][C:6]1[CH:11]=[C:10]([CH:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[C:9]([CH3:19])=[CH:8][C:7]=1[NH2:20])([CH3:4])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1-c1cc[n+](C)cc1
Agent: O=[Pt]=O
Agent: [BH4-]
Agent: [I-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)c(OC(C)C)cc1C1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-1-methyl-pyridinium iodide from the previous step (0.697 mmol) is dissolved in CH3OH (20 mL) and cooled to 0° C. NaBH4 (264 mg, 6.97 mmol, 10 equiv.) is slowly added. After this addition is complete, the cooling bath is removed and the reaction is stirred at room temperature for 1 h. The reaction is quenched by the slow addition of 1N aqueous HCl (14 mL). The CH3OH is partially removed by vacuum. The resulting residue is partitioned between EtOAc and 1 N aqueous NaOH. Additional 50% aqueous NaOH is added until the aqueous layer pH>12. The EtOAc layer is washed with 1 N aqueous NaOH (2×), the organic layer is then dried over Na2SO4, filtered, and concentrated under vacuum. After concentration, the crude product (175 mg) is dissolved in acetic acid (10 mL). TFA (0.15 mL, 3 equiv.) and PtO2 (53 mg, 30% w/w) are added and the reaction is placed under 50 psi H2 gas in a Parr Shaker for 14 h. The reaction mixture is filtered and the filtrate is concentrated under vacuum. The resulting residue is partitioned between EtOAc and 1 N aqueous NaOH. Additional 50% aqueous NaOH is added until the aqueous layer pH>12. The EtOAc layer is washed with 1 N aqueous NaOH (2×), the organic layer is then dried over Na2SO4, filtered, and concentrated under vacuum to give 2-Isopropoxy-5-methyl-4-(1-methyl-piperidin-4-yl)-phenylamine which is used in Step 4 without further purification: ESMS m/z 263.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][N:9]=[CH:10][C:11]1([C:19]([OH:21])=[O:20])[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][NH:9][CH2:10][C:11]1([C:19]([OH:21])=[O:20])[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC1CC(C=NOCc2ccccc2)(C(=O)O)C1
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCCCC1CC(CNOCc2ccccc2)(C(=O)O)C1
Temperature: 0 °C

Procedure:
A solution of 1-(benzyloxyimino-methyl)-3-butyl-cyclobutanecarboxylic acid (5.62 g, 19.4 mmol) in methanol (200 mL) at 0° C. under a nitrogen atmosphere was added a trace amount of methyl orange. A solution of saturated methanolic HCl was added until a persistent red color was observed. Sodium cyanoborohydride (1.59 g, 25.3 mmol) was added portionwise alternately with methanolic HCl to maintain the red color. The reaction mixture was maintained at 0° C. for an additional 0.5 h and the volatiles were removed in vacuo. The product was used without further purification. MH+292.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][S:12][C:7]=1[N:6]=[CH:5]2.C1C(=O)N([Cl:20])C(=O)C1.C([O-])(O)=O.[Na+]>CC(O)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:20][C:11]1[S:12][C:7]2[N:6]=[CH:5][N:4]3[CH:3]=[N:2][N:1]=[C:9]3[C:8]=2[CH:10]=1
Reactant: c1cc2c(ncn3cnnc23)s1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: Clc1cc2c(ncn3cnnc23)s1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (123 mg, 0.7 mmol) in HOAc (1 mL) was added NCS (200 mg, 1.5 mmol), Pd(OAc)2 (48 mg, 0.21 mmol). The reaction mixture was stirred at 120° C. overnight. The reaction was neutralized with a saturated NaHCO3 solution and extracted with DCM. This product was purified via an isco column to give 8-chlorothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine as the major product. Retention time (min)=1.663, method [1], MS (ESI) 211.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1I>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(S)c(C)c1
Reactant: Fc1cccc(Br)c1I
Product: Cc1ccc(Sc2c(F)cccc2Br)c(C)c1

Procedure:
Prepared from 2,4-dimethyl-benzenethiol and 1-bromo-3-fluoro-2-iodo-benzene.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Br:9][C:10]1[C:15](Br)=[N:14][CH:13]=[CH:12][N:11]=1>C1COCC1>[Br:9][C:10]1[N:11]=[CH:12][C:13]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[N:14][CH:15]=1
Reactant: C1COCCN1
Reactant: Brc1nccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cnc(N2CCOCC2)cn1
Reaction time: 0.25 h

Procedure:
To sodium hydride (0.20 g) taken in THF (15 ml), morpholine (0.735 ml) was added under nitrogen, at 0° C. The reaction mixture stirred for about 15 minutes, then 2,3-dibromopyrazine (2 g) dissolved in dry THF (15 ml) was added. The reaction mixture was allowed to stir at reflux conditions for overnight. The reaction mixture was quenched with water (5 ml), and volatiles were removed under vacuum. The resulting crude mass was purified by column chromatography to afford pure 4-(5-bromopyrazin-2-yl)morpholine.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8]O)[N:7]=1.C1(C([O-])=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O.Cl.Cl.[NH2:28][CH2:29][CH2:30][SH:31]>>[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8][S:31][CH2:30][CH2:29][NH2:28])[N:7]=1
Reactant: Nc1nc(CO)c[nH]1
Reactant: NCCS
Agent: Cl
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Product: NCCSCc1c[nH]c(N)n1

Procedure:
Reaction of 2-amino-4-hydroxymethylimidazole hydrochloride (which is obtained by treating the picrate salt with hydrochloric acid) with cysteamine hydrochloride by the procedure of Example 1 gives 2-amino-4-[(2-aminoethyl)thiomethyl]imidazole.