Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1=[N:3][C:4]2([CH2:21][O:22][CH2:23][CH2:24]1)[C:17]1[CH:16]=[C:15]([OH:18])[CH:14]=[C:13]([F:19])[C:12]=1[O:11][C:10]1[C:5]2=[CH:6][C:7]([Br:20])=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[CH2:36](I)[C:37]([CH3:40])([CH3:39])[CH3:38]>O>[Br:20][C:7]1[CH:6]=[C:5]2[C:10]([O:11][C:12]3[C:13]([F:19])=[CH:14][C:15]([O:18][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:16][C:17]=3[C:4]32[CH2:21][O:22][CH2:23][CH2:24][C:2]([NH2:1])=[N:3]3)=[CH:9][CH:8]=1
Reactant: NC1=NC2(COCC1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1cc(F)c2c(c1)C1(COCCC(N)=N1)c1cc(Br)ccc1O2
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A vial was charged with (E)-5-amino-7′-bromo-4′-fluoro-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-2′-ol (222.7 mg, 0.566 mmol), cesium carbonate (738 mg, 2.265 mmol), and DMF (2832 μL) to give a yellow suspension. The resulting mixture was stirred for 10 min, then neopentyl iodide (225 μL, 1.699 mmol) was added. The vial was capped and heated to 100° C. for 2 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0-10% MeOH/DCM) to give (E)-7′-bromo-4′-fluoro-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:13]([C:15]2[CH:19]=[CH:18][S:17][C:16]=2[CH:20]=O)[CH:14]=1)#[N:2].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:13]([C:15]2[CH:19]=[CH:18][S:17][C:16]=2[CH2:20][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[CH:14]=1)#[N:2]
Reactant: CCNCC
Reactant: N#Cc1ccccc1-c1cc(-c2ccsc2C=O)cn(-c2ccccc2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CC)Cc1sccc1-c1cc(-c2ccccc2C#N)c(=O)n(-c2ccccc2)c1
Reaction time: 3 h

Procedure:
A solution of 20 mg of 3-(2-cyanophenyl)-5-(2-formylthiophen-3-yl)-1-phenyl-1,2-dihydropyridin-2-one, 0.1 ml of a 2M solution of diethylamine in tetrahydrofuran and 0.1 ml acetic acid in 2 ml of tetrahydrofuran was stirred at room temperature for 15 minutes, 20 mg of sodium triacetoxyborohydride were added and the mixture was stirred for 3 hours more. A 2N aqueous solution of sodium hydroxide was added thereto, the mixture was extracted with ethyl acetate and the organic layer was washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by an NH silica gel column chromatography to give 15 mg of the title compound as white powder.
Reaction SMILES: Br[C:2]1[N:6]([C@@H:7]2[O:12][C@H:11]([CH3:13])[C@@H:9]([OH:10])[C@H:8]2[F:14])[C:5]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:4]=2[N:3]=1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:5]2[N:6]([C@@H:7]3[O:12][C@H:11]([CH3:13])[C@@H:9]([OH:10])[C@H:8]3[F:14])[C:2]([NH:24][CH:21]([CH3:23])[CH3:22])=[N:3][C:4]=2[CH:18]=1
Reactant: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](F)[C@@H]1O
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1F
Yield: 85 %

Procedure:
2-Bromo-5,6-dichloro-1-(2,5-dideoxy-2-fluoro-beta-D-ribofuranosyl)-1H-benzimidazole (0.075 g, 0.2 mmoles) was heated in a solution of isopropylamine (Fluka, 2 mL) and absolute ethanol (6 mL) in a 90° C. oil bath for 18 hrs. The solvents were removed in vacuo. The residue was partitioned between water and ethyl acetate. The ethyl acetate solution was dried with MgSO4, filtered and solvent removed in vacuo to give the product (0.06 g) in 85% yield. MS (APCl+): m+1/z, 362; 1H NMR (DMSO-6) δ7.39 (s, 1H, Ar—H), 7.18 (s, 1H, Ar—H), 6.94 (d, 1H, NH, J=7 Hz), 6.09 (d, 1H, H-1′, J=19 Hz), 5.72 (d, 1H, OH-3′, J=6 Hz), 5.26 (d, 1H, H-2′, J=53 Hz), 3.9 (m, 3H,), 1.35 (d, 3H, H-5′, J=6 Hz), 1.18 (m, 6H, CH3).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:13])[C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1.CS(C)=O.Cl[CH2:19][CH:20]=[CH2:21]>O>[CH2:21]([O:13][C:6]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=[C:4]([CH3:3])[CH:5]=1)[CH:20]=[CH2:19]
Reactant: C=CCCl
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOc1cc(C)ccc1[N+](=O)[O-]

Procedure:
A solution of 26.1 g of sodium hydroxide in 50 ml of water was added drop-by-drop over 5 minutes to a stirred mixture of 100 g of 3-methyl-6-nitrophenol, 400 ml of dimethyl sulfoxide (DMSO) and 53.6 g of 3-chloropropene initially at room temperature. The temperature of the mixture rose to 43° C. The mixture was heated at 90°-110° C. for two hours, poured into water and filtered, to give 1-(2-propenyloxy)-3-methyl-6-nitrobenzene (1A), as a light yellow solid, m.p.: 30°-32° C.
Reaction SMILES: NC1C=C2C(CCC(C)(C)N2)=CC=1.[CH2:14]([C:16]1([CH2:29][CH3:30])[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][C:20]([N+:26]([O-])=O)=[CH:21][CH:22]=2)[NH:17]1)[CH3:15]>CCOC(C)=O.CCO.[Pd]>[NH2:26][C:20]1[CH:19]=[C:18]2[C:23]([CH2:24][CH2:25][C:16]([CH2:29][CH3:30])([CH2:14][CH3:15])[NH:17]2)=[CH:22][CH:21]=1
Reactant: CCC1(CC)CCc2ccc([N+](=O)[O-])cc2N1
Agent: [Pd]
Agent: CC1(C)CCc2ccc(N)cc2N1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC1(CC)CCc2ccc(N)cc2N1
Yield: 93.8 %

Procedure:
This compound was prepared in a manner similar to that described for 7-amino-1,2,3,4-tetrahydro-2,2-dimethylquinoline (structure 19 of Scheme III, where R1=R2=Me) from for 2,2-diethyl-1,2,3,4-tetrahydro-7-nitroquinoline (0.311 g, 1.33 mmol) and 10% Pd/C (31 mg, 10% by weight) in EtOAc (4.0 mL) and EtOH (4.0 mL) to afford 255 mg (94%) of 7-amino-2,2-diethyl-1,2,3,4-tetrahydroquinoline. Data for 7-amino-2,2-diethyl-1,2,3,4-tetrahydroquinoline: Rf 0.26 (4:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) 6.77 (d, J=7.9H, 1H), 6.12 (dd, J=7.9,1.9,1H), 6.05 (d,J=2.0,1H), 4.68 (broad s,3H), 2.62 (t, J=6.7, 2H), 1.67 (t, J=6.7, 2H), 1.38-1.55 (m, 4H), 0.85 (t, J=7.4, 6H). P 2,2-Diethyl-7-fluoro-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyridono[5,6-g]quinoline (Compound 120, Structure 20 of Scheme III, where R1, R2=Et, R3=trifluoromethyl, R4=F)
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:8][CH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[C@H:23]([OH:24])[C@H:22]([OH:25])[C@@H:21]([CH2:26][O:27][CH3:28])[O:20]2)=[C:12]([NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:11]=1>N1C(C)=CC=CC=1C>[OH:24][C@@H:23]1[C@H:22]([OH:25])[C@@H:21]([CH2:26][O:27][CH3:28])[O:20][C@H:19]1[N:16]1[CH:15]=[N:14][C:13]2[C:17]1=[N:18][C:10]([CH2:9][NH:8][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[N:11][C:12]=2[NH:29][CH2:30][CH:31]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: Cc1cccc(C)n1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)C(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.7 %

Procedure:
Isopropylsulphonyl chloride (120 mg, 0.84 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (408 mg, 0.8 mmol) (example 1) in 2,6-lutidine (10 ml). The mixture was stirred at room temperature for 24 hr followed by stirring at 50° C. for a further 5 days. A second portion of isopropylsulphonyl chloride (120 mg, 0.84 mmol) and lutidine (4 ml) were added and the reaction stirred at 50° C. for 24 hr. A third portion of isopropylsulphonyl chloride (120 mg, 0.84 mmol) was added and heating at 50° C. continued for a further 24 hr. At the end of this period the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and aqueous ammonia. The organic phase was separated and the solvent removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (98:2:0.1) increasing to dichloromethane:methanol:ammonia (96:4:0.2). This gave the title compound (118 mg) as an oil. MS: 597 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[N:6][C:7]=1[CH:8]=[N:9][C@H:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([OH:13])[CH3:12].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)=[N:6][C:7]=1[CH2:8][NH:9][C@H:10]([CH:14]([CH3:15])[CH3:16])[CH:11]([OH:13])[CH3:12]
Reactant: CC(C)[C@@H](N=Cc1nc(-c2ccc(C(F)(F)F)nc2)ccc1F)C(C)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H](NCc1nc(-c2ccc(C(F)(F)F)nc2)ccc1F)C(C)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
Example 28A (399 mg, 1.477 mmol) and Example 107B (238 mg, 1.551 mmol) were dissolved in methanol (20 mL) and triethylamine (0.225 mL, 1.624 mmol). The orange solution was stirred at ambient temperature for 1 hour and 55 minutes, followed by the addition of sodium borohydride (123 mg, 3.25 mmol). After 4 hours, additional sodium borohydride (123 mg, 3.25 mmol) was added, and the reaction was stirred overnight at ambient temperature, quenched with 100 mL 1.0 N NaOH, and extracted twice with 100 mL dichloromethane. The combined organic phase was dried over Na2SO4, filtered, and concentrated to provide (3R)-3-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methylene}amino)-4-methylpentan-2-ol (500 mg, 1.354 mmol) as an orange oil. The imine (500 mg, 1.354 mmol) in methanol (20 mL) was added to 5% palladium on carbon (100 mg) in a 250 mL stainless steel pressure bottle. The mixture was pressurized with hydrogen (30 psi), and stirred for 18 hours at ambient temperature. The mixture was filtered through a nylon membrane, concentrated to a yellow oil, and chromatographed on a Grace Reveleris 40 g column, eluted with 0-50% EtOAc in dichloromethane (30 mL/min) to provide the title compound (250 mg, 0.673 mmol, 49.7% yield) as a yellow oil, a 3:1 mix of diastereomers by proton NMR. MS (ESI+) m/z 372.0 (M+H); 1H NMR (300 MHz, MeOH-D4) δ 9.39 (d, J=1.8, 1H), 8.71-8.64 (m, 1H), 8.02 (dd, J=8.6, 3.6, 1H), 7.92 (d, J=8.3, 1H), 7.76-7.66 (m, 1H), 4.27-4.04 (m, 2H), 3.95-3.86 (m, 0.25H), 3.83-3.73 (m, 0.75H), 2.37 (t, J=5.6, 0.25H), 2.27 (dd, J=6.1, 4.6, 0.75H), 2.00-1.88 (m, 1H), 1.25-1.18 (m, 3H), 1.08-1.01 (m, 3H), 1.00-0.93 (m, 3H).
Reaction SMILES: BO[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([CH3:16])([CH3:15])[O:13][C:12]([NH:17][C@H:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[N:11][S:10]2(=[O:37])=[O:36])=[CH:5][CH:4]=1.[C:38]([O-])(=[O:40])[CH3:39].[K+].C(Cl)(=O)C>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Si:22]([O:21][CH2:20][CH2:19][C@H:18]([NH:17][C:12]1[O:13][C:14]([CH3:15])([CH3:16])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:38](=[O:40])[CH3:39])=[CH:8][CH:7]=2)[S:10](=[O:37])(=[O:36])[N:11]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: BOc1ccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3F)=NS2(=O)=O)cc1
Agent: Cl[Pd]Cl
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3F)=NS2(=O)=O)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a suspension of [5-(4-boroxyphenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propyl]amine (400 mg) and potassium acetate (140 mg) in dioxane (6 ml) were added bis(triphenylphosphine)palladium(II)dichloride (60 mg) and acetyl chloride (120 μl), and the mixture was stirred at 50° C. overnight. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (172 mg) with a molecular weight of 562.8 g/mol (C28H39FN2O5SSi).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][NH:16][CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:25]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>C(#N)C>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C@H:25]([N:16]2[CH2:15][CH:14]([C@@H:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[C:10]([F:13])([CH3:12])[CH3:11])[CH2:17]2)[C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:39][CH:38]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of the crude amine from Step 1 and 3.4 g (1.1 mmole) of Cs2CO3 in 10 mL dry acetonitrile was stirred at rt in a flask fitted with a small Dean-Stark trap. After 15 minutes, 2.3 g (7.5 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile was added and the mixture was heated at 60° C. After 18 h, the solution was filtered through CELITE, and the residue was washed with acetonitrile. The combined filtrates were concentrated and the residue was purified by flash chromatography using a step gradient of 5 to 20 % ethyl acetate-hexane. Fractions containing the faster product diastereomer were pooled and concentrated to afford the title compound; 1H-NMR(CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H1), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H1), 4.24 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 8H); Mass Spectrum: mi/e=469 (M+1, 35Cl) and 471 (M+1, 37Cl).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[CH:14][N:15]([CH3:17])[CH3:16])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(Br)ccc1C(N)=O
Product: Cc1cc(Br)ccc1C(=O)N=CN(C)C
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.84 g of 4-bromo-2-methyl benzoic acid amide and 18 mL of N,N-dimethylformamide dimethylacetal was stirred at 70° C. for 30 minutes. After the completion of the reaction, the solvent was distilled off-under reduced pressure, and the residue was washed with 5 mL of hexane to obtain 0.67 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl.[H-].[Na+]>CN(C=O)C>[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31][N:3]1[C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]1[CH3:1]
Reactant: COCCOCCl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCN1C(C)=C(C(=O)OC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Temperature: 25 °C

Procedure:
The presently preferred method for preparing compounds of the invention is set forth in Scheme VI. An intermediate dihydropyridine diester derivative of formula 16 is prepared by means known in the art, e.g., by following the Hantzch method (Ann. Chim., 215, 1 (1882)), using reactants selected to provide the desired R1, R2, R3, X1, and X2 substitutions. The diester is then N-protected by mixing with a slight molar excess (preferably between 1.1 and 1.3 moles per mole of compound of formula 16) α-alkoxy-ω-chloromethoxyalkane and a slight molar excess (about 1.2 mol/mol 16) of a suitable strong base, preferably NaH, in a polar, aprotic solvent (preferably DMF or DMSO) at -10° to 0° C. for between about 60 and about 100 minutes, followed by warming to about room temperature for between about 50 and 200 minutes (preferably about 60 minutes), to produce an N-protected diester of formula 17. For example, 1 mol 2,6-dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine is reacted with 1.2 mol 1-methoxy-2-chloromethoxyethane and 1.2 mol NaH in DMF at -10° C. for 1 hour, then allowed to warm to about 25° C. for 1 hour to produce 1-(2-methoxyethoxy)methyl-2,6-dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine (17). (Scheme VI, Step 1)
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:38])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:37])[C@H:13]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[NH:14][C:15](OC(C)(C)C)=[O:16])[CH:2]([CH3:4])[CH3:3].Cl.C(N1CCOCC1)C.[C:48]12([CH2:58]C(Cl)=O)[CH2:57][CH:52]3[CH2:53][CH:54]([CH2:56][CH:50]([CH2:51]3)[CH2:49]1)[CH2:55]2>C(OCC)(=O)C>[CH2:1]([NH:5][C:6](=[O:38])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:37])[C@H:13]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[NH:14][C:15](=[O:16])[CH2:58][C:48]12[CH2:57][CH:52]3[CH2:51][CH:50]([CH2:56][CH:54]([CH2:53]3)[CH2:55]1)[CH2:49]2)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
2.72 g (0.005 mol) of Nα -tert.butoxycarbonyl-Nε -benzyloxycarbonyl-L-lysyl-L-proline isobutylamide were treated with 15 ml of 2.5M hydrogen chloride in ethyl acetate at room temperature for 0.75 hour. The solvent was removed by evaporation and the solid was washed with diethyl ether. The solid was taken up in 15 ml of dimethylformamide and the solution was cooled to 0° C. 1.27 ml (0.01 mol) of N-ethylmorpholine and 1.3 g (0.006 mol) of 1-adamantaneacetyl chloride were added and the mixture was stirred at room temperature for 3 hours. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate/water. The organic solution was washed with 5% citric acid solution, water, 5% sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated. Chromatography on 60 g of silica gel using ethyl acetate for the elution yielded 0.9 g (29%) of Nα -(1-adamantaneacetyl)-Nε -benzyloxycarbonyl-L-lysyl-L-proline isobutylamide as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]3)=[CH:4][C:3]=2[CH3:21])=[N:24][CH:25]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1Nc1ccc(Br)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
tert-Butyl (RS)-2-(6-amino-5-methylpyridin-3-yl)morpholine-4-carboxylate (60 mg), 2,5-dibromopyridine (72.7 mg, CAS 624-28-2) and cesium carbonate (100 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (14.1 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (12.6 mg) were then added. The reaction mixture was then capped and stirred at 100° C. overnight and then at 120° C. for 2 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 100% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-(5-bromopyridin-2-ylamino)-5-methylpyridin-3-yl)morpholine-4-carboxylate (26 mg, 28%) as a yellow amorphous solid. MS (ISP): 451.1 ([{81Br}M+H]+), 449.1 ([{79Br}M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4]([F:11])[CH:3]=1.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:19]\[NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH3:9])=[C:4]([F:11])[CH:3]=1.[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:19]/[NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH3:9])=[C:4]([F:11])[CH:3]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1ccc(Br)cc1F
Solvent: CCO
Product: C/C(=N/Nc1ccccc1)c1ccc(Br)cc1F
Product: C/C(=N\Nc1ccccc1)c1ccc(Br)cc1F

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 1-(4-bromo-2-fluorophenyl)ethanone (17 g, 78.34 mmol, 1.00 equiv) in ethanol (200 mL), 1-phenylhydrazine (8.5 g, 78.70 mmol, 1.00 equiv), TSA-H2O (740 mg, 3.89 mmol, 0.05 equiv). The resulting solution was heated to reflux for 2 h in an oil bath, then concentrated under vacuum to yield (Z)-1-(1-(4-bromo-2-fluorophenyl)ethylidene)-2-phenylhydrazine and (E)-1-(1-(4-bromo-2-fluorophenyl)ethylidene)-2-phenylhydrazine as a yellow solid. MS (m/z): 307 [M+H]+
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1[CH2:18]Br.[H-].[Na+].O>CN(C)C=O.ClCCl>[C:1]1([S:7]([N:10]2[CH2:18][C:17]3[S:16][CH:15]=[N:14][C:13]=3[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ncsc1CBr
Reactant: NS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)N1Cc2ncsc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
Benzenesulfonamide (638 mg) and 4,5-bis(bromo-methyl)thiazole (1.10 g) were dissolved in dimethylformamide (10 ml), 60% sodium hydride in oil (357 mg) was added at a time, and the mixture was stirred at room temperature for 3 hours. Water and dichloromethane were added to conduct liquid separation. After the resultant oil layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by column chromatography on silica gel (dichloromethane:ethylacetate=9:1) to obtain the title compound (137 mg) as colorless powder.