Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[C:15](O)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.OP(O)(O)=O.ClC1C=CC(C(OC(C)C)=O)=CN=1>ClCCl.O.CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)O
Agent: CC(C)OC(=O)c1ccc(Cl)nc1
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Reaction time: 14 h

Procedure:
A mixture of 6-chloronicotinic acid (12.0 g, 76 mmol) and thionyl chloride (65 mL) was heated at reflux for 3.0 h. The excess thionyl chloride was removed under reduced pressure, and the residual liquid was diluted with dichloromethane (20 mL) and then added to a solution of tert-butyl alcohol (71 mL, 760 mmol) in dichloromethane (40 mL). To the mixture was added triethylamine (31.7 mL, 760 mmol) and N,N-dimethylpyridine (0.5 g, 4.0 mmol), and the reaction mixture was stirred overnight (14 h) at reflux under nitrogen. The solution was diluted with dichloromethane (200 mL), washed with a saturated aqueous solution of sodium bicarbonate (3×100 mL), washed with water (3×100 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure provided Preparation 3 (11.4 g, 70.3%) as a yellow solid. The product had an analytical HPLC retention time=3.18 min. (Column: YMC ODS 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4) and a LCMS M+1=214. The purity of the product was about 96%. The major impurity was the iso-propyl 6-chloronicotinate with an analytical HPLC retention time=2.88 min. and a LC/MS M+1=200.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O>C(O)C.O.[Fe]>[Cl:3][C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Yield: 89.9 %

Procedure:
To a refluxing mixture of iron powder (2.68 g, 48.4 mmol) and ammonium chloride (323 mg, 6.05 mmol) in ethanol (45 mL) and water (8 mL) was added 1-(2,4-dichlorophenoxy)-2-nitrobenzene (AMR01025, 2.5 g, 8.8 mmol) and the resulting mixture was stirred at reflux for 2 h. After removal of the solvent, the residue was diluted in aqueous sodium hydrogen carbonate (40 mL) and extracted with DCM (3×20 mL). The organic layer was dried (MgSO4), filtered and evaporated to give 2-(2,4-dichlorophenoxy)phenylamine (2.01 g, 90%) as a colorless oil which was used in the next step without further purification. Rf: 0.56 (DCM) 1H NMR (400 MHz, CDCl3) δ 3.85 (2H, br s, NH2), 6.75 (1H, m, ArH), 6.84 (1H, d, J=8.8 Hz, ArH), 6.84 (1H, dd, ArH), 6.87 (1H, dd, J=7.6, 1.6 Hz, ArH), 7.04 (1H, m, ArH), 7.17 (1H, dd, J=8.8, 2.4 Hz, ArH) and 7.49 (1H, d, J=2.4 Hz, ArH).
Reaction SMILES: ClCC1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35](O)[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1.[NH:40]1[CH:44]=[C:43]([CH2:45][O:46]C2C=C(N3CCOCC3)C=CC=2)[N:42]=[CH:41]1>>[NH:40]1[CH:44]=[C:43]([CH2:45][O:46][C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[N:42]=[CH:41]1
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: c1cc(OCc2c[nH]cn2)cc(N2CCOCC2)c1
Agent: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: c1ccc(N2CCOCC2)c(OCc2c[nH]cn2)c1

Procedure:
In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 3-morpholinophenol and converted to 4-[3-(1H-imdazol-4-ylmethoxy)-phenyl]-morpholine as a white solid. MS (ISP): 260.3 ([M+H]+)
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([N:18]=[N+:19]=[N-:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22](C)=O>>[CH:1]([N:14]1[CH2:15][CH:16]([N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)[CH2:17]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)=O
Reactant: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Product: c1ccc(C(c2ccccc2)N2CC(n3ccnn3)C2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of 1.05 g (3.98 mmol) of N-benzhydryl-3-azidoazetidine in 50 ml of acetone cooled to -78° C. in a steel reaction vessel was bubbled 36 g of acetylene. The sealed reaction vessel after warming up to room temperature was heated at 80° C. for 17 hr. The solution was then cooled to room temperature, filtered and evaporated to yield the crude product which after chromatography over silica gel (2.5% methanol chloroform) yielded 0.88 g (76%) of the desired product as a solid, m.p. 167°-168° C. 1H NMR (CDCl3) δ: 7.88 (S, 1H), 7.73 (S, 1H), 7.55-7.07 (m, 10H), 5.35-5.1 (m, 1H), 4.53 (S, 1H), 3.76 (t, 2H), 3.5 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH2:14][OH:15]>CCO>[NH2:13][C:12](=[N:14][OH:15])[C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C#N)ccc1Cl
Reactant: NO
Solvent: CCO
Product: COC(=O)c1cc(C(N)=NO)ccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
Methyl 2-chloro-5-cyanobenzoate (1.55 g; 7.92 mmol; 1 eq.) was suspended in EtOH (31 mL). Hydroxylamine (1.17 mL; 39.62 mmol; 5 eq.) was added in one portion. The reaction mixture was stirred at RT for 6 hours. The mixture was concentrated affording the title compound as a beige solid (1.65 g, 91%). 1H NMR (DMSO-d6, 300 MHz) δ 9.92 (br s, 1H), 8.19-8.18 (m, 1H), 7.92-7.90 (m, 1H), 7.68-7.65 (m, 1H), 6.04 (br s, 2H), 3.95 (s, 3H). LC/MS (Method B): 229.0 (M+H)+; 227.0 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:27])[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]=[CH2:19])[CH:13]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:27])[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][CH3:19])[CH:13]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1cc(-c2c(CCCCC(=O)O)c(C)nn3c(CC)ccc23)ccn1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(-c2c(CCCCC(=O)O)c(C)nn3c(CC)ccc23)ccn1
Reaction time: 6 h
Yield: 92.8 %

Procedure:
A solution of 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (15 mg) in MeOH was added 10% Pd/C (2 mg). The mixture was stirred under hydrogen atomosphere (1 atm) for 6 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was triturated with hexane to give 5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (14 mg) as an yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.Cl>>[ClH:9].[NH:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1ccccc1N
Reactant: Clc1nc2ccccc2[nH]1
Agent: Cl
Product: Cc1ccccc1Nc1nc2ccccc2[nH]1
Reaction time: 2 h
Yield: 9.1 %

Procedure:
2-Methylaniline (0.5 g) and 2-chlorobenzimidazole (0.71 g) were mixed in a flask and then kept at 250° C. for 2 h. After cooling, the residue was dissolved out of the flask at boiling heat using 1 N HCl, the insoluble material was filtered off with suction, and the filtrate was evaporated. The residue was purified by means of preparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). The clean fractions were combined, the acetonitrile was stripped off, the residue was rendered alkaline using potassium carbonate solution, extracted three times with EA, and the combined phases were then dried, filtered, and concentrated. The residue was taken up using 2 N HCl and the solution was freeze-dried. 110 mg of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[N:7]=1
Reactant: c1nc[nH]n1
Reactant: COc1cc(C)nc(Cl)n1
Solvent: C1CCOC1
Product: COc1cc(C)nc(-n2cncn2)n1
Yield: 48.2 %

Procedure:
In anhydrous tetrahydrofuran, 159 mg of 2-chloro-4-methoxy-6-methylpyrimidine was substituted with 69 mg of 1,2,4-triazole. The reaction mixture was treated according to the procedure as in Example 5 to yield 92 mg of 4-methoxy-6-methyl-2-(1,2,4-triazol-1-yl)-pyrimidine, recrystallized from n-hexane, having a melting point of 142.5°-143° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]([O:24]CC)=[O:23])[CH:13]=3)[S:10][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[OH-].[Na+].Cl>COCCOC>[F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]([OH:24])=[O:23])[CH:13]=3)[S:10][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: CCOC(=O)Cn1cc(Cc2nc3c(F)c(F)cc(F)c3s2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C(O)Cn1cc(Cc2nc3c(F)c(F)cc(F)c3s2)c2ccccc21
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A solution of give 3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid, ethyl ester (5.91 g, 14.6 mmol) in 1,2-dimethoxyethane (73 mL, 0.2 M) was cooled to 0° C. and treated with aq. NaOH (1.25 N, 58 mL, 73.1 mmol) in a dropwise manner over 15 min. After the addition was complete, the solution was stirred for an additional 30 min, acidified to pH 3 with 2N HCl, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed with sat'd. aq. NaCl (30 mL). The organic extract was dried over Na2SO4, filtered and concentrated. The resulting material was stirred as a suspension in heptane, filtered and dried to give 3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid (5.38 g, 98%) as a pale yellow solid: mp 177-178° C.; Rf 0.44 (20% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 7.74-7.65 (m, 1 H), 7.53 (d, J=7.5 Hz, 1 H), 7.46 (s, 1 H), 7.40 (d, J=8.1 Hz, 1 H), 7.15 (b t, J=6.9 Hz, 1 H), 7.03 (b t, J=7.2 Hz, 1 H), 5.03 (s, 2 H), 4.65 (s, 2 H); LRMS calcd for C18H11F3N2O2S: 376.4; found 375.0 (M−1)−. Anal. Calcd for C18 H11F3N2O2S: C, 57.44; H, 2.95; N, 7.44; S, 8.52. Found C, 57.58; H, 2.99; N, 7.38; S, 8.51.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH:22]([N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1)([CH3:24])[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH:22]([CH3:24])[CH3:23])[N:26]=2)[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=1
Reactant: CC(C)n1ccc(N)n1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)n1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Temperature: 110 °C
Yield: 92.5 %

Procedure:
A mixture of 5A (80 mg, 0.245 mmol), 1-isopropyl-1H-pyrazol-3-amine (36.8 mg, 0.294 mmol), Pd2(dba)3 (11.23 mg, 0.012 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (7.10 mg, 0.012 mmol) and Cs2CO3 (160 mg, 0.491 mmol) in dioxane (2.0 mL) was degassed with argon. The mixture was heated at 110° C. under a nitrogen atmosphere overnight. After cooling to room temperature, the mixture was concentrated to remove dioxane and then water was added. The resulting precipitate was collected by filtration, rinsed with water and dried to give crude 48A (94 mg, 92%) as a dark brown solid. HPLC Rt=3.416 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=415.
Reaction SMILES: C(N(CC)CC)C.Cl[Si:9]([CH3:12])([CH3:11])[CH3:10].[CH:13]([O:16][C:17]1[C:18]([OH:27])([CH3:26])[C:19](=[O:25])[C:20]=1[O:21][CH:22]([CH3:24])[CH3:23])([CH3:15])[CH3:14]>C(OCC)C>[CH:13]([O:16][C:17]1[C:18]([O:27][Si:9]([CH3:12])([CH3:11])[CH3:10])([CH3:26])[C:19](=[O:25])[C:20]=1[O:21][CH:22]([CH3:23])[CH3:24])([CH3:15])[CH3:14]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)OC1=C(OC(C)C)C(C)(O)C1=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)OC1=C(OC(C)C)C(C)(O[Si](C)(C)C)C1=O
Reaction time: 18 h
Yield: 94.2 %

Procedure:
Triethylamine (28 mL, 0.20 mol) and chlorotrimethylsilane (13 mL, 0.10 mol) were successively added to a stirred solution of 3,4-diisopropoxy-2-hydroxy-2-methylcyclobut-3-ene-1-one (14.3 g, 0.0667 mol) in diethyl ether (250 mL). The mixture was allowed to stir at ambient temperatures for 18 hrs. The mixture was filtered through SiO2 contained in a sintered glass funnel. The filter cake was washed with additional diethyl ether. The ether was removed to leave 3,4-diisopropoxy-2-trimethylsilyloxy-2-methylcyclobut-3-ene-1-one (18 g, 94% yield) as a clear oil. Trimethylsilyl trifluoromethanesulfonate (150 μL, 0.78 mmol) was added to a stirred solution of the silyl ether (18 g, 0.0628 mol) and 1,2-bis(trimethylsilyloxy)ethane (16.2 mL, 0.066 mmol) in tetrahydrofuran (36 mL). The solution was stirred for 1 hr at 22° C. and additional trimethylsilyl trifluoromethanesulfonate (150 μL) was then added. The solution was stirred for an additional 0.25 hr and was concentrated to dryness. The residue was flash chromatographed on SiO2 (200 g) with diethyl ether-hexanes (1:1) to afford 2,2-ethylenedioxy-3-isopropoxy-4-methylcyclobut-3-ene-1-one (9 g, 73% yield) as a
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]([OH:11])=O)=[O:6])[CH:2]=[CH2:3].C(Cl)(=O)C([Cl:15])=O.CN(C)C=O>O1CCCC1>[CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]([Cl:15])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)OCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCOC(=O)OCC(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A solution of 2-(allyloxycarbonyloxy)acetic acid (3.03 g, 18.9 mmol) obtained from Example 39-(3) in tetrahydrofuran (30 ml) was cooled to 0° C., and to the solution were added oxalyl chloride (2.64 g, 20.8 mmol) and N,N-dimethylformamide (30 μl). The mixture was warmed to room temperature. After the mixture was stirred for 30 minutes, the solvent was distilled off under reduced pressure, and the resulting residue was purified using simple distillation under reduced pressure to give the title compound (3.04 g, yield 90%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[O:35]1[CH2:37][CH2:36]1>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][N:1]([CH2:37][CH2:36][OH:35])[CH:5]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CO1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Product: OCCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 71 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and oxirane, 152 was obtained as a light yellow solid (102 mg, 71%) over two steps. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.941-8.942 (d, J=0.5 Hz, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.57-7.60 (t, J=16 Hz, 1H), 7.22-7.26 (t, J=20.5 Hz, 1H), 6.36-6.37 (d, J=8 Hz, 1H), 4.30-4.32 (t, J=9.5 Hz, 2H), 4.05-4.07 (t, J=9.5 Hz, 2H), 3.77-3.82 (m, 4H), 3.11-3.13 (t, J=10.5 Hz, 2H), 2.88-2.91 (t, J=11.5 Hz, 2H), 2.26 (s, 2H), 1.97-2.01 (m, 2H); MS (ESI) m/z: 405 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][C:8]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:12][C:11]([NH:13]C(=O)C(C2C=CC=CC=2)C)=[N:10][N:9]1[C:24](=[O:27])[CH2:25][CH3:26])(=[O:4])=[O:3].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>>[NH2:13][C:11]1[S:12][C:8]([CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:9]([C:24](=[O:27])[CH2:25][CH3:26])[N:10]=1
Reactant: CCC(=O)N1N=C(NC(=O)C(C)c2ccccc2)SC1(CCNS(C)(=O)=O)c1ccccc1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Product: CCC(=O)N1N=C(N)SC1(CCNS(C)(=O)=O)c1ccccc1
Yield: 67.1 %

Procedure:
In the same manner as that in Step 2 of Reference Example 20, from the one diastereomer of N-[5-(2-methanesulfonylaminoethyl)-5-phenyl-4-propionyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2-phenylpropanamide (4.41 g, 9.03 mmol) eluted later obtained in Step 1 mentioned above, cerium chloride heptahydrate (3.37 g, 9.05 mmol) and sodium borohydride (3.42 g, 90.5 mmol), optically active N-[2-(5-amino-2-phenyl-3-propionyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl]methanesulfonamide (2.16 g, 67%) was obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:14][C:15]1[C:16]([C:23](O)=[O:24])=[N:17][C:18]([Cl:22])=[C:19]([NH2:21])[N:20]=1>>[NH2:14][C:15]1[C:16]([C:23]([NH:13][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:24])=[N:17][C:18]([Cl:22])=[C:19]([NH2:21])[N:20]=1
Reactant: Nc1cnccc1N1CCCCC1
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Product: Nc1nc(N)c(C(=O)Nc2cnccc2N2CCCCC2)nc1Cl
Yield: 76 %

Procedure:
Following method 11, 4-(piperidin-1-yl)pyridin-3-amine was coupled to 3,5-diamino-6-chloropyrazine-2-carboxylic acid yielding 3,5-diamino-6-chloro-N-(4-(piperidin-1-yl)pyridin-3-yl)pyrazine-2-carboxamide (76%). LCMS (m/z): 347.8 (MH+); LC Rt=2.17 min.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)=[CH:9][N:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[CH:17]=[N:16][N:15]=1)[N:7]=3>C(#N)C.[Pd]>[CH:19]([N:18]1[CH:17]=[N:16][N:15]=[C:14]1[N:8]1[N:7]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[CH:2][CH:23]=[CH:22][C:5]=32)=[CH:9]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1cnnc1-n1cc2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd]
Solvent: CC#N
Product: CC(C)n1cnnc1-n1cc2c(n1)-c1ccccc1OCC2
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Alternatively, a degassed solution of 8-bromo-2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (122 mg, 0.326 mmol) in IMS (10 mL) was added 10% Pd/C (15 mg), the reaction mixture stirred under an atmosphere of hydrogen for 1 h before the reaction mixture was filtered and the filtrate concentrated in vacuo. The resultant residue was dissolved in DCM and the solution washed with water, the organic layer dried (Na2SO4), filtered and concentrated in vacuo to give a residue. The residue was dissolved in acetonitrile and water and the solution freeze dried to give 2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene as a white solid (54 mg, 56%). 1H NMR (400 MHz, CDCl3): δ 8.27-8.23 (m, 2 H); 8.12 (t, J=1.02 Hz, 1 H); 7.30-7.24 (m, 1 H); 7.14-7.06 (m, 2 H); 5.38-5.29 (m, 1 H); 4.36 (t, J=5.10 Hz, 2 H); 3.16 (td, J=5.10, 1.06 Hz, 2 H); 1.63-1.54 (d, J=6.59 Hz, 6 H). LCMS: RT=10.29 min, M+H+=296
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)[CH3:2].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[C:36]([F:39])([F:38])[F:37])[NH:32][CH2:31][CH2:30]2>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:15][C:16]([N:32]2[C:33]3[C:29](=[CH:28][C:27]([O:26][CH3:25])=[C:35]([C:36]([F:38])([F:39])[F:37])[CH:34]=3)[CH2:30][CH2:31]2)=[O:24])[CH:4]=1)[CH3:2]
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2cccnc2)c1
Solvent: CN(C)C=O
Product: CCc1cc(NC(=O)N2CCc3cc(OC)c(C(F)(F)F)cc32)cc(-c2cccnc2)c1
Yield: 41.9 %

Procedure:
The title compound (0.15 g, 40%) was prepared as a tan powder using the methodology of Example 28 from phenyl N-(3-ethyl-5-(pyrid-3-yl)phenyl carbamate (D30) (0.26 g, 0.81 mmol) and 5-methoxy-6-trifluoromethyl indoline (D11) (0.177 g, 0.81 mmol) in DMF (10 ml). Melting point: 205° C.-207° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12.Cl.O1CCOCC1.[I-:28].[Na+]>O1CCCC1>[I:28][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of ethyl (4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate (10 g; 32.3 mmol) in tetrahydrofurane (100 ml) at room temperature was slowly added a 4N solution of hydrochloric acid in dioxane (56.5 mL; 226 mmol). The mixture was stirred at 60° C. for 1 h and then concentrated under reduced pressure. The residue was dissolved in acetonitrile (75 mL), sodium iodide (38.7 g; 258 mmol) was added and the mixture was heated at reflux for 48 h. The volatiles were removed under reduced pressure, the residue dissolved in ethyl acetate and was successively washed with water, a solution of sodium thiosulphate, water and brine. The organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford 10.83 g (71%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14])=O.S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([Cl:22])=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1c(F)cncc1F)c1c(Cl)cccc1Cl
Product: Fc1cncc(F)c1N=C(Cl)c1c(Cl)cccc1Cl
Temperature: 85 °C
Reaction time: 26 h

Procedure:
A stirred suspension of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-benzamide (14.5 g, 47.8 mmol) in thionyl chloride (130 mL) was heated at 85° C. for 20 hours and then at 90° C. for 26 hours under argon. After cooling to room temperature, the volatiles were removed under reduced pressure, azeotroped with toluene (×3) to afford the title compound as a yellow solid (15.7 g, quantitative). LCMS (Method D): RT=4.16 min, m/z: 321 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:17](O)=[O:18])[CH:8]=[CH:9][C:10]=1[C:11]2=[O:16].COC1C=CC=C2C=1OC1C=C(C(O)=O)C=CC=1C2=O.[CH2:40]([N:42](CC)[C:43]([C:45]1C=CC2CC3C(OC=2C=1)=CC=CC=3)=O)[CH3:41]>>[CH2:40]([N:42]([CH2:43][CH3:45])[C:17]([C:7]1[CH:8]=[CH:9][C:10]2[C:11](=[O:16])[C:12]3[C:3]([O:4][C:5]=2[CH:6]=1)=[C:2]([Br:1])[CH:15]=[CH:14][CH:13]=3)=[O:18])[CH3:41]
Reactant: O=C(O)c1ccc2c(=O)c3cccc(Br)c3oc2c1
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2
Agent: COc1cccc2c(=O)c3ccc(C(=O)O)cc3oc12
Product: CCN(CC)C(=O)c1ccc2c(=O)c3cccc(Br)c3oc2c1

Procedure:
Using an adaptation of the method described in Procedure 16, substituting 5-bromo-9-oxo-9H-xanthene-3-carboxylic acid, 3d for 5-methoxy-9-oxo-9H-xanthene-3-carboxylic acid, 3c, title compound 5-bromo-9-oxo&9H-xanthene-3-carboxylic acid diethylamide, 4d was obtained. MS m/z (MH+) 374/375.8.