Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:28]1([CH2:37][C:38](O)=[O:39])[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]1=[O:30]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:38](=[O:39])[CH2:37][N:28]1[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]1=[O:30])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccccc2[N+](=O)[O-])s1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccccc2[N+](=O)[O-])s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13. 1H NMR (400 MHz; DMSO-d6) δ 11.29 (s, 0.6H), 11.28 (s, 0.4H), 9.21 (brs, 0.6H), 9.10 (brs, 0.4H), 8.26–8.21 (m, 1H), 7.97–7.89 (m, 3H), 7.33 (d, 0.6H), 7.26 (d, 0.4H), 4.68 (s, 1.2H), 4.45 (s, 0.4H), 4.33 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (q, 1.2H), 4.07 (s, 1.2H), 3.59 (t, 1.2H), 3.47–3.40 (m, 2H), 3.28 (t, 0.8H), 1.74 (s, 3H), 1.24 (t, 1.2H), 1.18 (t, 1.8H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[S:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH3:29])=[CH:23]3)[CH:11]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)[CH:11]=2)=[CH:2]1
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Reactant: OB(O)c1ccoc1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccoc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 3-furanboronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to Example 2 above. 1H NMR (400 MHz, CD3OD) δ8.02 (d, 1H), 7.91 (s, 1H), 7.53 (m, 1H), 7.35 (s, 1H), 7.31 (d, 1H), 7.27 (d, 1H), 6.94 (dd, 1H), 6.77 (m, 1H), 6.54 (d, 1H), 6.10 (s, 1H), 2.40 (s, 3H), RP18-HPLC RT: 5.39 minutes; API MS: 346 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[OH:12].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:16][CH2:15][O:12][C:4]2[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[NH2:9])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: COc1ccc(N)cc1OCCN1CCOCC1

Procedure:
The title compound was prepared from 2-methoxy-5-nitrophenol and 4-(2-chloroethyl)morpholine hydrochloride using a similar procedure to Descriptions 1 and 2 (63%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[N:5][N:4]=[N:3]1.CCCCCCC.CCO>C(#N)C>[CH3:1][N:2]1[C:6]([C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C1CC(c2cc(=O)[nH]o2)CCN1C(=O)OCc1ccccc1
Solvent: CCCCCCC
Solvent: CC#N
Solvent: CCO
Product: Cn1nnnc1[C@H]1C[C@@H](c2cc(=O)[nH]o2)CCN1C(=O)OCc1ccccc1
Yield: 47.3 %

Procedure:
Benzyl 2-(1-methyl-1H-tetrazol-5-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (488 mg, 1.27 mmol) was subjected to chiral preparative HPLC (Column: Chiralpak AS (250×20), 5 μm particle size, mobile phase: Heptane/EtOH/DEA 60/40/0.1, flow rate 18 mL/min) to yield (2R,4S)-benzyl 2-(1-methyl-1H-tetrazol-5-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (231 mg, 47%), chiral purity 98% ee, Optical rotation [α]D20=+14.5 (acetonitrile, c=1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:10]2[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.BrC1C=CC(C(C2C=CC=CC=2)(C2N(S(C3C=CC(C)=CC=3)(=O)=O)C=CN=2)O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2C(O)(c2ccccc2)c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccnc2C(O)(c2ccccc2)c2ccc(Br)cc2)cc1
Product: OC(c1ccccc1)(c1ccc(Cl)cc1)c1ncc[nH]1

Procedure:
Using the procedure described in Example IB but substituting an equivalent amount of α-(p-chlorophenyl)-α-phenyl-1-(toluene-p-sulphonyl)imidazole-2-methanol for the α-(p-bromophenyl)-α-phenyl-1-(toluene-p-sulphonyl)imidazole-2-methanol, α-(p-chlorophenyl)-α-phenylimidazole-2-methanol was obtained. Its melting point was 163°-165° C.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH:23](OS(C(F)(F)F)(=O)=O)[CH:22]4[C:16]([CH2:17][CH2:18][N:19]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:20][CH2:21]4)=[N:15]3)[CH2:10][CH2:9]2)C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:23]=[C:22]3[C:16]([CH2:17][CH2:18][N:19]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:20][CH2:21]3)=[N:15]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2=NN(C3CCN(Cc4ccccc4)CC3)C(OS(=O)(=O)C(F)(F)F)C2CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cn(C3CCNCC3)nc2CC1

Procedure:
A mixture of 1,1-dimethylethyl 2-[1-(phenylmethyl)-4-piperidinyl]-3-{[(trifluoromethyl)sulfonyl]oxy}-3,3a,4,5,7,8-hexahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 48) (355 mg, 0.64 mmol) in ethyl acetate (9 ml) and methanol (3 ml) was treated with triethylamine (0.443 ml, 3.18 mmol) and then Pd(OH)2/C (20% w/w, 70 mg) and the resulting mixture stirred under an atmosphere of H2 for 18.5 h. The mixture was then filtered through kieselguhr and reduced under vacuum. Purification by Mass Directed Autopreparation afforded the title compound (D49). MS (ES+) m/e 321 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+]>CC(C)=O.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccnc3)c3cc(Br)cnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: Brc1cnc2[nH]cc(-c3cccnc3)c2c1
Temperature: 65 °C

Procedure:
To a solution of 5-bromo-3-(pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (662 mg, 1.55 mmol) in acetone (30 mL) and methanol (20 mL) was added 2N NaOH (1.8 mL). The reaction was heated in a 65° C. oil bath for 1 h and then evaporated to near dryness. The crude reaction product was partitioned between EtOAc and 1N NaOH and extracted. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give product that was used for the next step without any further purification. LCMS-ESI+: calc'd for C12H8BrN3: 274.0 (M+H+); found: 274.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([OH:11])=O)=[O:6].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][CH2:52][CH2:53][NH2:54])=[CH:47][CH:46]=1>C(Cl)Cl>[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][CH2:52][CH2:53][NH:54][C:9]([C@@H:8]([NH:7][C:5](=[O:6])[C:4]2[CH:21]=[CH:22][CH:23]=[C:2]([CH3:1])[CH:3]=2)[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:47][CH:46]=1
Reactant: COc1ccc(NCCN)cc1
Reactant: Cc1cccc(C(=O)N[C@@H](CCCc2ccccc2)C(=O)O)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(NCCNC(=O)[C@H](CCCc2ccccc2)NC(=O)c2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
L-Styryl alanine 1 (50 mg, 0.26 mmol) was dissolved in MeOH (5 mL) and the reaction vessel was flushed with nitrogen. Catalytic amount of palladium (10% on carbon) was added and the reaction vessel was placed under a hydrogen atmosphere. The mixture was stirred for 2 h at room temperature, then filtered over celite. The organic solvent was removed in vacuo to yield (S)-2-amino-5-phenyl-pentanoic acid 2 (51 mg, quant.) as a white powder: 1H-NMR (400 MHz, CD3OD) δ=7.42–7.25 (m, 5H), 3.71 (t, J=6.0, 1H), 2.69 (t, J=6.4, 2H), 1.85 (m, 2H), 1.70 (m, 2H). MS calcd. for C11H16NO2 (M+H+) 194.12. found 194.4. Step B: (S)-2-Amino-5-phenyl-pentanoic acid 2 (23 mg, 0.12 mmol) was dissolved in H2O (1 mL) containing equimolar amounts of NaOH (5 mg, 0.12 mmol). The solution was cooled to 0° C., then m-Toluic acid chloride (16 μL, 0.12 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 12 h. After acidification with 1 M HCl (1 mL), the product was extracted from the reaction mixture with DCM (4 mL). The organic layer was separated and the solvent was removed in vacuo to yield (S)-2-(3-methyl-benzoylamino)-5-phenyl-pentanoic acid 3 (21 mg, 56%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.83–7.09 (m, 9H), 4.62 (dd, J=5.0, J=9.1, 1H), 2.65 (m, 2H), 2.37 (s, 3H), 2.01–1.67 (m, 4H). MS calcd. for C19H22NO3 (M+H+) 312.16. found 312.4. Step C: (S)-2-(3-Methyl-benzoylamino)-5-phenyl-pentanoic acid 3 (21 mg, 0.07 mmol) was dissolved in DCM (2 mL), HOBt (20 mg, 0.14 mmol) and DIC (23 μL, 0.14 mmol) were added and the solution was stirred for 10 min at room temperature. N-(4-Methoxyphenyl)-ethane-1,2-diamine (24 mg, 0.14 mmol) was added and the solution was stirred for 3 h at room temperature. The solvent was removed in vacuo, and the remainder was purified by reverse HPLC to afford the title compound (S)-N-{1-[2-(4-Methoxy-phenylamino)-ethylcarbamoyl]-4-phenyl-butyl}-3-methyl-benzamide 4 (18 mg, 0.04 mmol, 56%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.56–7.48 (m, 2H), 7.36–7.16 (m, 7H), 6.96–6.87 (m, 4H), 4.48 (dd, J=6.2, J=13.7, 1H), 3.82 (s, 3H), 3.78–3.64 (m, 2H), 3.58–3.50 (m, 2H), 2.71–2.64 (m, 2H), 2.35 (s, 3H), 2.06–1.70 (m, 4H). MS calcd. for C28H34N3O3 (M+H+) 460.26. found 460.5.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:15].C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>CN(C)C=O>[NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6]([Cl:25])=[O:7])=[CH:4][C:3]=1[Cl:15]
Reactant: O=S(Cl)Cl
Reactant: CON=Cc1cc(C(=O)O)cc(Cl)c1N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CON=Cc1cc(C(=O)Cl)cc(Cl)c1N
Temperature: 70 °C

Procedure:
In a 5-liter three-necked round-bottomed flask was placed 180 g of the previously prepared 4-amino-3-chloro-5-methoxyirninomethylbenzoic acid, 2 l of toluene, 3 mL of dimethylformamide and 104 g (64 mL) of thionyl chloride. The resulting mixture was heated at 70° C. for 2 hours, filtered while hot and the solvent removed using a rotary evaporator yielding 178.1 g of the expected 4-amino-3-chloro-5-methoxyiminomethylbenzoyl chloride.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]([NH2:14])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.[CH3:18][C:19]([O:22][C:23]([O:25]C(OC(C)(C)C)=O)=O)([CH3:21])[CH3:20].C(O)([C:35]([F:38])([F:37])[F:36])=O>C(Cl)Cl>[C:19]([O:22][C:23](=[O:25])[NH:14][C:5]1[CH:6]=[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:2]([C:35]([F:38])([F:37])[F:36])=[CH:3][C:4]=1[N+:15]([O-:17])=[O:16])([CH3:21])([CH3:20])[CH3:18]
Reactant: Nc1cc(OCC(F)(F)F)c(I)cc1[N+](=O)[O-]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared via the di-Boc-compound from 4-iodo-2-nitro-5-(2,2,2-trifluoro-ethoxy)-phenylamine [prepared by stirring 5-chloro-4-iodo-2-nitro-phenylamine (Example A1), 2,2,2-trifluoroethanol and KOH in DMSO at 23° C. for 32.5 days.] and Boc2O, followed by treatment with 2 eq. TFA in CH2Cl2 according to the general procedure B (method c). Obtained as a yellow solid (18.955 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([N:12]3[CH2:15][C:14]([F:17])([F:16])[CH2:13]3)=[CH:10][N:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:21][C:22]1([CH2:26][C:27]([NH2:29])=[O:28])[CH2:25][O:24][CH2:23]1>>[NH2:29][C:27](=[O:28])[CH2:26][C:22]1([NH:21][C:18]([C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:11]([N:12]3[CH2:13][C:14]([F:16])([F:17])[CH2:15]3)=[CH:10][N:9]=2)=[O:20])[CH2:25][O:24][CH2:23]1
Reactant: NC(=O)CC1(N)COC1
Reactant: O=C(O)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1
Product: NC(=O)CC1(NC(=O)c2cc(OCC3CC3)c(N3CC(F)(F)C3)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 4-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 53e) and 2-(3-Amino-oxetan-3-yl)-acetamide (CAN 1417638-25-5) as starting material and isolated (31 mg, 36%); MS (ESI, m/z): 397.6 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2cccc(Cl)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (73 mg, 91%), MS (ISP) m/z=322.4 [(M+H)+], mp 241.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([OH:21])=[O:20])[C:3]=1[O:22][CH3:23].C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CS(C)=O.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:20])[C:3]=1[O:22][CH3:23]
Reactant: BrCc1ccccc1
Reactant: COc1c(C(=O)O)nc(-c2ccc(Cl)c(OC)c2F)c(F)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(C(=O)OCc2ccccc2)nc(-c2ccc(Cl)c(OC)c2F)c(F)c1N
Temperature: 100 °C
Yield: 70.8 %

Procedure:
To a solution of 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-3-methoxypicolinic acid (140 mg, 0.406 mmol) in DMSO (1.354 mL) were added K2CO3 (67.4 mg, 0.487 mmol) and (bromomethyl)benzene (76 mg, 0.447 mmol). The reaction mixture was heated at 100° C. for 5 min in a Biotage microwave. The reaction mixture was then diluted with H2O and extracted with CH2Cl2. The organic extracts were separated from the aqueous layer in a Biotage phase separator. The organic layer was then concentrated, and the residue was purified by flash chromatography (eluting with 0-50% acetone in hexanes) to afford a white solid (125 mg, 69%): mp 119° C.; 1H NMR (400 MHz, acetone-d6) δ 7.56-7.49 (m, 2H), 7.43-7.27 (m, 5H), 5.98 (s, 2H), 5.40 (s, 2H), 3.97 (d, J=1.1 Hz, 3H), 3.85 (s, 3H), ESIMS m/z 436 ([M+H]+), 434 ([M−H]−).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[OH:17])[N:13]=[CH:12][CH:11]=[C:10]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:2][CH2:3][OH:4])[N:13]=[CH:12][CH:11]=[C:10]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
A solution of 2-bromo-ethanol (226 mg) in N,N-dimethylformamide (6 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (100 mg) and potassium carbonate (250 mg), and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (51.3 mg, yield 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([CH3:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH2:21][CH2:20]2)[C:15]1=[O:35].[H][H]>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([CH3:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[C:15]1=[O:35]
Reactant: Cc1cc(N[C@H]2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)c(F)cc1S(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)cc1S(C)(=O)=O
Yield: 102.2 %

Procedure:
(S)-Benzyl 4-(3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (906 mg, 1.80 mmol) was dissolved in EtOH (15 mL) and 10% Pd/C was added and stirred under balloon pressure of hydrogen overnight. The reaction was filtered and concentrated to afford (S)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (680 mg, 1.84 mmol, 102% yield).
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[CH3:6][S:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][NH2:18].O>O1CCCC1.C(N(C(C)C)C(C)C)C>[CH3:1][O:2][C:3]([NH:18][NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][S:7][CH3:6])=[O:4]
Reactant: COC(=O)Cl
Reactant: CSCCOc1ccccc1NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NNc1ccccc1OCCSC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
5.6 ml of chloroformic acid methyl ester are added dropwise at 0° C. to 14.4 g of 2-(2-methylthioethoxy)-phenylhydrazine in 100 ml of tetrahydrofuran and 14 g of N-ethyldiisopropylamine. The reaction mixture is stirred at 20° C. for 2 hours; H2O is then added, and the mixture is repeatedly extracted with ethyl acetate. After customary further processing, a solid is obtained, and this is recrystallised from alcohol to thus yield the compond of the formula ##STR62## having a melting point of 92°-94° C.
Reaction SMILES: Cl[C:2]1[N:10]2[CH:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:20]2[C:21]([CH3:26])=[N:22][O:23][C:24]=2[CH3:25])[N:3]=1.[CH2:27]1[C@@H:31]([OH:32])[CH2:30][NH:29][CH2:28]1>CO>[CH3:26][C:21]1[C:20]([C:7]2[C:8]3[O:13][CH2:12][CH:11]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[N:10]4[C:2]([N:29]5[CH2:28][CH2:27][C@@H:31]([OH:32])[CH2:30]5)=[N:3][C:4]([C:9]=34)=[CH:5][CH:6]=2)=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: O[C@@H]1CCNC1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OCC3c1cccnc1
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(N3CC[C@@H](O)C3)n3c2c1OCC3c1cccnc1

Procedure:
The title compound was prepared by methods analogous to Example 157, substituting 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine and 3R-pyrrolidinol. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to afford the title compound as a mixture of diastereomers (13.3 mg, 75%). LCMS calc. for C23H24N5O3 (M+H)+: m/z=418.2. found: 418.2. The isomers were separated by prep chiral column chromatography using the following conditions: Column: phenomenex Lux Cellulose C-2 5 μm, 21, 2×250 mm, Mobile phase: 45% EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, Loading: 5.0 mg in 900 μL, run time: 18 min, peak time: 12.0, 14.0 and 16.0 min.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]2[C:22](=[O:25])[NH:23][N:24]=[C:14]2[C:13]2[CH:26]=[CH:27][CH:28]=[N:29][C:12]1=2)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[H-].[Na+].Cl[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36]>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:36][N:35]([CH2:34][CH2:33][N:23]1[C:22](=[O:25])[N:15]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:11]([C:9](=[O:10])[CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[C:12]3[N:29]=[CH:28][CH:27]=[CH:26][C:13]=3[C:14]2=[N:24]1)[CH3:37]
Reactant: CCCN(CCC)CC(=O)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CCCN(CCC)CC(=O)N1c2ccccc2-n2c(nn(CCN(C)C)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 21, to 2,9-dihydro-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling with (2-chloroethyl)dimethylamine in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-[(dimethylamino)ethyl]-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]-benzodiazepin-3-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[Si:16]([O:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:10])=[CH:5][CH:6]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Cl)nc1Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of (2,6-dichloropyridin-3-yl)methanol (from Step A above, 6.3 g) in DMF was added imidazole (3.06 g) and t-butyldimethylsilyl chloride (6.02 g) at 0° C. The mixture was warmed to room temperature and stirred for 1 h before poured into water. The solution was extracted with ethyl acetate. The organic layer was washed with water (5×), brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (hexanes/ethyl acetate) to give the title compound (8.7 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[CH2:8]([Li])[CH2:9][CH2:10]C.O.Cl.[CH2:15]1[CH2:19][O:18][CH2:17][CH2:16]1>>[CH:15]1([C:19](=[O:18])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:16][CH2:17][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: Cc1ccccn1
Agent: Cl
Solvent: O
Product: O=C(Cc1ccccn1)C1CCCCC1
Temperature: -78 °C
Reaction time: 40 h

Procedure:
A 100 mL round bottom flash was charged with 2-picoline (1.09 mL, 11.02 mmol) and anhydrous THF (15 mL). The solution was cooled to −78° C. and n-butyllithium (7.6 mL of a 1.6M solution in THF, 12.12 mmol) was added dropwise to the cooled solution. After addition was complete, the reaction mixture was warmed to room temperature over one hour and then cooled again to −78° C. N-methoxy-N-methyl cyclohexyl amide (2.0 g, 11.68 mmol) in THF (10 mL) was added dropwise to the reaction mixture. After addition was complete, the reaction was warmed to room temperature over one hour and then stirred for 40 hours. The reaction mixture was then treated with water and 1N HCl (keeping the pH at approximately 12). The reaction mixture was then extracted with methylene chloride (3×20 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide an orange oil which was purified by flash chromatography (ethyl acetate:hexane, 3:7, silica gel) to provide 1-cyclohexyl-2-(2-pyridyl)ethan-1-one (2.06 g).