Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]1[C:15]([C:22]([F:25])([F:24])[F:23])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>>[F:13][C:14]1[C:15]([C:22]([F:23])([F:24])[F:25])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: Fc1cccc(CBr)c1C(F)(F)F
Product: O=C1CNc2ncc(I)cc2N1Cc1cccc(F)c1C(F)(F)F
Yield: 54 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.051 g) was alkylated with 3-fluoro-2-(trifluoromethyl)benzyl bromide as in General Procedure 1 to give the title compound as a light brown solid (54% yield). M.p.>200° C., LCMS: m/z=451.79 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.17 (2H, s), 5.20 (2H, bs), 7.01 (1H, d, J=7.6 Hz), 7.17 (1H, s), 7.23 (1H, s), 7.42 (1H, m), 7.63 (1H, m), 7.86 (1H, m).
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][N:11](C(OC(C)(C)C)=O)[C@H:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:25]1[C:37]2[CH:36]=[CH:35][C:34]([NH2:38])=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24]>>[CH:1](=[C:8]1[CH2:12][NH:11][C@H:10]([C:20]([NH:38][C:34]2[CH:35]=[CH:36][C:37]3[N:25]([CH2:23][CH3:24])[C:26]4[C:31]([C:32]=3[CH:33]=2)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)O
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=Cc4ccccc4)CN3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 53% purity by LC/MS. MS(ESI+): m/z=396.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([F:26])([F:25])[F:24])=[N:19][NH:20][C:21]=3[CH3:22])=[C:13]([N+:27]([O-])=O)[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.Cl[Sn]Cl.Cl>CCO>[NH2:27][C:13]1[CH:12]=[C:11]([NH:10][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:9])[CH:16]=[CH:15][C:14]=1[C:17]1[C:18]([C:23]([F:26])([F:24])[F:25])=[N:19][NH:20][C:21]=1[CH3:22]
Reactant: Cc1[nH]nc(C(F)(F)F)c1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1[nH]nc(C(F)(F)F)c1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1N
Yield: 48 %

Procedure:
The mixture of 23 (340 mg, 1.24 mmol), SnCl2 2H2O (902 mg, 6.22 mmol), HCl (0.33 mL) in EtOH (50 mL) stirred at reflux under a N2 atmosphere for 1 h. The solvent was removed under vacuo, washed with NaOH to PH=14, extracted with CH2Cl2, dried over Na2SO4 and purified by column chromatography to give 24 (235 mg, 75% yield). 1H NMR (CDCl3, 300 MHz): δ=2.37 (s, 3H), 3.89 (s, 2H), 6.59 (s, 1H), 6.76-6.79 (m, 1H), 7.13 (d, 1H), 7.46-7.49 (m, 2H), 7.53 (d, 1H), 7.73 (s, 1H), 7.79-7.81 (m, 2H). LC-MS: 394.9 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2CC(C)(C)C(C)(C)C2)[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]1=[O:21].Br[C:23]1[CH:37]=[C:36]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH:35]=[CH:34][C:24]=1[O:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[O:25][C:24]1[CH:34]=[CH:35][C:36]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])=[CH:37][C:23]=1[C:6]1[CH:5]=[C:4]([C:17]([F:18])([F:19])[F:20])[C:3](=[O:21])[N:2]([CH3:1])[CH:7]=1
Reactant: Cn1cc(B2CC(C)(C)C(C)(C)C2)cc(C(F)(F)F)c1=O
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(-c2cc(C(F)(F)F)c(=O)n(C)c2)c1
Temperature: 90 °C
Yield: 33.6 %

Procedure:
A mixture of 1-methyl-5-(3,3,4,4-tetramethylborolan-1-yl)-3-(trifluoromethyl)pyridin-2-one (100 mg, 0.33 mmol), 1-(2-bromo-4-ethylsulfonylphenoxy)-2,4-difluorobenzene (100 mg, 0.27 mmol), Pd(dppf)Cl2 (24 mg) and K3PO4 (107 mg, 0.80 mmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen, capped, and heated to 90° C. for 4 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by prep-HPLC afford the title compound (43 mg, 34%) as a white solid. 1H NMR (CDCl3, 400 MHz) □ ppm 8.11 (s, 1H) 7.88 (s, 2H) 7.80 (m, 1H), 7.23-7.10 (m, 1H) 7.09-6.91 (m, 2H) 6.91-6.78 (m, 1H) 6.25 (s, 1H) 3.70 (s, 3H) 3.15 (q, J=7.2 Hz, 2H) 1.31 (t, J=7.2 Hz, 3H). LCMS (M+H)+=474.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([NH2:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:21](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:22]>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([N:19]=[C:21]=[S:22])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(F)(F)F)c(N)c1
Product: CC(C)(C)OC(=O)NCc1ccc(C(F)(F)F)c(N=C=S)c1
Yield: 86 %

Procedure:
The sub-title compound was prepared from tert.-butyl-N-(3-amino-4-trifluoromethyl-benzyl)carbamate with 1,1′-thiocarbonyldi-2-pyridone in analogy to example 1d.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccc(Cl)cc2)c(NC(C)=O)c2ccc(Cl)cc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-2-(4-chlorobenzoyl)-1-(ethoxycarbonyl)indole (step 1). m.p.: 175-176° C. (ethyl acetate/hexane)
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[C:7]([CH3:30])=[N:8][C:9]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](OC)=[O:27])(=[O:19])=[O:18])=[O:15])=[N:10][C:11]=1[CH3:12].[CH3:31][SH:32]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:7]([CH3:30])=[N:8][C:9]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([S:32][CH3:31])=[O:27])(=[O:19])=[O:18])=[O:15])=[N:10][C:11]=1[CH3:12]
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c(Cl)c(C)n1
Reactant: CS
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CSC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c(Cl)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylaluminum (6.0 ml, 2 M) is charged via syringe to 15 ml dry toluene under nitrogen atmosphere and 3.8 g N-[(5-chloro-4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide is added portionwise. After stirring at room temperature for one hour, methyl mercaptan (gas) is passed through the reaction mixture until the initial temperature rise subsided, whereupon the addition is discontinued. The reaction mixture is allowed to stir at room temperature for 1 hour, and quenched with 25 ml of 10% HCl. The resultant white suspension is filtered to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24](N)=[O:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl.[OH-:28].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:24]([OH:25])=[O:28])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2)ccc1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2nc(C(=O)O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 92.5 °C

Procedure:
A suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarboxamide (1.02 g) in a mixture of conc. HCl (40 ml) and dioxane (10 ml) was heated at 90-95° C. for 20 hours. Under ice-cooling, the reaction mixture was adjusted to pH 4 with 4N aq. NaOH solution to yield a precipitate. The precipitate was collected by filtration and dried at 60° C. under reduced pressure to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarboxylic acid as a solid (878 mg).
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[C:26](Cl)=[N:25][N:24]=1.[I-].[K+]>>[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[C:26]([N:18]2[CH2:19][CH2:20][CH:15]([N:5]3[C:6](=[O:14])[C:7]4[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=4)[N:3]([CH3:2])[C:4]3=[O:21])[CH2:16][CH2:17]2)=[N:25][N:24]=1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Reactant: COc1cc2c(Cl)nnc(Cl)c2cc1OC
Agent: Br
Agent: [I-]
Agent: [K+]
Product: COc1cc2c(Cl)nnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 49 %

Procedure:
The procedure similar to that described in Example 15 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound v) obtained in Example 41 was used, 1,4-dichloro-6,7-dimethoxyphthalazine was used in place of 4-chloro-6,7-dimethoxyquinazoline, and a catalytic amount of potassium iodide was added. As a result, 243.7 mg (yield: 49%) of Compound 76 was obtained as white crystals.
Reaction SMILES: C(OC(N[C@H](C1C=CC=CC=1)C(N1CCC[C@H]1C(O)=O)=O)=O)(C)(C)C.Cl.BrC1SC2=NC(N)=CN2C=1.[C:37]([O:41][C:42](=[O:70])[NH:43][C@@H:44]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@@H:48]1[C:52](=[O:63])[NH:53][C:54]1[N:55]=[C:56]2[N:60]([CH:61]=1)[CH:59]=[C:58]([Br:62])[S:57]2)=[O:46])(C)(C)[CH3:38]>>[CH2:37]([O:41][C:42](=[O:70])[NH:43][C@@H:44]([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@@H:48]1[C:52](=[O:63])[NH:53][C:54]1[N:55]=[C:56]2[N:60]([CH:61]=1)[CH:59]=[C:58]([Br:62])[S:57]2)=[O:46])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: Cl
Agent: Nc1cn2cc(Br)sc2n1
Product: CCOC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1

Procedure:
Compound 44 was synthesized from compounds 43 (0.377 mmol) and 11 (0.565 mmol), following the procedure as described for compound 12a, at room temperature overnight, to give compound 44 as a yellow oil in 66% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.10 (t, 3H), 1.80 (m, 2H), 1.95 (m, 2H), 3.10 (m, 1H), 3.81 (m, 1H), 3.99 (m, 2H), 4.40 (m, 1H), 5.42 (m, 1H), 7.31 (m, 5H), 7.50 (d, 1H), 7.81 (s, 1H), 8.16 (s, 1H), 10.61 (s, 1H); MS (ESI, EI+) m/z=520-522 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].C(O)(=O)C.[CH:17](N)=[NH:18]>COC(O)C>[N:1]1[C:2]2[C:3](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:4]([OH:5])=[N:18][CH:17]=1
Reactant: N=CN
Reactant: CCOC(=O)c1ccccc1N
Agent: COC(C)O
Solvent: CC(=O)O
Product: Oc1ncnc2ccccc12
Yield: 110.4 %

Procedure:
A solution of ethyl 2-aminobenzoate (5.0 g, 30 mmol) in methoxyethanol (20 mL) was treated with formamidine acetate (8 g, 77 mmol) under reflux for 17 h. A second portion of formamidine acetate (8 g, 77 mmol) was then added, and the reflux was continued for 7 more hours. The mixture was cooled, and the solvent was removed under vacuum. The residue was taken in saturated NaHCO3 and extracted with ethyl acetate. The organic layers were combined, washed with saturated NaHCO3, and dried with magnesium sulfate, and the solvent was removed under vacuum to give the desired compound (4.84 g, 91%), which was used for the next step without further purification. LC-MS: m/z 147.7 (M+H)+
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21](=[O:32])[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)([CH3:19])([CH3:18])[CH3:17].CC1(C)C2CCC1(C)[C:36](/[C:38]/2=[C:39](/[C:41](F)(F)F)\[OH:40])=[O:37].CC1(C)C2CCC1(C)[C:53](/C/2=C(/C(F)(F)F)\O)=[O:54].CC1(C)C2CCC1(C)C(/C/2=C(/C(F)(F)F)\O)=[O:71].[Eu]>C1COCC1>[C:16]([O:20][C:21]([CH2:22][N:23]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:36](=[O:37])[C@@H:38]1[O:40][C@@H:39]1[C:41]([O:54][CH3:53])=[O:71])=[O:32])([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1ccc(NCC(=O)OC(C)(C)C)cc1
Reactant: CC12CCC(/C(=C(/O)C(F)(F)F)C1=O)C2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Eu]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1O[C@H]1C(=O)N(CC(=O)OC(C)(C)C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 188.0 g (0.88 mol) of dicyclohexylcarbodiimide in 300 ml of THF was added dropwise, within 15 minutes, to a solution of 129.0 g (0.88 mol) of monomethyl (2R,2S)-2,3-oxirandicarboxylate and 196.0 g (0.8 mol) of t-butyl-N-(4-methoxyphenyl)glycinate [M. Shiozaki et al., Tetrahedron 40, 1795, (1984)] in 1100 ml of THF. The mixture was subsequently stirred for a further 30 minutes at room temperature, the resultant precipitate was separated off by filtration, and the filtrate solution was evaporated in vacuo. After purification of the product on 1.8 kg of silica gel (toluene:ethyl acetate=7:3), 263.2 g (90% of theory) of the title compound were obtained as crystals, melting point: 89° C. [α]D20 =-21.78° (c=0.435 in CHCl3). The enantiomer ratio, of 3:2, determined in the preparation example was confirmed by NMR-shift experiments using Eu(TFC)3.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:48])[CH2:19][CH2:20][N:21]([C:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16].Cl>ClCCl>[CH2:15]([O:17][C:18](=[O:48])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:39]1([C:45](=[O:46])[NH:2][OH:3])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[CH3:16]
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: NO
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCN(C1(C(=O)NO)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0 ° C. is treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture is allowed to warm to ambient temperature overnight This mixture is then cooled to 0° C. aind treated with a solution of (15.1 mmol) of the product from Step F in 73 mL of dichloromethane causing an exotherm to about 8° C. This mixture is stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction is then treated with 50 mL of 2N aqueous hydrochloric acid and was stirred at ambient temperature for one hour. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of the title compound in dichloromethane is used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([CH2:10][C:11]#[N:12])[CH2:8][CH2:7][C:6]1=[O:13])=[O:4].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:16][CH:15]=[CH2:14])[CH:9]([CH2:10][C:11]#[N:12])[CH2:8][CH2:7][C:6]1=[O:13])=[O:4]
Reactant: COC(=O)C1C(=O)CCC1CC#N
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCC1(C(=O)OC)C(=O)CCC1CC#N
Reaction time: 5 h
Yield: 69.4 %

Procedure:
5-Cyanomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester (100 mg, 0.58 mmol) and allyl bromide (121 mg, 1 mmol) were dissolved in acetone (5ml). Potassium carbonate (138 mg, 1 mmol) was added to the solution. The mixture was heated under refluxing with stirring for 5 hours and then was cooled and was filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by a silica gel column chromatography (ethyl acetate: n-hexane=1: 4) to obtain 89 mg of 1-allyl-5-cyanomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester as viscous oily product. Yield: 69%. Infrared spectrum(cm-1): 2235, 1755, 1730, 1640, 925. NMR spectrum (CDCl3) δ : 1.60 - 3.05 (m, 9H), 3.73 (s, 3H), 4.88 - 6.07 (m, 3H).
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[S:9][C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)=[N:7][CH:6]=1.[N+:16]([C:19]1[CH:23]=[N:22][NH:21][N:20]=1)([O-:18])=[O:17].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH3:15][C:10]1([C:8]2[S:9][C:5]([CH2:4][N:21]3[N:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:23]=[N:22]3)=[CH:6][N:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: CC1(c2ncc(CCl)s2)OCCO1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2ncc(Cn3ncc([N+](=O)[O-])n3)s2)OCCO1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-chloromethyl-2-(2-methyl-[1,3]dioxolan-2-yl)-thiazole (339 mg, 1.54 mmol) in DMF (2.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (160 mg, 1.40 mmol) in DMF (2.0 mL) pre-treated for 30 min with DIPEA (0.48 mL, 2.81 mmol) and the reaction mixture was stirred for 72 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (1:2 hept-EA)=0.39. LC-MS-conditions 02: tR=0.89 min; [M+H]+=298.13.
Reaction SMILES: [CH:1]1([C:4]2[O:8][C:7]([C:9]3[C:10]([O:17]CC[Si](C)(C)C)=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[CH:1]1([C:4]2[O:8][C:7]([C:9]3[C:10]([OH:17])=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CSc1ncc(-c2nnc(C3CC3)o2)c(OCC[Si](C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1ncc(-c2nnc(C3CC3)o2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.7 %

Procedure:
5-(5-Cyclopropyl[1,3,4]oxadiazol-2-yl)-4-(2-trimethylsilylethoxy)-2-methylthiopyrimidine (10.0 g) obtained in Step 5 was dissolved in THF (100 mL), and a TBAF-THF solution (1.0 mol/L, 42.8 mL) was added thereto. The mixture was stirred at room temperature for 12 hours. After completion of the reaction was confirmed by thin-layer chromatography, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography. The fraction of the desired product was collected, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to precipitate crystals. The resulting crystals were collected by filtration and dried thoroughly under reduced pressure to give 5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-4-hydroxy-2-methylthiopyrimidine [Compound (AB) in which —X—Y—Z— represents —O—C(c-C3H5)═N—, and R2B is methylthio] (6.26 g, yield 88%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:30][CH:29]3[NH:31][CH:26]([CH2:27][CH2:28]3)[CH:25]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16].[C:32]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C([O-])(O)=O.[Na+]>ClCCCl>[CH:32]1([N:31]2[CH:29]3[CH2:28][CH2:27][CH:26]2[CH:25]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=2)[CH2:30]3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=[N+]([O-])c1ccc(C2=CC3CCC(C2)N3)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(C2=CC3CCC(C2)N3C2CCCCC2)cc1
Reaction time: 1 h
Yield: 64 %

Procedure:
Sodium triacetoxyborohydride (460 mg, 2.17 mmol, 2.0 eq.) was added to a solution of 3-(4-nitrophenyl)-8-azabicyclo[3.2.1]oct-2-ene (250 mg; 1.1 mmol; 1.0 eq.) and cyclohexanone (168 μl; 1.63 mmol; 1.5 eq.) in DCE (10.00 mL) and the reaction mixture was heated at 500 under nitrogen atmosphere. After 1 h, the reaction mixture was poured into a saturated solution of NaHCO3. Aqueous phase was extracted twice with DCM and combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 90:10) to give the title compound as a beige solid (220 mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J=8.9 Hz, 2H), 7.68 (d, J=8.9 Hz, 2H), 6.68 (d, J=5.4 Hz, 1H), 3.79-3.68 (m, 2H), 2.80-2.75 (m, 1H), 2.31 (m, 1H), 2.07-1.66 (m, 8H), 1.52 (m, 2H), 1.23-1.09 (m, 5H). HPLC (max plot) 100.0%; Rt %3.01 min. UPLC/MS: (MS+) 313.4.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[C:19]([NH2:23])=[N:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]N1C(=O)CCC1=O>CN(C)C=O>[I:24][C:22]1[C:17]2[O:16][N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:18]=2[C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2onc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2onc(-c3ccc(Oc4ccccc4)cc3)c12
Yield: 64.7 %

Procedure:
3-(4-Phenoxyphenyl)isoxazolo[4,5-c]pyridin-4-amine (0.11 g, 0.36 mmol) and to N-iodosuccinimide (0.098 g, 0.43 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at ambient temperature for 30 minutes. The mixture was applied to a silica gel column and eluted with dichloromethane/ethyl acetate (8:2) to provide the title compound (100 mg): 1H NMR (DMSO-d6, 400 MHz) δ 8.26 (s, 1H), 7.71 (d, 2H), 7.46 (t, 2H), 7.15-7.25 (m, 5H), 6.45 (bs, 2H); Rt=3.78 min (Conditions a), MS m/e: 430 (M+H)+.
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][NH:7][C@H:6]1[CH3:10])([CH3:4])[CH3:3].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[CH3:20]>>[OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][N:7]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:20])[C@H:6]1[CH3:10])([CH3:4])[CH3:3]
Reactant: Cc1cc(C#N)ccc1F
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Product: Cc1cc(C#N)ccc1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using compound 1 and 4-fluoro-3-methylbenzonitrile as starting materials, the title compound was obtained by the same manner as shown in Example 1 (reaction temperature 90° C., reaction time 3 hr).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21](O)=[O:22])=[N:19][CH:20]=3)=[CH:14][C:6]1=2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:22])=[N:19][CH:20]=3)=[CH:14][C:6]1=2
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cn1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cn1)N1CCOCC1
Yield: 26 %

Procedure:
5-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-pyridine-2-carboxylic acid (32 mg) was reacted with morpholine as in General Procedure 8 to give the title compound as a yellow solid (26% yield). M.p. 111-113° C., LCMS: m/z=451.92 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.47-3.53 (m, 2H), 3.67-3.76 (m, 8H), 3.77-3.85 (m, 2H), 4.50 (s, 2H), 5.09 (s, 1H), 6.71 (d J=1.5 Hz, 1H), 6.92-7.04 (m, 2H), 7.05-7.12 (m, 1H), 7.69-7.74 (m, 2H), 7.78-7.83 (m, 2H), 8.60 (d, J=2.3 Hz, 1H).