Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Br[C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:29][CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 74 %

Procedure:
A solution of 4′-{[4-butyl-1-(4-hydroxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.3 g), ethyl 2-bromo-2-methylpropanoate (2.2 mL) and cesium carbonate (4.9 g) in dimethylacetamide (23 mL) was stirred at 100° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.1 g, 74%) as a pale-yellow liquid.
Reaction SMILES: NN.[CH3:3][C:4]1[C:5]([N+:15]([O-])=O)=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14]>C(O)C.CN(C)C=O>[NH2:15][C:5]1[C:4]([CH3:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7](=[O:14])[NH:8][CH:9]=[N:10]2
Reactant: Cc1ccc2nc[nH]c(=O)c2c1[N+](=O)[O-]
Agent: NN
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc2nc[nH]c(=O)c2c1N
Temperature: 25 °C

Procedure:
An aqueous hydrazine solution (83%, 10 ml) in ethanol (10 ml) was added carefully at 28° under a nitrogen atmosphere to a mixture of 6-methyl-5-nitroquinazoline-4-one (formula 16, prepared according to Example VI) (10.0 g, 490 m-mol) and palladium-one-charcoal (10%, 1.0 g) in ethanol (150 ml). The mixture was refluxed for 1 hour. Cooling of the mixture to room temperature yielded crystals which were dissolved in dimethyl formamide (150 ml) and separated from the catalyst by filtration. The filtrate was evaporated and the residue recrystallized from ethanol. This yielded 7.0 g (82%) of the formula 17 target compound in the form of light yellow crystals, m.p. 260°-261° (decomp.); ir (KBr): 3480, 3315 cm-1 (NH2); pmr (DMSO-d6): δ 2.13 (s, 3 CH3), 6.70 (d, 1, J=8.5 Hz, H7), 6.95 (m, 2, D2O-exchangeable NH2), 7.36 (d, 1, J=8.5 Hz, H8), 7.88 (s, 1, H2), 11.67 (m, 1, D2O-exchangeable NH); ms (70 eV): m/e 175 (100%, M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:17][C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=1.[OH-].[Na+]>C1COCC1.CO>[C:18]([CH2:17][C@H:16]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([Cl:8])[CH:4]=2)=[CH:10][CH:11]=1)([OH:20])=[O:19]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)NC(=O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Reaction time: 4.5 h
Yield: 70.2 %

Procedure:
To a solution of (R)-4-(1-(2′,5′-dichlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (106 mg, 0.234 mmol) in THF (2 ml) and MeOH (0.1 ml), 1M aqueous NaOH solution (1.406 mL, 1.406 mmol) is added at room temperature. After stirring for 4.5 hours, the reaction is quenched with 0.1 M aqueous HCl (3 ml), and the products are extracted with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude is triturated in DCM. The precipitates are collected on a funnel, washed with DCM, and dried under reduced pressure to give (R)-4-(1-carboxy-3-(3′-chlorobiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoic acid (64.0 mg) as white solid; HPLC retention time=1.24 minutes (condition A); MS (m+1)=424.07; 1H NMR (400 MHz, CD3OD) δ ppm 2.38-2.42 (m, 2H) 2.45-2.57 (m, 4H) 2.87 (A of ABX, Jab=13.6 Hz, Jax=7.6 Hz, 1H) 2.95 (B of ABX, Jab=13.6 Hz, Jbx=6.1 Hz, 1H) 4.44-4.51 (m, 1H) 7.30-7.37 (m, 6H) 7.47 (d, J=8.4 Hz, 1H).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[C:8]1([OH:16])[CH:15]=[C:13]([CH3:14])[CH:12]=[C:10]([OH:11])[CH:9]=1>[OH-].[Na+]>[CH3:5][O:11][C:10]1[CH:9]=[C:8]([OH:16])[CH:15]=[C:13]([CH3:14])[CH:12]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C)cc(O)c1
Yield: 43 %

Procedure:
Dimethyl sulfate (39 ml; 0.41 mol) was added to a solution of orcinol (64 g; 0.45 mol) in 10% aqueous sodium hydroxide solution (360 ml). The mixture was refluxed for 1½ hours and extracted with ether. The organic phase was evaporated and purified by flash chromatography eluting with dichloromethane/ethanol (98/2) to give 3-methoxy-5-methylphenol. Yield=43%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].[N:15]#[C:16]Br>>[CH2:13]([N:6]([CH2:5][C@H:2]1[CH2:3][O:4][C:16]([NH2:15])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: CCN(C[C@H](N)CO)c1ccccc1
Reactant: N#CBr
Product: CCN(C[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1.d (S)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol was reacted with cyanogen bromide to give (S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine. Off-white solid. MS (ISP): 220.4 ([M+H]+)
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10](=[NH:14])OCC)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][O:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1N.Cl.Cl.NC1C=CC(N2CCO[C@@H](C(N3CCCC3)=O)C2)=NC=1N>>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:14][C:21]4=[N:20][C:19]([N:23]5[CH2:28][CH2:27][O:26][C@@H:25]([C:29]([N:31]6[CH2:32][CH2:33][CH2:34][CH2:35]6)=[O:30])[CH2:24]5)=[CH:18][CH:17]=[C:16]4[N:15]=3)[CH:7]=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=N)c1cncc(C2CC2)n1
Reactant: Nc1ccc(N2CCO[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Product: O=C([C@H]1CN(c2ccc3nc(-c4cncc(C5CC5)n4)[nH]c3n2)CCO1)N1CCCC1

Procedure:
The title compound was prepared by a method analogous to Example 105 using ethyl 6-cyclopropylpyrazine-2-carbimidate (Intermediate 30) and (R)-(4-(5,6-diaminopyridin-2-yl)morpholin-2-yl)(pyrrolidin-1-yl)methanone (Intermediate 29). MS (ESI+) (M+H) 420.2; HPLC retention time 2.432 min (Method A).
Reaction SMILES: [C:1]([C@@H:3]([NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19]([C:21]1[N:22]([CH3:30])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:11])[CH2:4][CH2:5][C:6]([OH:8])=O)#[N:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:1]([C@@H:3]([NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19]([C:21]1[N:22]([CH3:30])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:11])[CH2:4][CH2:5][C:6]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:8])#[N:2]
Reactant: C1COCCN1
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)CCC(=O)O)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)CCC(=O)N2CCOCC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
The (S)-4-cyano-4-({(1R,2S)-2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-butyric acid (140 mg, 0.341 mmol), morpholine (50 μL, 0.57 mmol), EDCI hydrochloride (102 mg, 0.532 mmol), HOBT (50 mg, 0.37 mmol) and N-methyl morpholine (0.10 mL, 0.91 mmol) were dissolved in 5.0 mL of DMF and stirred at room temp for 4 hours. The reaction mixture was partitioned between 50 mL of water and 50 mL of ethyl acetate. The organic layer was washed with water (2×50 mL), dried with sodium sulfate, filtered and concentrated to give 98 mg (60%) of 1-Methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-4-morpholin-4-yl-4-oxo-butylcarbamoyl)-cyclohexyl]-amide as a white amorphous solid. MS: 480 (M+H+).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[OH-].[K+].[Br:10][C:11]1[C:12](=O)[NH:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1>O1CCCC1.C(OCC)(=O)C>[Br:10][C:11]1[C:7](=[O:6])[N:15]([CH3:16])[C:14]([S:17][CH3:18])=[N:13][CH:12]=1
Reactant: COS(=O)(=O)OC
Reactant: CSc1ncc(Br)c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ncc(Br)c(=O)n1C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a mixture containing 0.70 g (5.5 mmol) of dimethyl sulfate and 0.25 g (4.5 mmol) of potassium hydroxide in 10 ml of tetrahydrofuran was added 0.5 g (2.25 mmol) of 5-Bromo-2-(methylthio)pyrimidin-4(3H)-one in portions over 15 min. After complete addition, the mixture was stirred overnight then diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane gave 0.5 g (94%) of product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].[BrH:13]>>[Br:13][C:6]1[CH:5]=[CH:4][N+:3]([O-:12])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Br
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Product: Cc1c(Br)cc[n+]([O-])c1C
Temperature: 100 °C

Procedure:
A mixture of 2,3-dimethyl-4-nitropyridine N-oxide (5 g, 29.7 mmol) and hydrogen bromide (30% wt in acetic acid, 100 mL) was heated for 48 hours at 100° C. The mixture was then filtered, washing through with 2M sodium hydroxide and the filtrate was extracted with dichloromethane (×3). The combined organic solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate:pentane, 50:50, to afford the title product as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63]/[C:64](/[NH2:67])=[N:65]/O)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]>CN(C=O)C>[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63][C:64]3[N:65]=[C:6]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:10][CH:9]=4)[O:8][N:67]=3)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nc(Nc3ccc(C)c(-c4cc5cnc(C)cc5n(C)c4=O)c3)no2)cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6-Methylnicotinic acid (0.67 g, 4.89 mmol), HATU (1.86 g, 4.89 mmol), and DIPEA (0.85 mL, 4.89 mmol) were stirred in dry DMF (20 mL) for 1 h before 17 (1.5 g, 4.44 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling and filtration, the mixture was purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-(6-methylpyridin-3-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A51) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 9.27 (d, J=2.0 Hz, 1H), 9.10 (s, 1H), 8.73 (dd, J=2.0, 8.4 Hz, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.46 (dd, J=2.4, 8.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 2.87 (s, 3H), 2.79 (s, 3H), 2.19 (s, 3H). MS m/z 439.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:22]=[O:23])C.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[C:12]=2[CH:22]=[O:23])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cn1cc(-c2ccc(F)cc2)nn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(F)cc2)c1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1-methyl-1H-[1,2,3]triazole (709 mg, 4.0 mmol) in THF (20 mL) was added n-BuLi (1.6 M in hexane, 3.0 mL, 4.8 mmol) dropwise at −75° C. under Argon. The resulting solution was stirred at −75° C. for 1 h, then DMF (401 μL, 5.2 mmol) was added dropwise at −75° C. and the reaction mixture was allowed to warm up to room temperature over 1 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (773 mg, 94%) as a white solid. MS: m/e=206.2 [M]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]Br)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:31][CH:28]3[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:26][CH2:27]3)[N:7]=2)[C:3]=1[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: Cc1c(Br)ccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc2nn(CC3CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
5 g of 5-bromo-4-methyl-1H-indazole was dissolved in 110 ml DMF and treated with 11.5 g of caesium carbonate and 7.9 g of N-Boc-4-(bromomethyl)piperidine. The mixture was stirred for 3 hrs at 60° C. and overnight at RT. The reaction mixture was next diluted with ethyl acetate, and the organic phase was washed twice with water, dried over sodium sulphate, filtered and concentrated. The residue was purified chromatographically on the Biotage SP4 via a 65i-Si column Gradient: hexane/ethyl acetate 0-100%. Yield: 3.53 g of the title compound.
Reaction SMILES: [C:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2ccccc12
Reactant: BrCCCCCBr
Product: BrCCCCCOCc1cccc2ccccc12

Procedure:
1-Naphthalenemethanol (6.00 g) and 1,5-dibromopentane (11.5 ml) were treated according to the method of Intermediate 1. FCC eluting with ether-cyclohexane (1:49→2:48) gave the title compound as a colourless oil (8.41 g), t.l.c. (Cyclohexane-ether 19:1) Rf 0.22.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:14]([CH3:23])[N:13]=[N:12][C:11]=1[CH3:24].C(OCC)(=O)C>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]2[C:10]([N:6]3[CH:5]=[C:4]([CH3:3])[CH:8]=[N:7]3)=[C:11]([CH3:24])[N:12]=[N:13][C:14]=2[CH3:23])=[CH:21][CH:20]=1
Reactant: Cc1cn[nH]c1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cnn(-c2c(C)nnc(C)c2-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
87 mg of sodium hydride (55% oil dispersion) was added to 3 ml of DMF, and to this was added a solution of 0.16 g of 4-methylpyrazole in 3 ml of DMF, and the mixture was stirred for 0.5 hours at room temperature. To the resultant mixture was added 0.25 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine, and the mixture was stirred for 3 hours on an oil bath of 80° C. To the reaction mixture was added ethyl acetate, and washed with brine four times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.40 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.21 g of 5-(4-chlorophenyl)-3,6-dimethyl-4-(4-methyl-1-pyrazolyl)pyridazine (hereinafter, described as compound (5) of the present invention.).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH2:20])=[O:19])=[CH:17][C:12]=2[O:11][N:10]=1)=O.[C:21]([S@@:25]([NH2:27])=[O:26])([CH3:24])([CH3:23])[CH3:22].C(OCC)(=O)C>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:21]([S@@:25](/[N:27]=[CH:1]/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH2:20])=[O:19])=[CH:17][C:12]=2[O:11][N:10]=1)=[O:26])([CH3:24])([CH3:23])[CH3:22]
Reactant: NC(=O)c1ccc2c(-c3ccccc3C=O)noc2c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)/N=C/c1ccccc1-c1noc2cc(C(N)=O)ccc12
Temperature: 0 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
To a suspension of 3-(2-formylphenyl)benzo[d]isoxazole-6-carboxamide (Compound 7) (4.12 g) in tetrahydrofuran (50 mL) was added (S)-(−)-t-butylsulfinamide (1.97 g) followed by titanium (IV) ethoxide (4.8 mL). The mixture was stirred for three days then poured onto stirred ice-water (200 mL) and ethyl acetate (200 mL) added and filtered through dicalite and the plug of solid was washed with hot ethyl acetate (200 mL), the organic layer was dried over anhydrous magnesium sulfate and evaporated to give the title compound (5.7 g) as a partially solidified gum.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]1([O:33][C:34]([O:36][CH2:37]I)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:37][O:36][C:34]([O:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:35])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: O=C(OCI)OC1CCCCC1
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)OC3CCCCC3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 74.7 %

Procedure:
In the same manner as in Example 81, 372 mg of the title compound was prepared from 374 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 336 mg of cyclohexyloxycarbonyloxymethyl iodide.
Reaction SMILES: [C:1]1([C@@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([C@@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:25][C:26]#[N:27])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2c1c1cccc3c1n2[C@@H](c1ccccc1)CO3
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1cccc3c1n2[C@@H](c1ccccc1)CO3
Temperature: 70 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of (S)-(+)-1-Phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol 0.161 g, 0.534 mmol), bromoacetonitrile (0.074 mL, 1.07 mmol), potassium carbonate (0.148 g, 1.07 mmol), and DMF (2 mL) is stirred at 70° C. for 4 h. Additional bromoacetonitrile (0.074 mL) and potassium carbonate (0.074 g) are then added and the mixture is stirred overnight. Bromoacetonitrile and potassium carbonate (0.074 mL and 0.074 g, respectively) are then added and the temperature is increased to 90° C. The mixture is heated at that temperature for 5.5 h and then allowed to cool and stir overnight, after which the mixture is partitioned between ethyl acetate, aq. ammonium chloride, and brine. The organic layers are dried over magnesium sulfate, concentrated, and the residue is chromatographed on silica gel gel (40 mL) using first CH2Cl2/hexane (1:1) to elute unreacted starting material, and then ethyl acetate/CH2Cl2/hexane (5:45:50) to give 0.113 g of (S)-(+)-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>>[N:11]1[CH:12]=[CH:13][CH:14]=[N:15][C:10]=1[O:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1
Reactant: OCC1(CO)CCC1
Reactant: Clc1ncccn1
Product: OCC1(COc2ncccn2)CCC1

Procedure:
The title compound was prepared using the same experimental procedure as in example 25a from [1-(hydroxymethyl)cyclobutyl]methanol and 2-chloropyrimidine. 1H NMR (300 MHz, CDCl3) δ 8.50-8.47 (m, 2H), 6.95-6.89 (m, 1H), 4.48 (s, 2H), 3.63 (d, J=6 Hz, 2H), 3.02 (t, J=6 Hz, 1H), 2.01-1.78 (m, 6H). GC-MS m/z 195 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@:6]12[CH2:14][NH:13][CH2:12][C@H:11]1[CH2:10][S:9][C:8]([NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:7]2.CN(C)C(N(C)C)=N.[F:32][C:33]1[CH:34]=[N:35][C:36](Cl)=[N:37][CH:38]=1.O>CS(C)=O>[F:32][C:33]1[CH:34]=[N:35][C:36]([N:13]2[CH2:12][C@@H:11]3[C@@:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)([N:7]=[C:8]([NH:15][C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:9][CH2:10]3)[CH2:14]2)=[N:37][CH:38]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: O=C(NC1=N[C@@]2(c3cccs3)CNC[C@H]2CS1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(NC1=N[C@@]2(c3cccs3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 50 °C
Yield: 71 %

Procedure:
A solution of N-[(4aR,7aR)-7a-(2-thienyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (7.7 g, 22.4) and N,N,N′,N′-tetramethylguanidine (3.39 mL, 26.9 mmol) in dimethyl sulfoxide (61 mL) is treated with 5-fluoro-2-chloropyrimidine (2.25 mL, 23.54 mmol) and the resulting solution is heated at 50° C. for 4 hours. The solution is cooled to room temperature and added to water (500 mL). The crude product is purified over silica gel using a 5 to 50% gradient of ethyl acetate/hexanes to give the title compound (7 g, 71%). ES/MS (m/e): 440 (M+H).