Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6]>>[C:11]1([CH3:12])[CH:10]=[CH:9][C:8]([S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][N:1]=[N+:2]=[N-:3])(=[O:6])=[O:7])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCN=[N+]=[N-])cc1
Yield: 19 %

Procedure:
Sodium azide and tetraethylene glycol ditosylate were reacted according Example 7 p to yield 0.7 g (19%) of 8 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.44 (s, 3H), 3.38 (t, J=5.2 Hz, 2H), 3.55-3.70 (m, 12H), 4.16 (t, J=5.2 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 21.6, 50.7, 68.7, 68.8, 69.2, 70.0, 70.6-70.7, 127.9, 129.8, 133.1, 144.7 MS ESI (m/z): [M+H]+ calcd. for C15H24O6N3S, 374.2. found 374.2
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[C:11]([N+:16]([O-:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1>CN(C=O)C>[Br:1][C:14]1[CH:15]=[C:10]([OH:9])[C:11]([N+:16]([O-:18])=[O:17])=[N:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ncccc1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncc(Br)cc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 115.1 %

Procedure:
N-bromosuccinimide (165 g, 0.927 mole) was added portionwise over 5 h to a solution of 3-hydroxy-2-nitropyridine (100.0 g, 0.714 mole) in DMF (1 L) at 0° C. The resulting mixture was stirred at room temperature for 15 hr then was concentrated in vacuo. The residue was taken up in Et2O (500 mL) and stirred for 30 min. The precipitate was removed by suction filtration, and the filtrate was concentrated in vacuo to afford the title compound (180 g): MS (ES) m/e 219 (M+H)+. This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[NH:10][N:9]=2)=[C:4]2[NH:18][CH:19]=[C:20]([C:21](=[O:41])[C:22](=[O:40])[N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:32]=[N:31][N:30]=4)[CH2:25][CH2:24]3)[C:3]=12.O.[OH-].[Li+].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[NH:10][N:9]=2)=[C:4]2[NH:18][CH:19]=[C:20]([C:21](=[O:41])[C:22](=[O:40])[N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:33]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:32]=[N:31][N:30]=4)[CH2:25][CH2:24]3)[C:3]=12
Reactant: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Temperature: 100 °C
Yield: 56.6 %

Procedure:
To a rb flask containing ethyl 3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate (0.058 g, 0.10 mmol) in DMF (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.044g, 1.05 mmol). The mixture was heated to 100° C. for 21.5 h. The mixture was cooled to rt, and HCl was added to PH=1. Solids precipitated out of solution, and were collected by filtration to give the title compound as a yellow solid (0.03 g). LCMS: m/e 531.15 (M+H)+, ret time 2.10 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 14.37 (s, 1 H) 13.58 (s, 1 H) 12.23 (s, 1 H) 8.21-8.42 (m, 2 H) 7.52-7.77 (m, 5 H) 7.35 (s, 1 H) 3.08-3.76 (m, 8 H).
Reaction SMILES: NC1C=C2C(=CC=1)NN=C2Cl.[Cl:12][C:13]1[C:21]2[C:20]3[C:22](=[O:26])[C:23](=[O:25])[NH:24][C:19]=3[CH:18]=[CH:17][C:16]=2[NH:15][N:14]=1.[CH:27]1[C:32]([NH:33][NH2:34])=[CH:31][CH:30]=[C:29]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:28]=1.Cl>>[Cl:12][C:13]1[C:21]2[C:20]3[C:22](=[O:26])[C:23](=[O:25])[NH:24][C:19]=3[CH:18]=[CH:17][C:16]=2[NH:15][N:14]=1.[Cl:12][C:13]1[C:21]2[C:20]3[C:22](=[N:34][NH:33][C:32]4[CH:31]=[CH:30][C:29]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:28][CH:27]=4)[C:23](=[O:25])[NH:24][C:19]=3[CH:18]=[CH:17][C:16]=2[NH:15][N:14]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: Nc1ccc2[nH]nc(Cl)c2c1
Agent: O=C1Nc2ccc3[nH]nc(Cl)c3c2C1=O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4[nH]nc(Cl)c4c32)cc1

Procedure:
1-Chloro-3,6-dihydro-pyrrolo[3,2-e]indazole-7,8-dione was prepared from 5-amino-3-chloroindazole according to Procedure A in 38% yield: 1H NMR (DMSO-d6): δ7.08 (d, J=7.9 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 10.95 (s, 1H), 13.70 (s, 1H). Condensation of 1-chloro-3,6-dihydro-pyrrolo[3,2-e]indazole-7,8-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 45% yield: 1H NMR (DMSO-d6): δ7.11 (d, J=8.8 Hz, 1H), 7.26 (s, 2H), 7.51 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.82 (d, J=8.8 Hz, 2H), 11.17 (s, 1H), 13.25 (s, 1H), 13.41 (s, 1H): APCI−MS m/z 389/391 (M−H)−. Anal. Calcd for C15H11CIN6O3S: C, 44.86, H, 3.06; N, 20.93; S, 7.98. Found C, 45.02, H, 3.31; N, 20.92; S, 7.77.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[NH2:16][C:17]([NH:19][C:20]1[NH:21][C:22]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=2)=[CH:23][C:24]=1[C:25]([NH2:27])=[O:26])=[O:18].C(=O)([O-])O.[Na+]>CN(C)C=O.O.C(O)(=O)C>[NH2:16][C:17]([NH:19][C:20]1[NH:21][C:22]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][OH:11])=[CH:32][CH:33]=2)=[CH:23][C:24]=1[C:25]([NH2:27])=[O:26])=[O:18]
Reactant: OCCNCc1ccccc1
Reactant: NC(=O)Nc1[nH]c(-c2ccc(C=O)cc2)cc1C(N)=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Nc1[nH]c(-c2ccc(CN(CCO)Cc3ccccc3)cc2)cc1C(N)=O
Yield: 36 %

Procedure:
Acetic acid (30 μl N-benzylethanolamine (79 μL, 0.55 mmol) and sodium cyanoborohydride (35 mg, 0.55 mmol) were added to a solution of 2-aminocarbonylamino-5-(4-formylphenyl)pyrrole-3-carboxamide (Compound No. 14-1, 50 mg, 0.18 mmol) in N,N-dimethylformamide (3 mL) and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate (10 mL) and water (10 mL) were added to the reaction solution, extracted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography to give the target compound (26 mg) as a colorless solid (Yield 36%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[N:11]1[C:18]([Cl:19])=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13]>O1CCCC1>[Cl:13][C:12]1[N:11]=[C:18]([Cl:19])[N:17]=[C:15]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:14]=1
Reactant: Oc1ccc(F)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(Oc2nc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
EX-44B) To a solution of p-fluorophenol 1.00 g (8.92 mmol) in 30 mL of tetrahydrofuran at 0° C. was added a 60% dispersion of sodium hydride in mineral oil (0.36 g, 8.92 mmol). After 30 min, cyanuric chloride (1.64 g, 8.92 mmol) was added as a heterogeneous nixture in tetrahydrofuran at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After 14 h, the mixture was cooled to 0° C., and a saturated aqueous NH Cl solution was added. The aqueous solution was extracted with diethyl ether (3×50 mL). The combined ether extracts were washed with brine, dried (MgSO4), and concentrated in vacuo to afford 1.34 g (58%) of the desired 2,4-dichloro-6-(4-fluorophenoxy)-1,3,5-triazine product as an off white solid which was taken on to the next step without purification. MS m/z=260 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23]C3CCCCO3)=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][OH:23])=[CH:18][CH:19]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCO)cc1)Oc1ccc(F)cc1
Yield: 88.7 %

Procedure:
In a similar manner to that described in Reference example 3(f), a reaction was carried out using ethyl 2-(4-fluorophenoxy)-3-[4-[2-(tetrahydropyran-2-yloxy)ethoxy]-phenyl]propionate (3.75 g), which is the product of Reference example 37(c), and p-toluensulfonic acid monohydrate (2.15 g) and the reaction mixture was treated to afford the desired compound (2.68 g) as a colorless oil.
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)[CH:12]=O)[CH3:7].C(OP([CH2:31][C:32](=[O:43])[NH:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1)(=O)OCC)C.O.[OH-].[Li+]>C(OCC)(=O)C.O>[CH2:6]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:31]/[C:32]([NH:33][CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36][CH2:35]2)=[O:43])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)[CH3:7]
Reactant: CCOc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(CC(=O)NC1CCc2ccccc21)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 22.8 %

Procedure:
To a THF (8 mL) solution of 3-ethoxy-4-(4-methyl-1H-imidazole-1-yl)benzaldehyde (60 mg), (indan-1-ylcarbamoylmethyl)phosphonic acid diethyl ester (81 mg) and lithium hydroxide monohydrate (22 mg) were added, and the reaction mixture was agitated at room temperature for 14 hours. Water and ethyl acetate were added to the reaction solution after the reaction ended, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 1:4), and 23 mg (23%) of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(C)=O)cc3CO1)CC2
Yield: 96.9 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (100 mg, 0.323 mmol) and acetic anhydride (61.1 ul, 0.646 mmol) according to the procedure described for Example 48. Obtained the title compound as a light brown foam (110 mg, 97%), MS (ISP) m/e=352.2 [(M+H)+].
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:15]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:43])[NH:23][C@@H:24]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:25](NCCCN(CC)CC)=[O:26])=[CH:17][CH:16]=1.[CH:50]([NH:53][CH2:54][CH2:55][NH2:56])([CH3:52])[CH3:51].CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[C:15]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:43])[NH:23][C@@H:24]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:25]([NH:56][CH2:55][CH2:54][NH:53][CH:50]([CH3:52])[CH3:51])=[O:26])=[CH:17][CH:16]=1
Reactant: CC(C)NCCN
Reactant: CCN(CC)CCCNC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)NCCNC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1ccc(-c2ccccc2)cc1
Reaction time: 6 h
Yield: 56.2 %

Procedure:
To a mixture of EDC (0.08 g, 0.42 mmol), HOBT (0.056 g, 0.42 mmol) and (S)-2-(3-biphenyl-4-yl-ureido)-3-phenyl-propionic acid (Example 13, step A)(0.1 g, 0.28 mmol) in DMF (3 mL), N′-isopropyl-ethane-1,2-diamine (0.054 g, 0.42 mmol) was added at rt followed by N-methyl morpholine (0.056 g, 0.55 mmol). The solution was stirred for 6 h, diluted with EtOAc (100 mL), washed with saturated NaHCO3 (2×20 mL) and brine (2×20 mL), and dried (Na2SO4). The solvent was removed, and the residue was purified by flash column chromatography using 0–20% MeOH (1% NH4OH)/CH2Cl2 to afford 0.07 g (57%) of the desired product. MS (electrospray): mass calculated for C27H32N4O2, 444.25; m/z found, 445.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.89 (s, 1H), 8.18 (t, J=5 Hz, 1H), 7.61–7.2 (m, 14H), 6.53 (d, J=8 Hz, 1H), 4.46 (m, 1H), 3.16 (m, 2H), 2.9 (dd, J=13.7, 5.8 Hz, 1H), 2.86 (dd, J=13.7, 7.72 Hz, 1H), 2.79 (m, 1H), 2.58 (m, 2H), 0.98 (d, J=6.2 Hz, 6H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:14]([O-])(=[O:16])[CH3:15].[Na+].C(OC(=O)C)(=O)C.N>O.C(O)(=O)C>[C:14]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:12]([Cl:13])[C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: Clc1ccc2c(c1Cl)CNCC2
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1CCc2ccc(Cl)c(Cl)c2C1

Procedure:
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.001 mole) was treated with sodium acetate (0.001 mole), acetic anhydride (0.00125 mole), and 2 ml. of acetic acid and the mixture was heated at 95° C. for 15 minutes. The mixture was cooled, dilutes with water, made alkaline with aqueous ammonia and extracted with chloroform. Concentration of the extract and recrystallization of the residue from isopropanol gave 2-acetyl-7,8-dichloro-1,2,3,4-tetrahydroisoquinoline, m.p. 99.5°-100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([Cl:24])[C:21]([S:25][CH3:26])=[C:20]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:19]=2)=[CH:14][CH:13]=1)=S.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:9]1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:23]=[C:22]([Cl:24])[C:21]([S:25][CH3:26])=[C:20]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:19]=2)=[CH:16][CH:17]=1
Reactant: CSc1c(Cl)nc(-c2ccc(NC(=S)Nc3ccccc3N)cc2)nc1N1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CSc1c(Cl)nc(-c2ccc(Nc3nc4ccccc4[nH]3)cc2)nc1N1CCOCC1
Yield: 62.3 %

Procedure:
A mixture of 1-(2-amino-phenyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea (120 mg, 1.0 eq.) and DCC (0.18 g, 0.271 mmol, 1.1 eq.) in THF (8 ml) was reacted for 9 hrs at 80-90° C. The resulting mixture was dried in vacuo, crystallized in EA solution, filtered to give a yellow solid (69.5 mg, 62.3%), which was then dried in vacuo to give a product.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[O:10])[O:4][N:3]=1.Cl.O1CCOCC1>CCOC(C)=O>[OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:11][CH2:12][CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[O:10])[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CCc2cc(O)no2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(CCc1cc(O)no1)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)piperidine-1-carboxylate (step 1) (539 mg, 1.525 mmol) in EtOAc (15 mL) was added 4N HCl in dioxane (15 ml, 60.0 mmol). The suspension was stirred at RT for 2 hrs and then concentrated under reduced pressure to give 3-(3-hydroxyisoxazol-5-yl)-N-(piperidin-4-ylmethyl)propanamide as a gum.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]([OH:8])=[O:7].Cl[C:15]1[CH:16]=[C:17](C=C(C)N=1)C(O)=O.C(NC)C(C)C>>[CH2:1]([N:2]([CH3:13])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]([OH:8])=[O:7])[CH:16]([CH3:17])[CH3:15]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: Cc1cc(C(=O)O)cc(N(C)C)n1
Agent: CNCC(C)C
Product: Cc1cc(C(=O)O)cc(N(C)CC(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-dimethylamino-6-methyl-isonicotinic acid starting from 2-chloro-6-methyl-isonicotinic acid and using isobutyl-methyl-amine; LC-MS: tR=0.61 min, [M+H]+=223.10.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[O:6][S:7]([NH:10][C:11](=[O:22])OC1C=CC=CC=1OCC)(=[O:9])=[O:8])[CH3:2].[NH2:27][C:28]1[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[O:6][S:7]([NH:10][C:11]([NH:27][C:28]1[N:29]=[C:30]([O:36][CH3:37])[CH:31]=[C:32]([O:34][CH3:35])[N:33]=1)=[O:22])(=[O:8])=[O:9])[CH3:2]
Reactant: CCOc1ccccc1OC(=O)NS(=O)(=O)Oc1ccccc1OCC
Reactant: COc1cc(OC)nc(N)n1
Solvent: Cc1ccccc1
Product: CCOc1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 100 °C
Yield: 97.5 %

Procedure:
38.1 g of 2-ethoxyphenyl N-(2-ethoxyphenoxysulfonyl)carbamate are dissolved in 500 ml of toluene, 15.5 g of 2-amino-4,6-dimethoxypyrimidine are added at room temperature, and the mixture is heated for 2 hours at 100° C. After cooling to 30° C., the precipitate is filtered off and washed with 100 ml of toluene. 38.8 g of the desired product are obtained with a purity of 98.8%, corresponding to a yield of 96.4% of theory. The melting point for the product is 147°-149° C. 6.5 g of 2-ethoxyphenol are recovered from the mother liquor by distillation.
Reaction SMILES: [OH:1][CH:2]([C@H:7]1[CH2:11][N:10]([C@@H](C2C=CC=CC=2)C)[C:9](=[O:20])[CH2:8]1)[CH2:3][CH2:4][O:5][CH3:6].O>FC(F)(F)C(O)=O>[OH:1][C@@H:2]([C@H:7]1[CH2:11][NH:10][C:9](=[O:20])[CH2:8]1)[CH2:3][CH2:4][O:5][CH3:6]
Reactant: COCCC(O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COCC[C@@H](O)[C@H]1CNC(=O)C1
Temperature: 150 °C
Reaction time: 0.75 h

Procedure:
110 mg (4R)-4-(1-hydroxy-3-methoxypropyl)-1-((R)-1-phenylethyl)pyrrolidine-2-one (I.17) was dissolved in 5 mL trifluoroacetic acid and stirred at 150° C. in the microwave for 45 min. Water was added and the mixture was concentrated at 60° C. Co-evaporation with toluene and dichloromethane provided the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>C.[Mo].[Mo]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Mo]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a dimolybdenum carbide from H. C. Starck at 140° C. After 2 hours' reaction time, phenol conversion was 6.0%, wherein 5.1 g of phenyl chloroformate and 5.8 g of diphenyl carbonate were formed. Selectivity for carbonates was 97.3%.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[N:9]=[C:8](/[CH:10]=[CH:11]/[C:12]([NH:14][NH:15]C(OC(C)(C)C)=O)=[O:13])[CH:7]=[CH:6][C:5]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1.C(O)CCC.CC(OC)(C)C>CO>[ClH:1].[ClH:1].[CH3:2][O:3][C:4]1[N:9]=[C:8](/[CH:10]=[CH:11]/[C:12]([NH:14][NH2:15])=[O:13])[CH:7]=[CH:6][C:5]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: COc1nc(/C=C/C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCCCO
Solvent: CO
Solvent: COC(C)(C)C
Product: COc1nc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Conc. HCl (5.85 mL) was added to the suspension of tert-Butyl 2-{(2E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]prop-2-enoyl}hydrazinecarboxylate (1.17 g, 3.13 mmol) in methanol (5.85 mL) with an ice-bath cooling. The reaction mixture was stirred at room temperature for 30 minutes. 1-Butanol (5.85 mL) and MTBE (5.85 mL) were added to the reaction mixture, and the mixture was stirred for 20 minutes with an ice-bath cooling. The mixture was filtrated, and the residue was washed with 1-butanol-MTBE (2:8) (5.85 mL) and dried under the reduced pressure to obtain the title compound (937 mg, 78.2% yield).
Reaction SMILES: C([BH3-])#N.[Na+].[CH:5]([O:18][C:19]([C:21]1[N:26]2[C:27](=[O:40])[C@@H:28]([NH:29][C:30](=[O:39])[CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:25]2[S:24][CH2:23][C:22]=1N1CCOCC1)=[O:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)=O>O1CCCC1.C(Cl)Cl.C(O)(=O)C>[CH:5]([O:18][C:19]([C:21]1[N:26]2[C:27](=[O:40])[C@@H:28]([NH:29][C:30](=[O:39])[CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:25]2[S:24][CH2:23][CH:22]=1)=[O:20])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCOCC3)CS[C@H]12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=CO
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.05 g of sodium cyanoborohydride in 30 ml of tetrahydrofurane is added dropwise over 20 minutes to a solution of 5.86 g (10 mmols) of 7β-phenoxyacetylamino-3-morpholino-3-cephem-4-carboxylic acid benzhydryl ester in 50 ml of methylene chloride and 50 ml of glacial acetic acid, whereupon vigorous evolution of gas occurs. Then 20 ml of formic acid are added and the reaction mixture is stirred for 16 hours at room temperature. For working up, the reaction mixture is diluted with 300 ml of methylene chloride and the organic phase is washed four times with 100 ml of water, then dried over sodium sulfate. The solvent is distilled off in vacuo. The almost colourless crude product is chromatographed on silica gel with toluene/ethyl acetate (9:1), affording pure 7β-phenoxyacetylamino-3-cephem-4-carboxylic acid benzhydryl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[C:10]2[N:22]=[C:21](S(C)(=O)=O)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[C:10]2[N:22]=[C:21]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)c1nc2nc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Reactant: C1COCCN1
Product: Fc1cnccc1-c1nc2nc(N3CCOCC3)[nH]c2nc1-c1cccnc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of 5-(3-fluoropyridin-4-yl)-2-(methylsulfonyl)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine (0.060 g, 0.16 mmol) and morpholine (1.5 mL) were heated to 120° C. in a sealed tube. After 3 hours, the mixture was evaporated and the residue was purified by silica gel chromatography eluting with dichloromethane/methanol (95:5) to give the title compound (0.029 g, 48%) as a white solid.