Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15](=O)[CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:24][C:25]1[N:26]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH2:39])=[NH:38])=[CH:32][CH:31]=2)[CH:27]=[CH:28][N:29]=1>>[CH3:24][C:25]1[N:26]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:37]3[N:38]=[C:15]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:3]4[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7][C:2]=4[N:39]=3)=[CH:34][CH:35]=2)[CH:27]=[CH:28][N:29]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CC2CCOCC2)C1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 86 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (745 mg, 86%) was synthesised from tert-butyl 4-oxo-3-(2-(tetrahydro-2H-pyran-4-yl)acetyl)piperidine-1-carboxylate and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES−) m/z 503.3 (M−H)−
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.Cl>C1(C)C=CC=CC=1>[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=2)=[CH:34][CH:33]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2nc(C(F)(F)F)nc(-c3ccccc3)c2-c2ccccc2)cc1

Procedure:
4-Chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.2 g, 0.6 mmol, prepared according to the procedure described in PCT/IB03/02879) was heated to reflux with tetra-kis triphenyl palladium (0) (0.068 g, 0.058 mmol), aqueous solution of potassium carbonate (0.16 g in 0.16 ml water), 4-(methylthio)benzene boronic acid (0.168 g, 1 mmol) and toluene (20 ml) under a nitrogen atmosphere overnight. The reaction mixture was acidified with dilute hydrochloric acid 10 ml and extracted with ethyl acetate. The organic layer was concentrated; the crude material obtained was triturated with ether and filtered to yield the title compound. 1H-NMR (DMSO-d6) δ: 2.45 (s, 3H), 7.13-7.15 (m, 4H), 7.23-7.34 (m, 8H), 7.61 (d, 2H); MS m/z: 423.1 (M++1).
Reaction SMILES: [CH3:1][C:2]([C:4]1([CH2:7][CH3:8])[CH2:6][CH2:5]1)=[O:3].[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([OH:11])=[O:10]>>[CH2:7]([C:4]1([C:2]([CH:1]=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=2)=[O:3])[CH2:6][CH2:5]1)[CH3:8]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCC1(C(C)=O)CC1
Product: CCC1(C(=O)C=Cc2ccc(C(=O)O)cc2)CC1

Procedure:
2-(4-Carboxyphenyl)vinyl 1-ethylcyclopropyl ketone [III; Ar is 4-HO2CC6H4, R is C2H5 ] was prepared from 67.2 g. of 1-ethylcyclopropyl methyl ketone and 90 g. of p-carboxybenzaldehyde according to the procedure described above in Preparation A1, affording 40 g., m.p. 183.5°-184.5° C. when recrystallized from acetonitrile and then repeatedly from isopropyl alcohol.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][C@@H:33]1[O:35][C@@H:34]1[CH2:36][OH:37])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][C@@H:33]1[O:35][C@@H:34]1[CH:36]=[O:37])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](OCCCC[C@@H]1O[C@@H]1CO)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCCC[C@@H]1O[C@@H]1C=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Dry DMSO (114 mg, 0.4 mmol) was added dropwise to a stirring, −80° C. solution of oxalyl chloride (110 mg, 0.3 mmol) in dry CH2Cl2 (10 mL) under an argon atmosphere. After 20 min, a solution of ((2R,3S)-3-(4-(tert-butyldiphenylsilyloxy)butyl)oxiran-2-yl)methanol (200 mg, 0.1 mmol) in dry CH2Cl2 (50 mL) was added slowly. After 45 min, triethylamine (200 mg, 0.5 mmol) was added and the reaction mixture was warmed to 0° C. After 0.5 h, the reaction mixture was quenched with water (50 mL). The aqueous layer was separated and back-extracted with CH2Cl2 (2×10 mL). The combined organic extracts were washed with water, brine, and dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified via SiO2 column chromatography using 5% EtOAc/hexanes to give (2S,3S)-3-[4-(tert-butyldiphenylsilanyloxy)-butyl]-oxirane-2-carbaldehyde. The crude aldehyde was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].[CH3:10][O:11][C:12]1[CH:20]=[C:19]([CH3:21])[C:18]([Cl:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>CC(CC)=O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([Cl:22])[C:19]([CH3:21])=[CH:20][C:12]=1[O:11][CH3:10])[CH3:2]
Reactant: COc1cc(C)c(Cl)cc1C(=O)Cl
Reactant: CCN1CCCC1CN
Solvent: CCC(C)=O
Product: CCN1CCCC1CNC(=O)c1cc(Cl)c(C)cc1OC
Temperature: 5 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
In a 1 liter flask equipped with an agitator, a thermometer and a dropping funnel, there are put 46 g (0.36 mole) of 1-ethyl-2-aminomethylpyrrolidine and 45 ml of methylethylketone. While maintaining the temperature of the mixture at about 5° C, there are added dropwise 79 g (0.36 mole) of 2-methoxy-4-methyl-5-chlorobenzoyl chloride dissolved in 400 ml of methylethylketone. The introduction requires about 1 hour. There is precipitation of N-(1-ethyl-2-pyrrolidylmethyl)-2-methoxy-4-methyl-5-chlorobenzamide hydrochloride which is drained, washed on a filter with methylethylketone and air-dried. There are obtained 114 g (yield 91%) of product in the form of white crystals (m.p. 162°-163° C).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O>[Cl:8][C:6]1[CH:7]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=1
Reactant: CN1CCNCC1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Solvent: O
Product: CN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1

Procedure:
Two grams of 4,6-dichloro-2-phenylpyrimidine is added in small portions to 10 ml. of N-methylpiperazine with slight warming and stirring. An exothermic reaction takes place during the addition. The resulting mixture is heated on a steam bath for several minutes and then poured into 250 ml. of water. The product thus obtained is recrystallized from n-pentane to afford 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine, m.p. 91°-92.5°C.
Reaction SMILES: N1C(=O)[C@H](CC2N=CNC=2)NC(=O)[C@@H]1CC(C)C.[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:35]([OH:37])=O)[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:38][C@H:39]([C:46]([OH:48])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1.ClC(OCC(C)C)=O>>[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:35]([NH:38][C@H:39]([C:46]([OH:48])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:31][CH:32]([CH3:33])[CH3:34])=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[C@@H]1NC(=O)[C@H](Cc2c[nH]cn2)NC1=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
The cyclic dipeptide, cyclo-(Leu-His) is a known substance [F. Schneider, Hoppe-Seyler's Z. Phys. Chem. 338, 131 (1964)], which can be prepared according to the usual peptide synthesis. For example, condensation between N-benzyloxycarbonyl-(S)-leucine and methyl ester of (S)-histidine in the presence of isobutyl chloroformate is effected in accordance with the mixed acid anhydride process to obtain methyl ester of N-benzyloxycarbonyl-(S)-leucyl-(S)-histidine and then the ester is hydrogenolyzed in the presence of palladium-carbon, followed by cyclization under reflux in methanol.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[CH2:6]([SH:9])[CH:7]=[CH2:8].[CH3:10][CH2:11]OCC>>[CH2:10]([C:1]1([CH2:2][S:9][CH2:6][CH:7]=[CH2:8])[CH2:5][O:4][CH2:3]1)[CH3:11]
Reactant: C1CCOC1
Reactant: CCOCC
Reactant: C=CCS
Product: C=CCSCC1(CC)COC1

Procedure:
A solution of 2-(3-oxetane)butyl tosylate of example 3 in an inert solvent such as THF is stirred with one equivalent of allyl mercaptan at room temperature until reaction is complete. The solvent is stripped and the residue taken up in ether. The ether is washed with saturated aqueous NaHCO3, dried over MgSO4 and stripped to provide 3-ethyl-3-allythiomethyloxetane.
Reaction SMILES: C(O[C:4](=[O:14])[CH:5]([C:12]#[N:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.Cl.Cl.[CH2:17]([NH:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:26](N(CC)CC)C>C(O)C.C(OCC)(=O)C>[NH2:13][C:12]1[N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]=[C:4]([OH:14])[C:5]=1[C:6]1[CH:7]=[CH:8][C:9]([CH3:26])=[CH:10][CH:11]=1
Reactant: NNCc1ccccc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C(C#N)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(O)nn(Cc3ccccc3)c2N)cc1
Yield: 20 %

Procedure:
To a stirring suspension of ethyl-2-cyano-2-phenylacetate (10.34 g) and benzylhydrazine dihydrochloride (14.87 g) in ethanol (200 ml) at room temperature was added triethylamine (21.27 ml). The reaction mixture was heated to reflux for 24 hours. The solvent was removed under reduced pressure to yield the crude material as a brown oil. This was re-dissolved in ethyl acetate (100 ml) and washed with water (2×75 ml), then dried (MgSO4) and the solvent removed in vacuo to yield a pale brown oil. This was recrystallised from methanol to yield the title product as pale yellow crystals (2.5 g, ca. 20%)
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:16]2[C:30]([O:32]CC)=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>[Li+].[OH-].CO.C1COCC1>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[C:16]2[C:30]([OH:32])=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(N2CCCCC2)c2ccccc2n1CCCOc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(N2CCCCC2)c2ccccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 74A (30 mg) in 1N aqueous LiOH/methanol/THF (1 mL/1 mL/1 mL) was stirred at room temperature overnight. The reaction mixture was acidified with 1NHCl (1 mL), and extracted with ethyl acetate. The organic phase was dried (Na2SO4) filtered, and concentrated. The concentrate was purified by reverse phaseHPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (400 MHz, DMSO-d6) δ 16.82 (s, 1H), 8.08 (d, 1H), 7.96 (d, 1H), 7.85 (d, 1H), 7.69 (d, 1H), 7.48 (m, 3H), 7.36 (t, 1H), 7.24 (m, 1H), 7.13 (t, 1H), 6.83 (t, 1H), 4.89 (t, 2H), 4.16 (t, 2H), 3.24 (br, 4H), 2.33 (m, 2H), 1.70 (br, 6H).
Reaction SMILES: [ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH2:20][N:19](C(OC(C)(C)C)=[O:22])[CH2:18][C:16]=2[N:17]=1>O1CCCC1.O.C(OC)(C)(C)C>[OH2:22].[ClH:1].[ClH:1].[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH:3]1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH2:20][NH:19][CH2:18][C:16]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: c1ccc2c(c1)CC(Nc1ncc3c(n1)CNC3)C2
Temperature: 50 °C
Yield: 80.4 %

Procedure:
Charge 670 mL of 5 M hydrochloric acid (3.35 mol) to a solution of tert-butyl 2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H pyrrolo[3,4-d]pyrimidine-6-carboxylate (226 g, 641.25 mmol) in tetrahydrofuran (2.0 L) at 17° C., maintaining the internal temperature below 26° C. during the addition. Heat the resulting solution to 50° C. for 16 h, cool to 25° C. and dilute with 500 mL of water and 500 mL of tert-butylmethylether. Separate the resulting layers and extract with tert-butylmethylether (3×1 L). Concentrate the water phase down to a reaction volume of ca. 200 mL, and filter the resulting slurry. Rinse the cake with tert-butylmethylether (2×200 mL) and dry to give the title product (177 g, 80%) as a light brown solid. MS (m/z): 253.2 (M−2HCl—H2O+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]([O:11][CH2:12][C:13]2[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][CH2:10][CH2:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[O:11][CH2:12][C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CCC(OCc1ccccc1OC)c1cccc(Cl)c1
Product: COc1ccccc1COC(CCNCc1ccccc1)c1ccccc1

Procedure:
A secondary N-benzylamine can likewise be debenzylated to produce the desired primary amine. To prepare such a secondary benzlamine, 3-chloro-1-(o-anisyloxy)propylbenzene or other 1-substituted phenyl-3-chloropropylbenzene, utilized as an intermediate in an earlier procedure, can be reacted with benzylamine to yield N-benzyl 3-phenyl-3-(o-anisyloxy)propylamine.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)(=[O:36])[CH3:35].O>O1CCCC1>[Br:1][CH2:35][C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)=[O:36]
Reactant: [Br-]
Reactant: CC(=O)c1csc2ccccc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 63.5 %

Procedure:
A solution of phenyltrimethylammonium tribromide (9.6 g) in tetrahydrofuran (20 ml) was added dropwise over 15 minutes at ambient temperature to a stirred solution of 3-acetylbenzo[b]thiophen (5 g) in tetrahydrofuran (50 ml), then the mixture was stirred at ambient temperature for 35 minutes. Water (100 ml) was added, and the resulting solid was collected by filtration, washed with water (2×50 ml) and dried in vacuo at ambient temperature to give 3-(2-bromoacetyl)benzo[b]thiophen as a white solid (2.4 g).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[N:14]3[N:15]=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:17]=[C:18]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:31][NH2:32]>C(O)CCC>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([C:10]3[N:14]4[N:15]=[C:16]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:17]=[C:18]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]4=[N:12][CH:11]=3)=[CH:7][CH:6]=2)[NH:32][N:31]=1
Reactant: NN
Reactant: CC(C)CNc1cc(-c2ccccc2)nn2c(-c3ccc(C#N)c(F)c3)cnc12
Solvent: O
Solvent: CCCCO
Product: CC(C)CNc1cc(-c2ccccc2)nn2c(-c3ccc4c(N)n[nH]c4c3)cnc12
Temperature: 120 °C
Yield: 53 %

Procedure:
To a solution of 46 mg (119 μmol) 2-fluoro-4-[8-(isobutylamino)-6-phenylimidazo[1,2-b]pyridazin-3-yl]benzonitrile which was prepared according to intermediate example 11a in 2.5 mL n-butanol were added 232 μL hydrazine hydrate and the mixture was heated at 120° C. overnight. The precipitate was filtered, washed with 2-propanol and dried to give 26.5 mg (53%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]1[CH:12]([NH:32][C:33](=[O:39])OC(C)(C)C)[CH2:13][C:14]1[CH:22]=[C:21]([CH3:23])[C:20]2[C:16](=[CH:17][N:18](COCC[Si](C)(C)C)[N:19]=2)[CH:15]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH:56]1[CH2:61][CH2:60][CH:59]([N:62]2[CH2:71][C:70]3[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=3)[NH:64][C:63]2=[O:72])[CH2:58][CH2:57]1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]1[CH:12]([NH:32][C:33]([N:56]1[CH2:57][CH2:58][CH:59]([N:62]2[CH2:71][C:70]3[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=3)[NH:64][C:63]2=[O:72])[CH2:60][CH2:61]1)=[O:39])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([CH3:23])[CH:22]=1)[NH:19][N:18]=[CH:17]2
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: Cc1cn(Cc2cccc(F)c2)c(C(Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: Cc1cn(Cc2cccc(F)c2)c(C(Cc2cc(C)c3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)n1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
tert-Butyl 1-(1-(3-fluorobenzyl)-4-methyl-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (20.0 mg, 0.034 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.0 mL). The mixture was stirred under nitrogen for 3 days. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (6.0 mg, 0.037 mmol, 1.1 equiv) and N′N-diisopropylethylamine (24.3 μL, 3 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (8.5 mg, 0.037 mmol, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 16.1 mg (74%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.50-1.68 (m, 4H), 2.27 (s, 3H), 2.46 (s, 3H), 2.77 (m, 2H), 3.20 (m, 2H), 4.01-4.16 (m, 2H), 4.20 (s, 2H), 4.32-4.43 (m, 1H), 5.13-5.22 (m, 2H), 6.60-6.67 (m, 2H), 6.70 (s, 1H), 6.76-6.86 (m, 2H), 6.87-6.94 (m, 1H), 6.96 (dd, J=8.3, 6.7, 1H), 7.07-7.14 (m, 2H), 7.16 (dd, J=7.9, 7.6, 1H), 7.25 (s, 1H), 7.92 (s, 1H). Mass spec.: 621.4 (MH)+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[N:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[NH3:2].[CH:33]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:16]2[N:15]=[CH:14][N:13]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1)([CH3:35])[CH3:32]
Reactant: CC(C)=O
Reactant: CC(Nc1cc(-c2cc3nncn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2ncnn12
Product: N
Temperature: 70 °C
Reaction time: 2 h
Yield: 1 %

Procedure:
A solution of {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine (0.25 g, 0.61 mmol) in chloroform (5 mL) were added acetone (1 mL) and sodium triacetoxyborohydride (0.45 g, 2.14 mmol) and stirred at 70° C. for 2 h. Upon cooling to room temperature, the reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate, brine, and dried (K2CO3). Flash chromatography of the crude product with 1% 2M NH3 in MeOH/CHCl3 afforded the title compound as an off-white solid. MS (ES+): 455.2 [M+H]+, 453.2 [M−H]−.
Reaction SMILES: [N+:1]([O-])([O-])=O.[Na+].[NH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[NH:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=1>O.Cl>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[CH:9][C:8]2[N:17]([C:18]3[CH:19]=[CH:20][C:21]([O:22][CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:31][CH:32]=3)[N:1]=[N:6][C:7]=2[CH:12]=1
Reactant: CCOC(=O)C(CC)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(CC)Oc1ccc(-n2nnc3cc(C(F)(F)F)ccc32)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.1 g of sodium nitrate in 10 ml of water was added drop-by-drop to a stirred solution of 5.0 g of 3B in 150 ml of 12% hydrochloric acid at 5° C. The resulting mixture was stirred at room temperature for 2 days, diluted with 100 ml of water and extracted with ether. The ether was evaporated from the extract and the residue was chromatographed over silica gel, using as eluent a 20/4/1 v/v/v mixture of hexane, ethyl acetate and tetrahydrofuran, to give 3, as a reddish syrupy liquid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl-:1].[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][P+:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:4]=1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1oc(-c2ccco2)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]

Procedure:
4-Chloromethyl-2-(2-furyl)-5-methyloxazole and triphenylphosphine were reacted in the same manner as in Reference Example 7 to yield [2-(2-furyl)-5-methyl-4-oxazolylmethyl]triphenylphosphonium chloride. Melting point 284°-285° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.S1C=CC=C1CC([NH:21][CH:22]1[C:54](=[O:55])[N:24]2[C:25]([C:38]([O:40][CH:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])=[C:26]([C:29]3[S:30][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[N:32][N:33]=3)[CH2:27][S:28][C@H:23]12)=O.C(O)CCC>ClCCl>[NH2:21][CH:22]1[C:54](=[O:55])[N:24]2[C:25]([C:38]([O:40][CH:41]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])=[C:26]([C:29]3[S:30][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[N:32][N:33]=3)[CH2:27][S:28][C@H:23]12
Reactant: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCO
Solvent: c1ccncc1
Product: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: -40 °C
Yield: 40.6 %

Procedure:
To a suspension of 1.5 g of phosphorous pentachloride in 13 ml of dichloromethane is added 1.2 g of pyridine in 13 ml of dichloromethane under stirring at -40° C. To the resulting mixture is added 1.6 g of benzhydryl 7-thienylacetamido-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate in 32 ml of dichloromethane at -40° C. After stirring for one hour at 0° C., to the reaction mixture is added 6 g of n-butanol under stirring at -40° C. After working up as described in Example 26, the obtained residue is chromatographed on a column of silica gel [eluting with ethyl acetate-dichloromethane (1:1)] to give 0.522 g of benzhydryl 7-amino-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate as pale yellow needles.