Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[CH:9]2[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26]#N)=[CH:4][CH:3]=1.[H][H].[NH3:34]>C(O)C.[Ni]>[NH2:34][CH2:28][C:29]1[CH:30]=[CH:31][C:24]([CH:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:11](=[O:12])[CH:10]2[CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[OH:16])=[CH:25][CH:26]=1
Reactant: N#Cc1ccccc1C1C(CCC(O)c2ccc(F)cc2)C(=O)N1c1ccc(F)cc1
Reactant: N
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
200 mg of {1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile were dissolved in 20 ml of ethanol and, with 0.5 ml of conc. ammonia, hydrogenated over Raney nickel at a hydrogen pressure of 75 bar and at 25° C. for 30 hours. The catalyst was filtered off with suction, the mixture was concentrated under reduced pressure and the residue was purified by column filtration (SiO2, CH2Cl2/methanol/conc. NH3=100:10:1). This gives the product of molecular weight 422.5 (C25H22F2N2O2); MS (DCI+): 423 (M+H+), 405 (M+H+−H2O).
Reaction SMILES: [C:1]([OH:10])(=O)[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].S(Cl)([Cl:13])=O>C1C=CC=CC=1>[C:1]([Cl:13])(=[O:10])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCC(CCC)C(=O)O
Solvent: c1ccccc1
Product: CCCC(CCC)C(=O)Cl
Temperature: 50 °C

Procedure:
To 4.32 g (30 mmol) of valproic acid in an ice bath, thionyl chloride (3.60 g, 30 mmol) was slowly added, with stirring. The neat mixture was allowed to come to room temperature and then heated in a water bath at 50° C. for 30 minutes. 50 mL portions of dry benzene were twice added and removed under reduced pressure. The resultant product was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]([CH3:8])[CH2:6][O:5][C:3]1=[O:4].[NH3:9].ClCCl.CO>C(O)C>[CH3:1][C@@H:2]([C@@H:7]([CH3:8])[CH2:6][OH:5])[C:3]([NH2:9])=[O:4]
Reactant: C[C@@H]1C(=O)OC[C@@H]1C
Reactant: N
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: C[C@H](C(N)=O)[C@@H](C)CO
Yield: 60.9 %

Procedure:
(2S,3R)-2,3-dimethylbutyrolactone (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (2S,3R)-2,3-dimethyl-4-hydroxybutyramide.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31]([SH:33])[CH3:32]>CC(C)=O>[CH2:31]([S:33][C:7]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:20])([F:21])[F:22])[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:32]
Reactant: CCS
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1SCC
Yield: 57.8 %

Procedure:
This material was prepared as described in Example 11: 3.36 g (0.009 mol) of product of Example 27, 0.86 g (0.006 mol) of K2CO3 and 12 ml (0.180 mol) of ethanethiol in 25 ml of acetone were reacted affording an orange oil which was kugelrohr distilled at 33 Pa, pot temperature 79° C. to give 2.11 g (58.8%) of product as a clear oil, nD25 1.4507.
Reaction SMILES: C([Al](C[CH:11]([CH3:13])[CH3:12])CC(C)C)C(C)C.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:20]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:13][CH2:11][CH3:12]
Reactant: Cc1ccccc1
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Product: C=CCCCCCCCC

Procedure:
An autoclave with an inner volume of 5 L was charged with 3 L of the decene oligomer produced in (a) in nitrogen gas stream, and here were added trisacetylacetonatocobalt (catalyst weight: 3.0 g) dissolved in toluene and triisobutylaluminum (30 mmol) diluted with toluene. After the reaction system was purged with hydrogen twice, it was heated and kept at 80° C. under a hydrogen pressure of 0.9 MPa. Hydrogenation immediately proceeded exothermically. When four hours passed after the reaction started, the temperature was lowered to terminate the reaction. The pressure was released, the reaction mixture was taken out of the autoclave, and the fraction of boiling at 240 to 270° C. under 530 Pa (desired compound) was isolated by simple distillation.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(N([CH:15]([CH3:17])[CH3:16])CC)(C)C.[Br-:18].[OH-].[Na+]>CN(C=O)C.O.C1(C)C=CC=CC=1>[Br:18][C:16]1[CH:15]=[CH:17][C:3]([CH2:4][NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[CH:2][CH:6]=1
Reactant: [Br-]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)[C@H](NCc1ccc(Br)cc1)C(=O)O
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 153.4 %

Procedure:
52 mL (0.21 mol) of N,O-bistrimethylsilylacetamide is added under nitrogen atmosphere to a mixture made up of 23.5 g (0.20 mol) of L-valine and 38.5 mL (0.22 mol) of diisopropylethylamine in 12.5 mL of DMF. After 1 h at 80° C. the suspension changes to a clear solution. Then, in portions and controlling exothermy, 50 g (0.20 mol) of 4-bromobenzylo bromide is added and left to react at 80° C. for 2 h. The mixture is cooled to 20-25° C., 250 mL of toluene and a solution made up of 250 mL of water and 80 mL of NaOH 40% are added. The resulting aqueous phase is washed twice with 100 mL of AcOEt, the remains of solvent distilled and taken to pH 6-7 with HCl 3N. The solid obtained is filtered with 250 mL of IPA to give 43.9 g (76.5%) of N-(4-bromobenzyl)-L-valine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37].[OH:38][CH2:39][C:40](O)=[O:41].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[CH2:30]([O:29][NH:28][C:26]([CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:37])[N:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[NH:1][C:39](=[O:38])[CH2:40][OH:41])[CH:17]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:27])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: O=C(CO)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl

Procedure:
By condensing (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and hydroxyacetic acid using WSC and HOBt in accordance with Example 1, (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(glycoloylamino)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19](I)=[N:20][C:21]=3[NH:25][O:26][CH3:27])[C@H:13]([OH:29])[C@@H:12]1[OH:30].C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:20][C:21]=3[NH:25][O:26][CH3:27])[C@H:13]([OH:29])[C@@H:12]1[OH:30]
Reactant: C#Cc1ccccc1
Reactant: CONc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONc1nc(C#Cc2ccccc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
CuI (0.35 mg, 0.002 mmol) and phenylacetylene (2.1 mmol) were added to a solution of (4S,2R,3R,5R)-5-(hydroxymethyl)-2-[2-iodo-6-(methoxyamino)purin-9-yl]oxolane-3,4-diol (0.35 mmol), a compound of formula (5), in dry N,N-dimethylformamide (6 mL) and triethylamine (1.4 mL) under an atmosphere of nitrogen in the presence of bis(triphenylphosphine)palladium dichloride (5 mg, 0.007 mmol). The reaction mixture was stirred at room temperature for 5 hours. After evaporation under reduced pressure the residual oil was purified by silica gel column chromatography, eluting with chloroform/methanol 90/10. After evaporation in vacuo, the residual oil was purified by silica gel column chromatography, eluting with the suitable mixture of solvents, to provide (4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(methoxyamino)-2-(2-phenylethynyl)purin-9-yl]oxolane-3,4-diol, a compound of Formula I (mp 175-177° C.).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Br:12]N1C(=O)CCC1=O>OS(O)(=O)=O>[Br:12][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:4]=1
Reactant: CS(=O)(=O)c1ccccc1I
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1cc(Br)ccc1I
Reaction time: 4 h
Yield: 86.2 %

Procedure:
A suspension of 1-iodo-2-(methylsulfonyl)benzene (Intermediate 201; 1.45 g; 5.14 mmol) in conc. H2SO4 (4 mL) was treated with N-bromosuccinimide (1.01 g; 5.65 mmol) and the resulting mixture was stirred for 4 h. The reaction mixture was carefully poured on crushed ice and extracted with EtOAc. The organic phase was washed twice with NaOH 0.1 N and brine, dried over MgSO4, filtered and concentrated to dryness affording the title compound as a white solid (1.6 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[N:3]=1.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1.CCOC(C)=O>O>[ClH:1].[ClH:1].[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[N:3]=2)[CH2:33][CH2:32]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Cc1ccc(S(=O)(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NCCNc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc1
Product: Cl
Temperature: 140 °C

Procedure:
320 mg of the product obtained in Stage 1 above and 844 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to approximately 140° C. for approximately 3 hours then lowered to 80° C., 5 ml AcOEt, then 10 ml of water are added warm. The reaction medium is left to return to ambient temperature, followed by extracting with 2×10 ml of ethyl acetate, washing with 10 ml of a saturated solution of sodium chloride then drying. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 90/10/1, 1.5 ml of hydrochloric acid/ethanol 1.4N, is added followed by leaving to crystallize, filtering, rinsing with 5 ml of ether and drying under vacuum. In this way 173 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([O:17]C)=[O:16])[C@H:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C1COCC1.O.Cl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=[O:16])[C@H:9]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CN1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A solution of 0.016 g (0.034 mmole) of 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxy-carbonylmethyl)-3-(S)-phenylmorpholine (from Example 46) in 2 mL of THF and 0.5 mL of water was treated with 0.027 mL (0.067 mmole) of 2.5 N aqueous sodium hydroxide and the mixture was stirred at room temperature for 5 hr. The mixture was treated with 2 drops of 2N aqueous HCl and 3 mL of water and the solution was extracted with 15 mL of 1:1 hexanes:ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chormatography on 13 g of silica eluting with 250 mL of 100:3:0.1 methylene chloride:methanol:acetic acid then 100 mL of 50:2:0.1 methylene chloride:methanol:acetic acid to give 0.014 g (90%) of an oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([CH2:24][C@H:25]([NH2:32])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:21]1([CH2:24][C@H:25]([NH:32][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine in the presence of TBTU and DIEA to obtain the title compound; MS (EI): m/e=434.2 [MH+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][CH:10]([Cl:14])[C:11](Cl)=[O:12].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:9][CH:10]([Cl:14])[C:11]([NH:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:12]
Reactant: Nc1ncc(Cl)cn1
Reactant: O=C(Cl)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Cl)cn1)C(Cl)Cl

Procedure:
To 2-amino-5-chloropyrimidine (1.30 g) dissolved in N,N-dimethylformamide (30 mL), dichloroacetyl chloride (1.44 mL) and sodium hydrogencarbonate (1.26 g) were added, and the resultant mixture was stirred at room temperature for 1 hour. The solvent was distilled away under reduced pressure. Methylene chloride and water were added to the residue for partitioning the mixture. The aqueous layer was extracted with methylene chloride. The organic layers were combined, and the resultant mixture was washed with water, followed by drying over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane ethyl acetate=1:1). The resultant white solid was slurry-washed with a solvent mixture of hexane-diethyl ether (4:1), followed by filtration to recover, to thereby give the title compound (1.24 g) as a white solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[C:21](=[O:22])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:4].Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37]CNC[CH2:33]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>O>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[C:10]2[C:21](=[O:22])[CH:6]([CH2:5][N:3]3[CH2:2][CH2:33][N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][CH3:24])[CH2:37][CH2:4]3)[CH2:7][CH2:8][C:9]=2[O:13][N:12]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CN(C)CC1CCc2onc(-c3ccccc3F)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1N1CCN(CC2CCc3onc(-c4ccccc4F)c3C2=O)CC1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a solution consisting of 6,7-dihydro-5-dimethylaminomethyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one hydrochloride (2.40 g) in distilled water (24 ml) was added 1-(2-methoxyphenyl)piperazine hydrochloride (3.38 g) and potassium carbonate (1.02 g) at room temperature with stirring. The resulting reaction mixture was heated to reflux for 25 min. and allowed to cool to room temperature. Diethyl ether was then added and the layers separated. The aqueous phase was extracted twice with ether. The combined organics were washed with brine and dried (Na2SO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, ether) afforded 2.45 g of 6,7-dihydro-3-(2-fluorophenyl)-5-(4-(2-methoxyphenyl)-1-piperazinyl)methyl-1,2-benzisoxazol-4(5H)-one as a foam. The compound was flushed thru alumina with dichloromethane to give an oil. The maleate was prepared in ethanol and the resulting salt was washed with ether, m.p. 153°-155° C.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1>O>[CH2:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:40][CH2:41][N:32]1[C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=1[NH:21][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc2C1)c1ccncc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
Isonicotinoyl chloride hydrochloride (390 mg, 2.19 mmol, commercially available product) and triethylamine (449 l, 3.24 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 2-[2-amino-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline (315 mg, 1.08 mmol), obtained as described in Referential Example 21-2. The resulting mixture was warmed to room temperature and stirred for half an hour. Water was added to the mixture, and the resulting mixture was extracted three times with dichloromethane. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=2/1). Thus, N-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0621) (418 mg, 97.6%) was yielded as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][CH3:34])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.Cl.C([O:39][C:40]1[C:45]([O:46]C(=O)C)=[CH:44][N:43]=[C:42]([C:50](Cl)=[O:51])[CH:41]=1)(=O)C.C(=O)(O)[O-].[Na+]>O.CC(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][CH3:34])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][N:22]([C:50]([C:42]5[CH:41]=[C:40]([OH:39])[C:45]([OH:46])=[CH:44][N:43]=5)=[O:51])[CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCNCC3)CS[C@H]12)c1nsc(N)n1
Reactant: CC(=O)Oc1cnc(C(=O)Cl)cc1OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4cc(O)c(O)cn4)CC3)CS[C@H]12)c1nsc(N)n1
Yield: 47.9 %

Procedure:
To a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (255 mg) in a mixture of water (5 ml) and acetone (5 ml) was added 4,5-diacetoxy-2-pyridinecarbonyl chloride hydrochloride (309 mg), with maintaining the pH of the solution to 8.0-8.5 by addition of saturated aqueous sodium bicarbonate. After stirring for 30-minutes, acetone was removed by evaporation in vacuo and the residue was adjusted to pH 8 and stirred for 2 hours. The mixture was adjusted to pH 3.0 with 1N hydrochloric acid and chromatographed on Diaion HP-20 (50 ml), and the elution was carried out with 10% aqueous isopropyl alcohol. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[1-methyl-4(4,5-dihydroxy-2-pyridylcarbonyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (155 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](O)[N:11]3[N:15]=[CH:16][C:17](C([O-])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.CN(C)C1C=CC=CC=1>>[Cl:23][C:12]1[N:11]2[N:15]=[CH:16][CH:17]=[C:10]2[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C([O-])c1cnn2c(O)cc(-c3ccc(Cl)cc3)nc12
Solvent: CN(C)c1ccccc1
Product: Clc1ccc(-c2cc(Cl)n3nccc3n2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of 5-(4-chloro-phenyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (9.53 g, 0.03 mol), phosphorous oxychloride (11.0 mL, 0.12 mol), and N,N-dimethylaniline (1.3 mL, 0.01 mol) was stirred for 2 h at 100° C. The mixture was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The organic phase was washed with water, dried (Na2SO4) and evaporated in vacuo. The remaining solid was crystallized from AcOEt/hexane to give 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (6.80 g, 67%). Pale-yellow solid. MS (ISP) 336.0 [(M+H)+]; mp 133-135° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:15][CH2:14][CH2:13][N:12]=[C:11]1[SH:16].[I:17]I.[I-].[K+]>CO.O>[IH:17].[NH:12]1[CH2:13][CH2:14][CH2:15][N:10]=[C:11]1[S:16][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: SC1=NCCCN1
Reactant: II
Reactant: c1ccc2[nH]ccc2c1
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: I
Product: c1ccc2c(SC3=NCCCN3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 11.7 g indole in 50 ml methanol and 11.6 g 1,4,5,6-tetrahydro-2- pyrimidinethiol in 100 ml methanol is added to a well-stirred solution of 25.4 g iodine and 50 g potassium iodide in 100 ml water. The mixture is stirred for 12 hours at room temperature and cooled. The crystalline product is filtered off. The filtrate is concentrated to one third of the original volume, and cooled to yield more of the resulting product. The combined product is recrystallised from alcohol to give 3-(1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole hydriodide, melting at 251°.