Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:19].C(Cl)(Cl)Cl>C(C(C)=O)C.Cl>[O:19]=[C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=2)[N:5]1[CH2:4][CH:3]=[O:2]
Reactant: COC(Cn1c(=O)ccc2ncc(C(F)(F)F)cc21)OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCC(C)=O
Product: O=CCn1c(=O)ccc2ncc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of 90 mg of 1-(2,2-dimethoxyethyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one in 0.72 mL of methyl ethyl ketone, 38 μL of concentrated hydrochloric acid was added, and the mixture was heated under reflux while stirring for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, thereto were added chloroform and a saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 67 mg of (2-oxo-7-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a brown oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].C(O)(=O)C.[NH2:18][N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[N:22][N:21]=[C:20]1[S:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[N:18][N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[N:22][N:21]=[C:20]1[S:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])[CH3:2]
Reactant: Cc1nnc(SCc2ccccc2F)n(N)c1=O
Reactant: CCOc1cc(C=O)ccc1OC
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(C=Nn2c(SCc3ccccc3F)nnc(C)c2=O)ccc1OC
Temperature: 65 °C

Procedure:
0.054 g of 3-ethoxy-4-methoxybenzaldehyde and 0.017 ml of acetic acid were added to a solution of 0.080 g of 4-amino-3-(2-fluorobenzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one in 4 ml of ethanol, and the mixture was stirred at 65° C. The resultant precipitate was filtered off with suction, giving 4-[(3-ethoxy-4-methoxybenzylidene)amino]-3-(2-fluorobenzylsulfanyl)-6-methyl-4H-1,2,4-triazin-5-one.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:20])[C:6]([OH:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:2]#[CH:3].[CH2:21]=[O:22].Cl.[Cl-].[Na+]>CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>[OH:22][CH2:21][C:3]#[C:2][CH2:1][NH:4][C:5](=[O:20])[C:6]([OH:19])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=O
Reactant: C#CCNC(=O)C(O)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CS(C)=O
Product: O=C(NCC#CCO)C(O)(c1ccccc1)c1ccccc1
Temperature: 75 °C
Reaction time: 0.75 h
Yield: 65.1 %

Procedure:
A mixture of N-(2-propynyl)-2-hydroxy-2,2-diphenylacetamide (165.2 g), cuprous chloride (2.50 g) and potassium carbonate (1.73 g) in dimethylsulfoxide [330 ml) was stirred at 75° C. for 45 minutes under a nitrogen atmosphere. To the reaction mixture was added paraformaldehyde (25.3 g) and the mixture was stirred at 85° C. for 5 hours. The reaction mixture was poured into the mixture of 5% hydrochloric acid and 10% aqueous solution of sodium chloride (1:5), and extracted with ethyl acetate. The extracts were washed successively with brine, 5% aqueous solution of sodium thiosulfate and brine, dried over magnesium sulfate and evaporated in vacuo. To the residue was added a mixture of diisopropyl ether and chloroform (1:1) (100 ml) and the mixture was stirred at room temperature for 30 minutes. The resulting precipitates were collected by filtration, washed with a mixture of diisopropyl ether and chloroform (1:1) and dried to give N-(4-hydroxy-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (119.7 g).
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[Cl-].[CH3:12][S:13][C:14]1[CH:39]=[CH:38][C:17]([CH2:18][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:16][CH:15]=1.[F:40][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[C:46](=O)[CH:45]([CH3:51])[CH2:44]2>O.C1C=CC=CC=1>[F:40][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[C:46](=[CH:18][C:17]1[CH:16]=[CH:15][C:14]([S:13][CH3:12])=[CH:39][CH:38]=1)[CH:45]([CH3:51])[CH2:44]2
Reactant: CC1Cc2cc(F)ccc2C1=O
Reactant: CSc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: CSc1ccc(C=C2c3ccc(F)cc3CC2C)cc1
Temperature: 75 °C

Procedure:
169 Mg. (1.5 mm) of potassium t-butoxide was dissolved in 2 ml. of DMSO and treated with 651 mg. (1.5 mm) of p-methylthiobenzyltriphenylphosphonium chloride dissolved in 1 ml. of DMSO. To this solution was added 270 mg. (1.65 mm) of 5-fluoro-2-methyl-1-indanone in 2 ml. of DMSO. The solution was heated at 75°C for 15.5 hours. Benzene and water were added and the benzene layer was washed five times with water. The benzene layer was dried over Na2SO4 and evaporated to dryness under vacuum. The weight was 915.6 mg. This material was eluted through 8 g. of silica gel with benzene to remove triphenylphosphine oxide. The eluate weighed 372 mg. after removal of solvent. This was rechromatographed through 15 g. of silica gel using hexane and 95.9 mg. of 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-indane was isolated, melting point 67° to 70°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)C1C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:45]2[CH:46]=[CH:47][C:42]([C:41]([OH:49])=[O:40])=[CH:43][CH:44]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
To a stirred solution of 3-hydroxy-pyrrolidine-1-carboxylic acid t-butyl ester (3 g, 16.02 mmol) in dry THF (75 mL) was added triphenyl phosphine (4.62 g, 17.62 mmol) and 4-hydroxy-benzoic acid benzyl ester (4.02 g, 17.62 mmol). The reaction mixture was cooled to 0° C. and DEAD (2.78 mL, 17.62 mmol) was added dropwise over a period of 30 min. The reaction was gradually brought to room temperature and stirring continued for 16 hrs. The solvent was removed under vacuum and the residue purified by column chromatography (Flash 40) using a gradient of starting from EtOAc-heptane 1:20 to 1:5. Desired fractions were collected and the solvent evaporated in vacuo. The residue was dissolved in EtOH (80 mL) and 10% Pd/C (0.5 g) was added and the mixture was hydrogenated for 16 hrs. The mixture was filtered and the volatiles were evaporated in vacuo affording 3.4 g (69%) of 3-(4-carboxy-phenoxy)-pyrrolidine-1-carboxylic acid t-butyl ester as a solid.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][CH:27]=1>ClCCl.N1C=CC=CC=1>[F:31][C:28]([F:29])([F:30])[C:24]1[CH:23]=[C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=2)=[O:13])[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 15.1 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3-aminobenzotrifluoride (1.87 g, 11.6 mmol) in 15 mL of pyridine. The crude product was recrystallized from ethanol, then ethyl ether to yield 0.519 g of the title compound, mp 167-168° C.
Reaction SMILES: [OH-].[Na+].CC1OC(C2C=CC=CC=2)=NC=1COC1C=CC(CO/N=[C:24](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=CC=1.CO.Cl>O1CCCC1>[C:34]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 233.1 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (3 ml) was added to a solution of ethyl E-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (530 mg) in tetrahydrofuran (6 ml)-methanol (3 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (3.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[4-(5-methyl-2-pheny]-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoic acid (451 mg, yield 90%) as colorless crystals. m.p. 112-113° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][O:10][N:11](C)[C:12](OC)=O)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][O:10][NH:11][CH3:12])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)N(C)OCCNC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Product: CNOCCNC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A mixture of [2-(N-Methyl-N-methoxycarbonyl-aminooxy)-ethyl]-carbamic acid tert-butyl ester (630 mg, 2.54 mmol), as prepared in the previous step, KOH (439 mg, 6.65 mmol, 15% water), D2O (2.0 mL) was stirred at 90° C. for 18 h. The mixture was allowed to cool to room temperature (a bilayer formed), and extracted with DCM (2×10 mL). The organic layers were combined, dried (2×Na2SO4), and concentrated to give 408 mg of the title compound (contaminated with 10 mol % starting material) as a nearly colorless oil (2.15 mmol, 85% yield). 1H NMR (300 Hz, CDCl3) δ 3.72 (t, J=4.9 Hz, 2H), 3.33 (br t, J=4.7 Hz, 2H), 2.70 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:23])[N:4]([CH2:19][C@@H:20]2[CH2:22][O:21]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1>C(O)C>[Cl:1][C:2]1[C:3](=[O:23])[N:4]([CH2:19][C@@H:20]([OH:21])[CH2:22][NH:31][CH2:30][C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C[C@@H]3CO3)c(=O)c1Cl)C2(C)C
Reactant: NCc1ccncc1
Solvent: CCO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C[C@@H](O)CNCc3ccncc3)c(=O)c1Cl)C2(C)C
Yield: 30.2 %

Procedure:
4-Chloro-2-[(2R)-oxiran-2-ylmethyl]-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (0.141 mmol) in ethanol (2 mL) was stirred with 1-(pyridin-4-yl)methanamine (17 μL, 0.17 mmol) at 80° C. for 8 hours. After cooling, the reaction solution was concentrated, mixed with water and extracted with ethyl acetate, and the extract was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/methanol=9/1) to give the desired product (19 mg, 29% yield).
Reaction SMILES: C([N:4]1[CH2:8][C@H:7]([C:9](=[O:11])[CH3:10])[CH2:6][C:5]1=[S:12])(=O)C>Cl.CO>[C:9]([C@H:7]1[CH2:8][NH:4][C:5](=[S:12])[CH2:6]1)(=[O:11])[CH3:10]
Reactant: CC(=O)[C@@H]1CC(=S)N(C(C)=O)C1
Agent: Cl
Solvent: CO
Product: CC(=O)[C@H]1CNC(=S)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 81.9 %

Procedure:
(+)-(4R)-1-Acetyl-4-acetylthio-2-pyrrolidone (6 g) is dissolved in 5% hydrogen chloride-methanol solution, and the mixture is stirred at room temperature for 25 minutes. The mixture is evaporated to remove the solvent, and the residue is subjected to azeotropic distillation with toluene. To the residue is added acetyl chloride (6 ml), and the mixture is stirred for 4.5 hours. The precipitated crystals are collected by filtration, and dissolved in chloroform. The chloroform solution is washed with water, dried, and evaporated to remove the solvent to give (4R)-4-acetylthio-2-pyrrolidone (3.8 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[C:32]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[C:32]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OCc2ccccc2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCCCC3)c2OCc2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
Piperidine (0.038 g, 0.45 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.129 g, 0.68 mmol) were added to a methylene chloride solution (10 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.095 g, 0.23 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.060 g, 0.12 mmol, 55%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].Br[CH2:18][CH2:19][CH2:20][F:21]>C1COCC1>[CH2:9]([O:8][P:6]([CH:11]([CH2:18][CH2:19][CH2:20][F:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:5][CH2:3][CH3:4])=[O:7])[CH3:10]
Reactant: FCCCBr
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCF)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (2.72 g, 60% on mineral oil, 68.0 mmol) was washed several times with hexanes under an nitrogen atmosphere and was then suspended in dry THF (60 mL). Ethyl (diethoxyphosphoryl)acetate (13.3 g, 59.1 mmol) was added dropwise within 20 min at r.t. as a solution in dry THF (20 mL). After stirring for 2 h at r.t. 1-bromo-3-fluoropropane (10.0 g, 70.9 mmol) was added and the mixture was heated to reflux for 14 h. The mixture was then cooled to r.t. and the reaction was quenched by addition of sat. aq. ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine and dried over sodium sulphate. After evaporation of the solvent under reduced pressure the crude product was purified by column chromatography (silica, hexanes/ethyl acetate gradient).
Reaction SMILES: ON1C(=O)CCC1=O.[C:9]([OH:40])(=[O:39])[CH2:10][CH2:11][C@H:12]([NH:16][C:17]([C:19]1[CH:38]=[CH:37][C:22]([NH:23][CH2:24][C:25]2[N:36]=[C:35]3[C:28]([N:29]=[C:30]([NH:32][C:33]3=[O:34])[NH2:31])=[N:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:18])[C:13]([OH:15])=[O:14].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:56][CH:57]([NH2:63])[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>CS(C)=O>[C:9]([O-:40])(=[O:39])[CH2:10][CH2:11][C@H:12]([NH:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([NH:23][CH2:24][C:25]2[N:36]=[C:35]3[C:28]([N:29]=[C:30]([NH:32][C:33]3=[O:34])[NH2:31])=[N:27][CH:26]=2)=[CH:37][CH:38]=1)=[O:18])[C:13]([OH:15])=[O:14].[NH2:56][CH:57]([NH2:63])[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCC(N)N
Agent: O=C1CCC(=O)N1O
Solvent: CS(C)=O
Product: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc3)nc2c(=O)[nH]1
Reaction time: 2 h

Procedure:
8 mg NHS (N-Hydroxysuccinimide) was added to 16 mg folic acid in 4 ml DMSO solvent followed by 9 mg of DCC (dicyclohexyl carbodiimide) in 500 μl DMSO. It was then incubated at room temperature for 2 h then added to 4.7 mg Diaminohexane in 500 μl DMSO forming a white-yellow precipitate/suspension. It was left overnight to react to completion forming the folate-diaminohexane linker. 156 μl of this was then added to 1 mg of Sulfo-SBED (2-[(6-(Biotinamido)-2-(p-azidobenzamido)-hexanamido]ethyl-1-3′-dithio-propionate) (Pierce & Warriner product number 33033) in 100 μl DMF and incubated for a further 48 h during which time the solution clarified. This was followed by the addition of 750 μl distilled water to neutralise any tridentate-NHS ester groups which might have remained. After a further 4 h 500 μl of this hydrolysed tridentate-folate complex was added to 1 mg (500 μl) of antibody and incubated for a further 48 h.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][CH:9]1[O:13][N:12]=[C:11]([CH:14]([F:16])[F:15])[CH2:10]1.[NH4+].[Cl-]>C1COCC1>[F:15][CH:14]([F:16])[C:11]1[CH:10]2[CH:9]([CH2:8]2)[O:13][N:12]=1
Reactant: FC(F)C1=NOC(CCl)C1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: FC(F)C1=NOC2CC12
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of potassium tert-butoxide (1.0 M in THF, 66.3 mL, 66.3 mmol) was added dropwise to a solution of 5-(chloromethyl)-3-(difluoromethyl)-4,5-dihydroisoxazole (16a rac, 9.0 g, 53.1 mmol) in THF (70 mL) at 0° C. The reaction mixture was stirred for 30 min, then aqueous saturated NH4Cl solution was added slowly. The mixture was extracted with Et2O (2×), and the combined organic extracts were dried over MgSO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% Et2O/pentane gradient) to give the title compound as an oil (5.29 g, 75% yield)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](/[CH:14]=[N:15]/[NH:16][C:17]3[N:22]=[CH:21][C:20]([C@@H:23]([N:28]4[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]4)[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][C:5]=1[F:41])[CH3:2].C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:22]4[CH:21]=[C:20]([C@@H:23]([N:28]5[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:29]5)[C:24]([F:27])([F:25])[F:26])[CH:19]=[CH:18][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][C:5]=1[F:41])[CH3:2]
Reactant: CCOc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F
Agent: O=Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To tert-butyl (S)-1-((R)-1-(6-((E)-2-((7-ethoxy-6-fluoro quinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (368 mg, 0.638 mmol) in DCM was added iodosobenzene acetate (267 mg, 0.830 mmol) and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl (S)-1-((R)-1-(3-(7-ethoxy-6-fluoroquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (265 mg, 72.3% yield) as a beige solid
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)#[N:23].[BH4-].[Na+]>O1CCCC1>[C:16]1([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][CH2:28][C:27]4[CH:30]=[CH:31][C:24]([C:22]#[N:23])=[CH:25][CH:26]=4)=[CH:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(C(=O)N2CCN(c3ccccc3)CC2)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CNc2ccc(C(=O)N3CCN(c4ccccc4)CC3)cc2)cc1
Temperature: 50 °C

Procedure:
To a stirred solution of (4-amino-phenyl)-(4-phenyl-piperazin-1-yl)-methanone (0.5 g, 1.78 mmol) in tetrahydrofuran (10 mL) was added 4-cyanobenzaldehyde (0.4 g, 2.67 mmol) followed by sodium borohydride and the reaction was heated to 50° C. for 2 hours. On cooling, the reaction was quenched by the addition of water (10 mL) and the aqueous solution basified by the addition of ammonium chloride (˜pH 8). The aqueous mixture was extracted using dichloromethane (3×10 ml) and the organic extracts combined, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as an off white solid (604 mg, 98% yield). HPLC retention time 7.17 min. Mass spectrum (ES+) m/z 397 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[O:26])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)COCCCl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1C
Product: NC(=O)COCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of 37.8 g (0.15 mole) of 1-(diphenylmethyl)-piperazine, 27.5 g (0.2 mole) of 2-(2-chloroethoxy)-acetamide and 26.5 g of anhydrous sodium carbonate in 120 ml of xylene is heated for 4 hours to 90° to 120° C. Thereafter, 120 ml of benzene are added to the reaction mixture, the precipitate formed is filtered off and the organic phase is extracted with dilute hydrochloric acid (30 ml of concentrated hydrochloric acid and 100 ml of water). 40 ml of a concentrated aqueous solution of sodium hydroxide are added, followed by extraction with benzene. The benzene solution is washed with water, dried over anhydrous sodium carbonate and the benzene is evaporated off to dryness. The evaporation residue is triturated with diethyl ether and left to crystallize. 2-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethoxy]-acetamide is obtained in a yield of 73% of theory; M.P. 119°-120° C.