Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[NH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Li])CCC.Cl[P:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[N:13][P:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCNC(=N)c1ccccc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: CN(C)CCNC(=NP(c1ccccc1)c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Procedure as described for NP Amidine I using the following amounts and modifications: 0.956 g of N1-(2-(dimethylamino)ethyl)benzamidine (Amidine XII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the oily product was treated with 20 mL of pentane. After 1 hour stiffing at room temperature, a white solid formed. The solution was concentrated to approximately 10 mL and filtered while cold, yielding 0.891 g (47%) after drying.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[C:8]=2[C:26]2[CH:31]=[CH:30][C:29](OC)=[CH:28][C:27]=2[CH:34]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:43][OH:44]>CCO>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]3[O:22][CH2:23][CH2:24][O:25]3)[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:34]=[N:43][OH:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NO
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3C=O)n(CC3OCCO3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=NO)n(CC3OCCO3)c2c1
Yield: 95 %

Procedure:
To a solution of methyl methyl 3-cyclohexyl-1-(1,3-dioxolan-2-ylmethyl)-2-(2-formylphenyl)-1H-indole-6-carboxylate (prepared in analogous fashion to Example 4, Step 2, using 2-formylphenylboronic acid) in EtOH (0.05 M), were added aqueous solutions of sodium carbonate (2M; 1.3 eq) followed by hydroxylamine hydrochloride (2M; 1.3 eq). The reaction was stirred at RT for 2 h, before the EtOH was reduced in vacuo and the residue partitioned between EtOAc and water. The aqueous fraction was extracted a second time with EtOAc and the combined organics washed with water and then brine before being dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (95%); MS (ES+) m/z 463 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@@H:7]([NH2:29])[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[C:31](=N)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:1]([O:5][C:6](=[O:30])[C@@H:7]([N:29]=[C:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N=C(c1ccccc1)c1ccccc1

Procedure:
The 2(R)-amino-3-tritylsulfanyl-propionic acid tert-butyl ester is reacted with benzhydrylideneamine in dichloromethane at room temperature to form 2(R)-(benzhydrylidene-amino)-3-tritylsulfanyl-propionic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[S:19][N:20]=[C:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[N:22]3)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[OH-].[Na+].OO.CC(O)=[O:33]>CCO.CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[S:19][N:20]=[C:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[N:22]3)[C:12]([C:15]([NH2:16])=[O:33])=[N:13][CH:14]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1snc2ncccc12
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1snc2ncccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-((1R,2S)-2-aminocyclohexylamino)-3-(isothiazolo[3,4-b]pyridin-3-ylamino)pyrazine-2-carbonitrile (36 mg) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (1 mL) and aq. H2O2 (30%, 1 mL) were added. The mixture was stirred at room temperature for 20 h. After being neutralized with HOAc (0.3 mL), the mixture was purified by HPLC to give the titled compound (7 mg). MS found for C17H20N8OS as (M+H)+ MS 385.3. UV: λ=UV 207.4, 245.8, 298.6, 343.2 nm. 1H NMR: (CD3OD) δ 8.50 (dd, 1H), 8.22 (dd, 1H), 7.73 (s, 1H), 7.05 (dd, 1H), 4.70-4.62 (m, 1H), 4.12-4.05 (m, 1H), 2.14-1.60 (m, 8H).
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[C:23]1([C:20]2[N:19]=[N:18][C:17]([CH2:16][NH2:8])=[CH:22][CH:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(-c2ccccc2)nn1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCc1ccc(-c2ccccc2)nn1
Temperature: 30 °C
Reaction time: 1 h
Yield: 119.1 %

Procedure:
To a solution of 3-[bis(tert-butoxycarbony)aminomethyl]-6-phenylpyridazine (178 mg, 0.462 mmol) obtained in Reference Example 2-(b) in methylene chloride (2.33 ml) was added a 4N hydrogen chloride/1,4-dioxane solution (2.33 ml, 9.32 mmol), followed by stirring at 30° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure to afford the title compound (122 mg) substantially quantitatively as a slightly brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14](F)[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19].[N:24]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([NH:32][CH2:31][CH2:30][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19]
Reactant: NCCN1CCOCC1
Reactant: N#Cc1cnc2cnc(F)cc2c1NCc1ccc(F)c(Cl)c1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1NCc1ccc(F)c(Cl)c1
Yield: 48 %

Procedure:
Following the procedure described above in Example 34, 4-[(3-chloro-4-fluorobenzyl)amino]-6-fluoro-1,7-naphthyridine-3-carbonitrile was reacted with 2-morpholin-4-yl-ethylamine. The crude product was purified by flash column chromatography (1% methanol in methylene chloride) to give a yellow solid (0.14 g, 48%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.4 (m, 4 H) 2.6 (m, 2 H) 3.4 (m, 2 H) 3.6 (m, 4 H) 5.0 (d, J=7.1 Hz, 2 H) 6.5 (m, 1 H) 7.0 (s, 1 H) 7.3 (m, 1 H) 7.4 (m, 1 H) 7.5 (dd, J=6.9, 1.9 Hz, 1 H) 8.1 (s, 1 H) 8.5 (m, 1 H) 8.8 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[OH:7].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl.C(OCC)C>N1C=CC=CC=1>[C:8]1([CH:6]([OH:7])[CH2:5][O:4][CH2:3][CH2:2][O:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: OCCOCC(O)c1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCC(O)c2cccc3ccccc23)cc1
Temperature: -25 °C
Reaction time: 4 h

Procedure:
8.3 g of 2(2-hydroxyethoxy)-1-(1-naphthyl)ethanol was dissolved in 50 ml of pyridine. The solution was cooled to -25° C. Thereto was added 6.8 g of p-toluenesulfonyl chloride. The resulting mixture was allowed to stand at 0°-5° C. for 24 hours and further at room temperature for 4 hours. The reaction mixture was added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 20 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 6.3 g of colorless, oily 1(1naphthyl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][C:15](C)([O-])[CH3:16].[K+].IC(C)C>CN(C=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH:15]([CH3:16])[CH3:14])[CH3:13]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [K+]
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-bromophenylacetate (3.0 g, 12.3 mmol) and potassium tert-butoxide (1.38 g, 12.3 mmol) were combined in DMF (35 mL). 2-Iodo-propane (2.09 g, 12.3 mmol) was added and the reaction was stirred at room temperature for 1 hour. Aqueous workup provided the title compound.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C1COCC1.C(Cl)Cl>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3nc(C(C)C)no3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-((1S,2R)-2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)cyclopropyl)ethanol (1.7 g, 6.08 mmol), methyl 2-(4-hydroxyphenyl)acetate (1.5 g, 9.1 mmol) and triphenylphosphine (2.4 g, 9.1 mmol) were dissolved in THF (30 ml). The mixture was stirred at RT under N2 for 5 min and disisopropyl azodicarboxylate (1.78 ml, 9.1 mmol) was added. The mixture was stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with water, dried and evaporated. The crude material was purified by silica gel column (100 g SNAP, 5-25% EtOAc in hexane) to afford the desired product. LC/MS (m/z): 428 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[O:9][N:8]=2)[NH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]Br)[CH:31]=1>CN(C=O)C.O>[Br:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[CH2:36][N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[O:9][N:8]=2)=[N:5]1
Reactant: Cc1n[nH]c(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)n1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a suspension of 3-(5-methyl-2H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl) isoxazole (400 mg, 1.3 mmol) and K2CO3 (445 mg, 3.3 mmol) in DMF (5 mL) was added 1-bromo-3-(bromomethyl)benzene (323 mg, 1.3 mmol). The mixture was stirred at RT for 2 h, then diluted with H2O (30 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with H2O (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether:EA=1:1) to afford the title compound as a light yellow solid (350 mg, 56.6%). MS (ES+) C20H14BrF3N4O2 requires: 478. found: 479 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:18][CH2:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:25]=2[CH2:24][CH2:23]1)=[O:21])[CH2:8][CH:9]1[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:50](I)([CH3:52])[CH3:51]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:18][CH2:19][C:20]([N:22]1[CH2:23][CH2:24][C:25]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[CH:29][C:26]=2[CH2:27][CH2:28]1)=[O:21])[CH2:8][CH:9]1[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:17][CH:50]([CH3:52])[CH3:51])[CH:14]=2)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(CC1Cc3cc(O)ccc31)C(=O)OC(C)(C)C)CC2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)CCN(C(=O)CCN(CC1Cc3cc(OC(C)C)ccc31)C(=O)OC(C)(C)C)CC2
Reaction time: 24 h

Procedure:
1.4 g (2.7 mmoles) of the product of Step 1 are dissolved in 15 mL of DMF. There are then added 740 mg (2 equivalents) of potassium carbonate, 160 mg (0.18 equivalent) of caesium carbonate and 0.54 mL (2 equivalents) of isopropyl iodide. Heating is then carried out at 40° C. for 24 hours. The DMF is evaporated off using a rotary evaporator. The residue obtained is then diluted with water and extracted with CH2Cl2. The organic phase is then dried over MgSO4, filtered and evaporated to dryness. An oil is obtained which is purified by flash chromatography over 100 g of silica (eluant: CH2Cl2/ethyl acetate: 80/20) to yield the expected product in the form of a sticky meringue.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](=[S:5])[S-:4].C[NH2+]C.C(=S)=S.[N+:13]([CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:15])=[O:14]>CO>[CH3:1][N:2]([CH3:6])[C:3](=[S:4])[S:5][CH:17]([CH2:16][N+:13]([O-:15])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: C[NH2+]C
Solvent: S=C=S
Solvent: CO
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccccc1
Yield: 51 %

Procedure:
Dimethylammonium dimethyldithiocarbamate (16.6 grams, 0.10 mole), carbon disulfide (7.6 grams, 0.10 mole), and β-nitrostyrene (14.9 grams, 0.10 mole) were dissolved in methanol (50 ml.). A rapid exothermic reaction ensued and the product precipitated. The reaction temperature was held to 35° C. with ice cooling. After several hours at 25° C., the product was filtered off, washed with methanol, and dried in air. The crude product melted at ca. 103° C.-110° C. and weighed 22.9 grams (85%). Recrystallizations from hot methanol and from acetone-2-propanol solution (without heating) gave 13.8 grams of α-(nitromethyl)-benzyl dimethyldithiocarbamate melting at 104° C.-108.5° C. (prior sintering). The infrared spectrum was essentially identical to the spectrum of analytically pure material.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22](Cl)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:25][C@@H:26]1[CH2:30][NH:29][C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12>O.O1CCOCC1>[Cl:25][C@@H:26]1[CH2:30][N:29]([C:22]([O:21][CH2:20][CH:18]2[C:19]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:16]3[C:17]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:23])[C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O[C@H]1CO[C@H]2[C@@H]1NC[C@H]2Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1C[C@@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Reaction time: 1.08 h
Yield: 76 %

Procedure:
A solution of sodium carbonate (155 mg, 1.46 mmol) in water (2.5 mL) then a solution of 9-fluorenylmethoxycarbonyl chloride (189 mg, 0.73 mmol) in 1,4-dioxane (1.5 mL) was added whilst stirring to a solution of aminoalcohol (77) in 1,4-dioxane (1 mL). The mixture was stirred for 65 minutes then water (20 mL) was added and the product extracted into dichloromethane (3×10 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 10:90 to 50:50 gave alcohol (78) (194 mg, 76%) as a white solid. TLC (Rf=0.45, EtOAc:heptane 1:1), analytical HPLC single main peak, Rt=15.51 min., HPLC-MS 386.1/388.1 [M+H]+, 408.1/410.1 [M+Na]+; [α]D23.0−7.46° (c=2.01, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers 1:1; 1.15 (0.5H, s, OH), 3.05 (0.5H, t, J=9.58 Hz, FmocNCH2), 3.09 (0.5H, s, OH), 3.23 (0.5H, t, J=10.38 Hz, FmocNCH2), 3.43 (0.5H, d, J=4.37 Hz, FmocNCH), 3.53 (0.5H, brs, OCH2CHOH), 3.62 (0.5H, dd, J=10.20 and 1.92 Hz, OCH2CHOH), 3.75 (0.5H, dd, J=10.21 and 4.53 Hz, OCH2CHOH), 3.84-3.97 (2H, m, 1×FmocNCH2, 0.5×OCH2CHOH and 0.5×CHCl), 4.02 (0.5H, dd, J=9.96 and 4.65 Hz, OCH2CHOH), 4.06-4.12 (0.5H, m, CHCl), 4.15-4.26 (1.5H, m, Fmoc CH and 0.5×FmocNCH), 4.39-4.46 (1.5H, m, 0.5×OCH2CHOH, 0.5×Fmoc CH2 and 0.5×CHCHCl), 4.50 (0.5H, dd, J=10.64 and 6.70 Hz, Fmoc CH2), 4.67 (0.5H, t, J=4.29 Hz, CHCHCl), 4.75 (0.5H, dd, J=10.86 and 3.69 Hz, Fmoc CH2), 4.82 (0.5H, dd, J=10.82 and 3.97 Hz, Fmoc CH2), 7.30-7.81 (8H, aromatic CH); δC (125 MHz, CDCl3) 47.22/47.41 (Fmoc CH), 50.55/50.93 (FmocNCH2), 54.60/55.28 (CHCl), 65.94/67.60 (Fmoc CH2), 69.08/69.56 (FmocNCH), 75.00/75.35 (OCH2CHOH), 76.23/76.86 (OCH2CHOH), 81.27/81.84 (CHCHCl), 119.87/119.92/120.09/124.42/124.46/124.82/124.88/127.10/127.50/127.51/127.89/127.96/127.98/128.53 and 128.65 (aromatic CH), 141.24/141.36/141.44/143.44/143.57/143.83 and 143.84 (aromatic quaternary), 153.41/154.42 (Fmoc C═O).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:25]=[C:24]([C:35](Cl)=[O:36])[CH2:23]2)=[CH:18][CH:17]=1>C(Cl)Cl>[N:2]1([NH:1][C:35]([C:24]2[CH2:23][CH:22]([C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)[N:26]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:25]=2)=[O:36])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN1CCCCC1
Reactant: O=C(Cl)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CCCCC1)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Aminopiperidine (0.6 mL, 5.6 mmol) and triethylamine (4 mL) were dissolved in methylene chloride (25 mL) under nitrogen atmosphere. The resulting mixture was cooled to 0° C. and a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride in methylene chloride (15 mL) was added drop wise. The resulting reaction mixture was stirred at room temperature (approximately 25° C.) overnight. The reaction mixture was washed with water, followed by a saturated aqueous solution of sodium bicarbonate, again with water, dried over sodium sulfate, filtered and evaporated to dryness in a rotavapor. The resulting crude solid was crystallised from ethanol. The crystallised solid was removed via filtration and the mother liquors were concentrated to yield a second fraction of crystallised product. The two fractions were combined to give a total amount of 1.7 g (57% of theoretical yield) of the title compound having a melting point of 183-186° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:14]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cc(F)cc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-5-fluoro-benzoic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([C@H:3]1[O:8][C@@H:7]([CH2:9][CH3:10])[CH2:6][N:5]([C:11]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=2[CH:13]=O)[CH2:4]1)[CH3:2].[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>CO>[CH2:9]([C@H:7]1[O:8][C@@H:3]([CH2:1][CH3:2])[C@@H:4]2[C:28]3([CH2:13][C:12]4[C:11]([N:5]2[CH2:6]1)=[CH:18][CH:17]=[C:16]([N+:19]([O-:21])=[O:20])[CH:15]=4)[C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]3=[O:30])[CH3:10]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CC[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@H](CC)O1
Solvent: CO
Product: CC[C@@H]1CN2c3ccc([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](CC)O1
Temperature: 80 °C
Yield: 47.9 %

Procedure:
2-(cis-2,6-Diethylmorpholin-4-yl)-5-nitrobenzaldehyde (1.58 g, 5.39 mmol) is combined with barbituric acid (767 mg, 5.39 mmol, Aldrich) in a flask with MeOH (17 mL). The sealed reaction is stirred with heating at 80° C. overnight. The solvent is removed by rotary evaporation and the product is purified on a Biotage Flash 40M+ using a 10% MTBE in CH2Cl2 as eluent. The product is dried under vacuum and re-crystallized from CH3OH/heptane. The large crystals are crushed and dried under vacuum @ 100° C. yielding 1.04 g (48%) of bright yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86, 0.97, 1.08, 1.24, 1.45, 1.58, 2.84, 3.03, 3.34, 3.60, 3.97, 4.26, 7.01, 7.84, 7.98, 11.56, 11.87.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[CH3:27][N:28]=[C:29]=[O:30]>>[CH3:27][NH:28][C:29]([NH:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6])=[O:30]
Reactant: CN=C=O
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Product: CNC(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(methylamino)carbonyl]amino]-1-oxopropyl]hydrazide (12) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared as described above in Example 9, and methylisocyanate, in the manner described in Example 10 above, on a one mmol scale to yield 0.17 g (40%) of product. Analysis calculated for C19H20N5O4C1 0.4 H2O (M.W. 425.06): C, 53.69; H, 4.93; N, 16.48; Cl, 8.34. Found: C, 53.96; H, 4.87; N, 16.06; Cl, 8.46.