Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28]Br)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CC(C)([O-])C.[K+]>CN(C)C=O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=3)[C:2]([CH3:14])([CH3:1])[CH2:3]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A process vial with a suspension of 1 g 3,3-dimethyl-6-nitro-2,3-dihydro-1H-indole, 1.59 g 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester and 1.17 g potassium tert-butoxide in 10 ml N,N-dimethylformamide was sealed with a teflon septum and placed in the microwave cavity. The reaction mixture was stirred for 15 minutes at 100° C. by microwave-assisted heating (Emrys Optimizer, Personal Chemistry). After removal of the solvent under reduced pressure the residue was purified by flash chromatography on silica gel with a n-heptane/ethylacetate gradient. The fractions containing the product were combined and evaporated to yield a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11](O)[CH:10]([NH:14][CH2:15][CH2:16][OH:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([N:8]1[CH2:12][CH:11]2[CH:10]([NH:14][CH2:15][CH2:16][O:17]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCNC1CN(Cc2ccccc2)CC1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CN2CC3NCCOC3C2)cc1

Procedure:
15.6 g (66mmol) of 1-benzyl-4-hydroxy-3-(2-hydroxyethylamino)-pyrrolidine are heated under reflux in a mixture of 60 ml of concentrated sulphuric acid and 20 ml of water for 6 hours. The mixture is rendered alkaline with concentrated sodium hydroxide solution, the sodium sulphate which has precipitated is filtered off with suction and the filtrate is extracted with chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:3]1=[O:20]
Reactant: CC(C)C(=O)Cl
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, isobutyryl chloride, and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white foam upon removal of the solvent: m.p. 87°-107° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]([C:15]#[C:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21](C(O)=O)[CH2:20][CH2:19]2)=[CH:5][N:4]=1)#[N:2]>O1CCOCC1.Cl>[CH3:12][C:11]([CH3:14])([CH3:13])[CH2:10][NH:9][C:7]1[C:6]([C:15]#[C:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:5][N:4]=[C:3]([C:1]#[N:2])[N:8]=1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCN(C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
To a solution of 4-{3-[2-cyano-4-(2,2-dimethyl-propylamino)-pyrimidin-5-yl]-prop-2-ynyl}-piperazine-1-carboxylic acid .tert.-butyl ester (2.9 mmol) in dioxane (5 ml), 4N hydrogenchloride in dioxane (15 ml) is added at 0° C. The reaction mixture is stirred at room temperature for 1 day and then evaporated under reduced pressure. To a solution of residual solid, CH2Cl2 is added at room temperature, pH is adjusted to 9.0 by triethylamine. The mixture is quenched with ammonium chloride and extracted with CH2Cl2. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue is purified by silica gel column chromatography to afford title compound in 72% yield. Rf=0.11 (MeOH:CH2Cl2=1:9)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[N:25]1([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:33]1[CH2:34][CH2:35][CH2:36][CH:31]([CH2:30][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:32]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: C1CNCC(CN2CCCC2)C1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCCC(CN3CCCC3)C2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 3-(pyrrolidin-1-ylmethyl)piperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.05 minutes; C26H29Cl2N5O2 (514.45); mass spectrum: (M+H)+=514.2.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]([F:30])([F:29])[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=[C:13]([C:25]([F:28])([F:27])[F:26])[N:12]=1.[C:31](=[O:33])=[O:32]>COCCOC>[F:30][C:10]([F:29])([F:9])[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH2:23][CH3:24])[C:14]([C:31]([OH:33])=[O:32])=[C:13]([C:25]([F:28])([F:27])[F:26])[N:12]=1
Reactant: O=C=O
Reactant: CCOC(=O)c1c(OCC)cc(C(F)(F)F)nc1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: COCCOC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)O)c1OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
This material was prepared in 52.7% yield from 0.06 mol of LDA and 0.024 mol of product of Example 6 according to the following general procedure as a beige solid, mp 115°-117° C. To a -78° C. solution of 2.5 eq (0.06 mol) of LDA in DME was added a solution of 1 eq (0.024 mol) of starting material, the monocarboxylate product (Example 6) in dry DME. The resulting dark colored solution was stirred for 30 minutes at -78° C. To the above solution was added excess of dry ice. The reaction mixture was stirred at -78° C. for 15 minutes and warmed to room temperature in 1 hour. The reaction mixture was poured into ice water (100 ml) and extracted with ether. The aqueous layer was made acidic. The oil precipitate was extracted with ether. The ether extract was dried (MgSO4) and concentrated in vacuo to give the desired product.
Reaction SMILES: B(Cl)(Cl)Cl.C[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:19][CH:18]=3)=[O:16])=[C:13]([C:32]3[CH:37]=[CH:36][C:35]([O:38]C)=[CH:34][CH:33]=3)[S:12][C:11]=2[CH:40]=1.CO>ClCCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:16])[C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:21][CH:22]=3)=[C:13]([C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)[S:12][C:11]=2[CH:40]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCCl
Solvent: CO
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 35 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
Boron trichloride gas is condensed into a cold graduated cylinder (2.8 ml), and added to a solution of [6-methoxy-2-(4-methoxyphenyl)-benzo-[b]-thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl] methanone (6.37 g, 12.7 mmol) in 52 ml of 1,2-dichloroethane. The resulting solution is heated to 35° C. After about 16 hours the reaction is complete. Methanol (30 ml) is added to the reaction mixture over a 20 minute period, causing the methanol to reflux. The resulting slurry was stirred at 25° C. After 1 hour, the crystalline product is filtered, washed with cold methanol (8 ml), and dried at 40 ° C. in vacuo to give 5.14 g of the title compound. mp 225° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O.CCOCC>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: [OH-]
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc1
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: COCCOC
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
1.7 g (3.99 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-(p-methoxy-phenylmethyl)-dihydrofuran-2-(3H)-one in 43 ml of dimethoxyethane and 11 ml of water are hydrolysed with 16 ml of 1M lithium hydroxide solution. Stirring in ether yields the pure title compound: TLC Rf (F)=0.53; tRet (I)=14.2 min; FAB-MS (M+Na)+ =466.
Reaction SMILES: P(=O)(O)(O)O.[Cl:6][C:7]1[S:11][C:10]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1.C(O)(=O)C>O>[Cl:6][C:7]1[S:11][C:10]2[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[C:9]=2[CH:8]=1
Reactant: O=C(O)CCCc1ccc(Cl)s1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2sc(Cl)cc21
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
First 0.096 ml (1.41 mmol) of orthophosphoric acid and then 4.12 g (20.14 mmol) of 4-(5-chloro-2-thienyl)butanoic acid are added to 5 ml of acetic acid, and the mixture is stirred at 120° C. for 2.5 h. The cooled reaction mixture is added to water and extracted with dichloromethane, and the extract is washed with 2 M NaOH. After washing with water, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The residue is extracted with diethyl ether. Undissolved crystals are filtered off with suction and discarded. The ether phase is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate). This gives 1.07 g of 2-chloro-6,7-dihydro-1-benzothiophen-4(5H)-one.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][C:14](=[O:16])[CH3:15])[CH:12]=1)[CH:8]=[CH2:9])(=[O:3])[CH3:2].[C:17]([O:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)(=[O:19])[CH3:18].C([O-])(O)=O.[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:8]=[CH:9]/[C:24]2[CH:25]=[CH:26][C:21]([O:20][C:17](=[O:19])[CH3:18])=[CH:22][CH:23]=2)[CH:10]=[C:11]([O:13][C:14](=[O:16])[CH3:15])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Br)cc1
Reactant: C=Cc1cc(OC(C)=O)cc(OC(C)=O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(/C=C/c2cc(OC(C)=O)cc(OC(C)=O)c2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A flask equipped with magnetic stirrer was charged with 50 mg (0.23 mmol, 1 eq) of 3,5-diacetoxystyrene, 49 mg (0.23 mmol) of 4-acetoxybromobenzene, 46 mg (0.27 mmol) of NaHCO3 and 78 mg (0.54 mmol, 2.4 eq) of tetrabutylammoniumchloride. The reactants were suspended in 2 ml DMF and the mixture was flushed with argon and then evacuated. The argon flushing and evacuation procedure was carried out three times. The reaction was started by adding 0.76 mg of palladium acetate in 50 μl of de-aerated DMF (3 μmol, 1.5 mol %), and stirred at 100° C. for three hours. Work-up of the reaction mixture following the procedure of Example 5 gave (E)-3,4′,5-triacetoxystilbene.
Reaction SMILES: [CH3:1][S:2][CH:3]1[N:6]([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5](=[O:23])[CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][S:2]([CH:3]1[N:6]([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:5](=[O:23])[CH2:4]1)=[O:32]
Reactant: CSC1CC(=O)N1CC(=O)CCCCCCCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)C1CC(=O)N1CC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-methylthio-1-(9-phenyl-2-oxononyl)azetidin-2-one (0.993 g, 2.98 mmol) in dry dichloromethane (90 ml) was cooled to -50° C. and mCPBA (0.95 g, 2.58 mmol) in dry dichloromethane (50 ml) was added dropwise over 30 minutes, then stirred for 90 minutes at room temperature. This was washed with dil Na2SO3, dil NaHCO3 and water (×2), dried (MgSO4)and evaporated to a solid (1.09 g). This was purified by flash chromatography on silica gel eluted with petroleum ether/ethyl acetate 1 ethanol to give 4-methylsulphinyl-1-(9-phenyl-2-oxononyl)azetidin-2-one (Example 5) as a white waxy solid (0.718 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([Br:31])[N:14]=1)[N:11]([C@@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Yield: 67.7 %

Procedure:
A mixture of (R)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (90 mg, 0.225 mmol) and N-bromosuccinimide (44 mg, 0.248 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 73 mg of the title compound as a yellow solid. MS: (−) m/z 477.19, 479.15 (M-1, 79/81Br).
Reaction SMILES: [N+:1]([C:4]1[CH:49]=[CH:48][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([C:37](=O)[C:38]6[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=6)=[CH:33][CH:32]=5)=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([SiH](CC)CC)C.ClC(Cl)C.C(Cl)(Cl)Cl>ClCCl>[N+:1]([C:4]1[CH:49]=[CH:48][C:7]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([CH2:37][C:38]6[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=6)=[CH:33][CH:32]=5)=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc(Cc2ccc(Cc3ccc(Cc4ccc(C(=O)c5ccc([N+](=O)[O-])cc5)cc4)cc3)cc2)cc1)c1ccc([N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc(Cc6ccc([N+](=O)[O-])cc6)cc5)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.8 %

Procedure:
In a 1-liter four-necked flask equipped with a stirring device, a thermometer, a condenser and a nitrogen substituting device, 17.7 g of 1,1-bis(4-(4-(4-nitrobenzoyl)phenylmethyl) phenyl)methane was dissolved in 150 milliliters of dichloromethane, 14.5 g of triethylsilane and 20.7 g of boron trifluoride ethyl ether complex were added, and they were stirred for 20 hours at reflux of dichloroethane. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was cooled to room temperature, poured in 100 milliliters of ice water, and then 150 milliliters of chloroform was added for extraction. Thereafter, the solution was washed with a 6N-HCl aqueous solution of from 50° to 55° C., an aqueous solution of sodium hydrogencarbonate, brine and water, removed off chloroform and dichloroethane by a rotary evaporator, and then recrystallized from a chloroform solvent, to obtain 16.4 g of 1,1-bis(4-(4-(4-nitrophenylmethyl)phenylmethyl)phenyl)methane as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH:16]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH2:14][CH2:15][CH:16]3[CH2:17][CH2:18][C:19](=[O:20])[CH2:24][CH2:25]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc([C@H]2CC[C@H](CCC3CCC4(CC3)OCCO4)CC2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=CO
Product: O=C1CCC(CC[C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 31.1 g of 4-chloro-1-[trans-4-[2-(1,4-dioxa-8-spiro[4.5]decyl)ethyl]cyclohexyl]benzene, 207 ml of toluene and 103 ml of formic acid is stirred at room temperature for 1.25 hours while gassing with nitrogen. Thereafter, the reaction mixture is poured into 500 ml of water and extracted with methylene chloride. The organic phases are washed with saturated sodium hydrogen carbonate solution and with water, dried over sodium sulphate and filtered. Concentration of the filtrate gives 4-[2-[trans-4(4-chlorophenyl)cyclohexyl]ethyl]cyclohexanone.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:20](C3CCCCO3)[N:19]=2)=O)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([NH:15][CH2:16][C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[NH:20][N:19]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc(NCc2ccccc2)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Fc1ccc(-c2cc(CNc3cccc(NCc4ccccc4)n3)n[nH]2)cc1
Yield: 14.1 %

Procedure:
Boran dimethylsufide (50 μL) was added to a solution of N-(6-(benzylamino)pyridin-2-yl)-5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide 4 (180 mg, 0.38 mmol) in THF (10 ml). The reaction mixture was refluxed over night and cooled. MeOH was added, followed by conc. HCl and the reaction mixture was heated for 5 hrs. Then the reaction mixture was concentrated in vacuum, diluted with water (5 ml) and extracted with chloroform (50 ml×2). The combined organic layers were washed with water and brine, then dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified on silica gel (50% EtOAc: pet-ether) to give N2-benzyl-N6-((5-(4-fluorophenyl)-1H-pyrazol-3-yl)methyl)pyridine-2,6-diamine 5 (20 mg) as an oily material, which was treated with methanolic hydrochloric acid for 2 hrs. The solvent was evaporated under reduced pressure to give a gummy material (20 mg).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][C:10]([O:13][CH3:14])([CH3:12])[CH2:9]2)C=CC=CC=1.C(O)(=O)C.P([O-])([O-])(O)=O.[K+].[K+].[F:32][C:33]1[CH:34]=[C:35]([N+:40]([O-:42])=[O:41])[CH:36]=[CH:37][C:38]=1F>O1CCCC1.C(O)C.CS(C)=O.O.[OH-].[OH-].[Pd+2].CCCCCC.C(OCC)(=O)C>[F:32][C:33]1[CH:34]=[C:35]([N+:40]([O-:42])=[O:41])[CH:36]=[CH:37][C:38]=1[N:8]1[CH2:11][C:10]([O:13][CH3:14])([CH3:12])[CH2:9]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: COC1(C)CN(c2ccc([N+](=O)[O-])cc2F)C1
Yield: 93.7 %

Procedure:
A solution of 1-(diphenylmethyl)-3-methoxy-3-methylazetidine (2.20 g, 8.2 mmol) in 25% tetrahydrofuran/ethanol was treated with glacial acetic acid (1.60 g, 1.50 mL, 24.7 mmol) and then palladium hydroxide on carbon (0.220 g) under a nitrogen stream. The reaction mixture was shaken on a Parr apparatus under 35 psi of H2. At this time TLC analysis (9:1 hexane/ethyl acetate) revealed the reaction to be complete. The mixture was filtered through Celite® (ethyl acetate wash) and the filtrate concentrated in vacuo to give an oil. This material was dissolved in dimethyl sulfoxide (15 mL) and the solution treated with dipotassium hydrogen phosphate (8.60 g, 49.2 mmol) and 3,4-difluoronitrobenzene (1.30 g, 0.886 mL, 8.0 mmol) at ambient temperature. The yellow reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and dried in vacuo to give a yellow solid. Chromatography over silica gel, eluting with 8:1 hexane/ethyl acetate, afforded, after concentration of appropriate fractions, 1.80 g (90%) of the title compound as a yellow solid with mp 110°-111° C. and MS(EI) 240 (M+).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:17][OH:18])[CH2:9]1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)(Cl)Cl>[CH2:29]([O:28][C:26]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:17][OH:18])[CH2:9]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: OCc1cccc2c1CN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1Cc2cccc(CO)c2C1
Yield: 66.7 %

Procedure:
To a mixture of 5.27 g of 2-benzyl-4-hydroxymethylisoindoline and 2.43 g of sodium carbonate in 25 ml of chloroform was added dropwise 2.49 g of ethyl chloroformate under ice-cooling while stirring. After stirring for 2 days at room temperature, the mixture was washed with water and concentrated. The residue was purified by chromatography on silica gel (chloroform/methanol =10/1) to obtain 3.25 g of 2-ethoxycarbonyl-4-hydroxymethylisoindoline.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:13][NH2:14])(=O)[CH:9]([CH3:11])[OH:10].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=O)[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[C:8]([CH:9]([CH3:11])[OH:10])=[N:13][N:14]=2)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(O)C(=O)NN
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(-n2c(-c3ccc([N+](=O)[O-])cc3)nnc2C(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3 ml of triethylamine were added at ambient temperature to a solution of 2 equivalents of -lactic acid hydrazide in 60 ml of toluene and then, 4.3 g of N-(4-methoxyphenyl)-4-nitrobenzene carboximidoyl chloride (Step A of Example 1) were added in two lots with stirring for 4 hours at ambient temperature. The mixture was then refluxed for 4 hours to obtain cyclization and the toluene was eliminated under reduced pressure. After washing with water, filtering and drying, 4.34 g of crude product were obtained which was purified by chromatography under pressure (eluent-chloroform-ethyl acetate-methanol: 47:50:3) to obtain 3 g of 5-[4-nitrophenyl]-4-(4-methoxyphenyl)-methyl-4H-1,2,4-triazol-3-methanol melting at 140° C.