Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[CH2:26][CH2:25][N:24]([CH2:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[CH2:26][CH2:25][N:24]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(CCC(=O)OC(C)(C)C)CC4)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(CCC(=O)O)CC4)no2)cc1Cl
Yield: 106.1 %

Procedure:
1,1-Dimethylethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]propanoate (Preparation 18) (25 mg, 0.049 mmol) was stirred at room temperature for 18 hours in 4M HCl in 1,4-dioxane (10 ml). Evaporation and trituration with diethylether yielded the title compound 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]propanoic acid hydrochloride (13 mg, 0.026 mmol, 54.1% yield) as a yellow gum. MS (ES) C24H2635ClN3O4 requires 455; found 456 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([C:25](=[CH:26]O)[C:24](=O)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:31][CH3:32])([CH3:4])([CH3:3])[CH3:2].[CH3:33][NH:34][NH2:35]>C(O)C>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([C:25]4[C:24](=[N:35][N:34]([CH3:33])[CH:26]=4)[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:31][CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2C(=O)C3=CO)ccc1C(C)(C)C
Reactant: CNN
Solvent: CCO
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2nn(C)cc23)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
A mixture of 1′-(4-tert-butyl-3-methoxy-benzoyl)-3-(hydroxymethylene)-spiro[chromane-2,4′-piperidine]-4-one (50 mg, 0.12 mmol) and methylhydrazine (6.7 μL, 0.13 mmol) in ethanol (1.6 mL) was allowed to stir at 25° C. for 3 h. The mixture was filtered and then purified by reverse phase HPLC to provide (4-tert-butyl-3-methoxy-phenyl)-(2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (8 mg, 15%) (peak 1) and (4-tert-butyl-3-methoxy-phenyl)-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (peak 2). (4-tert-Butyl-3-methoxy-phenyl)-(2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone: ESI-MS m/z talc. 445.2, found 446.3 (M+1)+; Retention time: 1.87 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.2-7.20 (m, 1H), 7.17-7.10 (m, 1H), 7.06-6.94 (m, 2H), 6.93-6.83 (m, 2H), 4.25-4.05 (m, 1H), 4.02-3.93 (m, 1H), 3.85-3.75 (m, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 3.55-3.40 (m, 1H), 2.37-2.18 (m, 2H), 1.35 (s, 9H), 1.30-1.15 (m, 2H). (4-tert-Butyl-3-methoxy-phenyl)-(1-methylspiro-[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone: ESI-MS m/z talc. 445.2, found 446.3 (M+1)+; Retention time: 2.10 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=7.5 Hz, 1H), 7.32-7.25 (m, 2H), 7.18 (t, J=7.7 Hz, 1H), 7.08-6.88 (m, 3H), 6.84 (t, J=7.5 Hz, 1H), 4.43-4.32 (m, 1H), 4.20-4.05 (m, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.76-3.55 (m, 2H), 2.26-2.25 (m, 2H), 1.80-1.50 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=O)[CH:8]=2)[O:3]1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:29]3[CH2:30][CH2:31][CH:26]([C:22]4[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=4)[CH2:27][CH2:28]3)[CH:8]=2)[O:3]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(c3)CCC(C)(C)O4)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2,2-dimethyl-6-chromanecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 421.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11].C1N2CN3CN(C2)CN1C3.[C:22](=O)(O)[O-:23].[Na+]>FC(F)(F)C(O)=O>[OH:11][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8]=2[C:9]([CH:22]=[O:23])=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1ccc2c(c1O)CCC2
Reactant: O=C([O-])O
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C=O)c2c(c1O)CCC2
Temperature: 87.5 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a clear solution of 5-Methyl-indan-4-ol (6 gm, 0.0405 mole) in 30 ml Trifluoroacetic acid, Hexamine (5.7 gm, 0.0405 mole) was added at 25-28° C. The reaction mixture was heated and stirred at 85-90° C. for 6 hours. The cooled reaction mixture was poured into saturated Sodium bicarbonate solution and extracted with Ethylacetate (2×200 ml). The organic layer was dried over Sodium sulphate and distilled under vacuum to give a crude product which was purified by column chromatography using Ethyl acetate:Hexane (10:90) as mobile phase The collected fractions were distilled to give 5.4 gm of desired product as a solid.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH:9]12[O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]2.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: C1CCC2OC2C1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1nccn1C1CCCCC1O
Reaction time: 16 h

Procedure:
A suspension of 0.565 g (5 mmole) of 2-nitroimidazole, 50 ml of ethanol, 5.0 ml of cyclohexene oxide, and 0.25 g of potassium carbonate was refluxed with stirring under nitrogen for 16 hr. The resulting yellow solution was evaporated and the residue dissolved in 100 ml of chloroform and filtered. The filtrate was evaporated and the residue purified by preparative TLC with ethyl acetate: benzene (2:1) as eluant to provide 0.359 g (34.0%). It was recrystallized from ethyl acetate-ether, mp 141° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:16]C(=O)CC)(=[O:15])[CH2:13][CH3:14].C([O-])(=O)CC.[Na+].[OH-].[NH4+]>>[CH3:14][C:13](=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:12]([OH:16])=[O:15]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCC(=O)OC(=O)CC
Agent: CCC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Temperature: 0 °C

Procedure:
A mixture of 75 g. of 3-nitrobenzaldehyde, 98 g. of propionic anhydride and 48 g. of sodium propionate was heated at 170° to 175° C. for 1.25 hours, and then it was cooled and poured into 750 ml. of ice-water. Concentrated ammonium hydroxide was then added until a basic pH was obtained. The mixture was warmed on a steam bath for a few minutes and then the small amount of insoluble material was removed by filtration. The filtrate was acidified with concentrated hydrochloric acid and the solid was recovered by filtration. This crude product was recrystallized from aqueous ethanol to give 81 g. of the title compound, m.p. 200.5°-202° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc(Br)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Br)c2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 220 mg of 3-bromo-2-fluorobenzoic acid, 199 mg of tert-butyl piperazine-1-carboxylate and 5.0 ml of chloroform was added 171 mg of hydroxybenzotriazole monohydrate and 215 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride under cooling with ice, successively. After stirring at room temperature for 4 hours, saturated sodium bicarbonate was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 1/1) to give the title compound.
Reaction SMILES: O=C(CCC=C(C)CCC=C(C)CCC=C(C)C)CC(OC)=O.[O:24]=[C:25]([CH2:33][CH2:34][CH:35]=[C:36]([CH3:48])[CH2:37][CH2:38][CH:39]=[C:40]([CH3:47])[CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])[CH2:26][P:27](=[O:32])([O:30]C)[O:28]C>>[OH:24][CH:25]([CH2:33][CH2:34][CH:35]=[C:36]([CH3:48])[CH2:37][CH2:38][CH:39]=[C:40]([CH3:47])[CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])[CH2:26][P:27](=[O:28])([OH:32])[OH:30]
Reactant: COP(=O)(CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C)OC
Agent: COC(=O)CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(O)CP(=O)(O)O

Procedure:
This compound was prepared similarly by the method described in Step 2 of Example 1 except that methyl 3-oxo-7,11,15-trimethylhexadeca-6,10,14-trienoate was replaced by dimethyl [2-oxo-6,10, 14-trimethyl-pentadeca-5,9,13-trienyl]phosphonate and the product from this reaction was used in the hydrolysis step similarly to the method used in Step 2 in Example 2 to give, after lyophilization, title compound as a nearly colorless gum.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C@@H:24]([C:26]5[O:27][CH:28]=[C:29]([CH2:31]OS(C)(=O)=O)[N:30]=5)[CH3:25])=[O:22])=[CH:19][N:18]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C-:45]#[N:46].[Na+]>CN(C=O)C>[C:45]([CH2:31][C:29]1[N:30]=[C:26]([C@H:24]([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[CH:19]=2)=[O:22])[CH3:25])[O:27][CH:28]=1)#[N:46]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(COS(C)(=O)=O)co1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(CC#N)co1
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
In a round-bottomed flask, methanesulfonic acid 2-((R)-1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-oxazol-4-ylmethyl ester (146 mg, 0.18 mmol) was dissolved in DMF (0.5 ml). Sodium cyanide (27 mg, 0.55 mmol) was added and the reaction mixture was stirred at 80° C. overnight. The reaction was cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-60% EtOAc) to isolate 37 mg (36%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyanomethyl-oxazol-2-yl)-ethyl]-amide as a yellow solid.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:10]1[C:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>O1CCCC1.CO.O>[C:35]([O:34][C@@H:9]([C:10]1[C:11]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1cc2nc(-c3ccccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 45 °C
Yield: 89 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-2-yl)quinolin-6-yl)ethyl pivalate (45.2 mg, 0.085 mmol) in tetrahydrofuran and methanol (5:1, 1 mL) was added 1 M sodium hydroxide (2 mL) and the reaction was heated to 45° C. overnight. The reaction was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude extract was co-evaporated two times with acetonitrile to give a clear oil (33.8 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H28ClN2O2: 447.18. found: 447.72.
Reaction SMILES: C(O)C.[OH-].[K+].C([O:8][C:9](=[O:32])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][C:18]([CH3:30])([CH3:29])[C:17]2=[O:31])C>O>[CH2:23]([C:22]1[CH:21]=[C:20]2[C:16]([C:17](=[O:31])[C:18]([CH3:30])([CH3:29])[CH2:19]2)=[CH:15][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][C:9]([OH:32])=[O:8])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCc1cc2c(cc1OCCCC(=O)OCC)C(=O)C(C)(C)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCc1cc2c(cc1OCCCC(=O)O)C(=O)C(C)(C)C2
Yield: 87.8 %

Procedure:
A mixture of 60 ml of ethanol, 0.4 g (7.2 mmol) of potassium hydroxide, 1.8 g (4.8 mmol) of ethyl4-(6-hexyl-2,2-dimethyl-3-oxoindan-5-yloxy)butyrate and 20 ml of water is heated for 2 hours at the reflux point of the solvents. The solvents are evaporated off and the residue is placed in water and extracted with ether. The aqueous phase is acidified and then extracted with ether. Concentration of the solvents gives 1.46 g of product, which is purified by flash chromatography (95/5 dichloromethane/methanol): 1.18 g; m.p.: 82° C.; 71%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[N:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Br:12]N1C(=O)CCC1=O>C(O)(=O)C.C(#N)C.ClCCl>[Br:12][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=[N:7][C:6]=1[OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccc(C(F)(F)F)nn1
Solvent: CC(=O)O
Solvent: CC#N
Solvent: ClCCl
Product: Oc1nnc(C(F)(F)F)cc1Br
Temperature: 60 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
A mixture of 6-trifluoromethyl-pyridazin-3-ol (9.0 g, 54.9 mmol) (D3) and N-bromosuccinimide (12.7 g, 71.4 mmol) in a mixture of acetic acid (15 ml) and acetonitrile (350 ml) was stirred at 60° C. for 6 h. and at room temperature for a further 16 h. After this period, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of sodium thiosulfite. The organic layer was separated, dried (MgSO4) and the solvent evaporated in vacuo to yield D4 (12.7 g, 95%) as a yellow solid. C5H2BrF3N2O requires 243; Found 244 (MH+).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([O:14][CH3:15])[C:6]=1[O:16][CH3:17])#[N:2].[Cl-].[NH4+]>C(O)C.C(Cl)Cl.[Fe]>[C:1]([CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([O:14][CH3:15])[C:6]=1[O:16][CH3:17])[NH2:11])#[N:2]
Reactant: COc1cc([N+](=O)[O-])cc(OCC#N)c1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(N)cc(OCC#N)c1OC
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of 1.4 g of 1-cyanomethoxy-2,3-dimethoxy-5-nitrobenzene in 75 mL ethanol with 1.65 g of iron and 1.65 g of ammonium chloride was refluxed for 4 h, cooled to RT, diluted with DCM, filtered, extracted with DCM and the combined organic were dried with sodium sulfate and evaporated to give 1 g 82% of the desired product 3-cyanomethoxy-4,5-dimethoxyaniline, MS (m/e): 209 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[C:24]1([CH2:30]CC(O)=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: O=C(O)CCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.208 g, 0.66 mmol) and 3-phenylpropanoic acid (100 mg, 0.66 mmol) taken in dry DCM (30 mL), DIPEA (430 mg, 3.32 mmol) followed by HATU (504 mg, 1.33 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.225 g, 82.72%) as solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[C:12]([O:27][CH2:28][C:29]2[N:30]([CH2:34][CH3:35])[N:31]=[CH:32][N:33]=2)=[N:13][N:14]2[C:19]=1[CH:18]=[N:17][N:16]=[C:15]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26]>>[CH2:34]([N:30]1[C:29]([CH2:28][O:27][C:12]2[C:11]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:19]3[N:14]([C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])=[N:16][N:17]=[CH:18]3)[N:13]=2)=[N:33][CH:32]=[N:31]1)[CH3:35]
Reactant: OB(O)c1ccncc1
Reactant: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccncc1
Yield: 21 %

Procedure:
This was prepared in 21% yield using a similar procedure to that described in Example 18 except using pyridine-4-boronic acid instead of 3-trifluoromethylbenzeneboronic acid and 3-bromo-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazine instead of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine. Data for title compound: mp=214-217° C.; 1H NMR (360 MHz, CDCl3) δ 1.35 (3H, t, J=7.2 Hz), 4.12 (2H, q, J=7.2 Hz), 5.60 (2H, s), 7.31 (1H, t, J=9.2 Hz), 7.42 (1H, t, J=7.6 Hz), 7.62 (2H, d, J=6.0 Hz), 7.68 (1H, m), 7.82 (1H, m), 7.90 (1H, s), 8.72 (2H, d, J=5.6 Hz), 9.53 (1H, s); MS (ES+) m/e 417 [MH]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].Br[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.O>CN(C)C=O>[O:8]=[C:4]1[N:5]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:6][CH2:7][N:3]1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: O=C1NCCN1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(CN2CCN(Cc3ccc(C#N)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To sodium hydride (2.4 g, 60 mmol) in dimethylformamide (50 mL) at 0° C. was added imidazolin-2-one (2.6 g, 30 mmol). After stirring for 20 minutes 4-(bromomethyl)benzonitrile (13 g, 66 mmol) was added and the mixture was warmed to ambient temperature. After stirring for 1 hour the reaction was poured into water and a solid formed. The solid was filtered to give 4,4'-[(2-oxoimidazolin-1,3-diyl)bis(methylene)]-bis(benzonitrile). NMR (CDCl3) 7.65 (d,4), 7.4 (d,4), 4.45 (s,4), 3.2 (s,4) ppm.
Reaction SMILES: [C:1]1([CH:7]([NH2:19])[CH2:8][Se:9][CH2:10][CH:11]([NH2:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([Se:26][Se:27]C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.C1COCC1.[PH2](O)=O>CCOCC.C1COCC1>[C:1]1([CH:7]([NH2:19])[CH2:8][Se:9][CH2:10][CH:11]([NH2:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[SeH-:26]=[Se:27]
Reactant: c1ccc([Se][Se]c2ccccc2)cc1
Agent: NC(C[Se]CC(N)c1ccccc1)c1ccccc1
Agent: O=[PH2]O
Solvent: C1CCOC1
Solvent: CCOCC
Product: [Se]=[SeH-]

Procedure:
A preferred compound is phenyl-2-aminoethyl selenide and salts thereof. Phenyl-2-aminoethyl selenide (PAESe) was synthesized by employing the following procedure. Diphenyl diselenide, 24.707 g (79.16 mmol) was dissolved into 100 ml of tetrahydrofuran THF) with steam heating. To the intensely dark red THF solution was added 9.84 ml (95 mmol, 1.2 eq.) of 50% hypophosphorous acid and the reaction was refluxed under argon for 6 hours, cooled, and diluted with 200 ml of Et2O and washed with 200 ml of 0.127 M NaOAc buffer pH 5.0 to remove the phosphoric acid by-product. Both the Et2O and the buffer were deoxygenated by bubbling argon through fritted glass for over 1 hour in order to prevent reoxidation of phenylselenol to diphenyl diselenide. The washed organic phase was then concentrated to yield a yellow oil (diselenide contaminant) with residual salt-containing water pockets The crude product was pumped down to remove residual solvent prior to distillation which yielded the desired phenylselenol (12.6g, 51% yield). pNMR (CDCl3) (s,1H) 1.54 d (m,5H) 7.35 d. Yields as high as 70% have been obtained for this reaction.
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[S:22]>>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]1[N:8]([CH2:7][CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:9][CH2:10][S:22]1
Reactant: Cc1cccc(N=C=S)c1C
Reactant: ClCC[NH2+]CC1CCCC1
Agent: [Cl-]
Product: Cc1cccc(N=C2SCCN2CC2CCCC2)c1C

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dimethylphenyl isothiocyanate to give 2-(2,3-dimethylphenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11]C)=[CH:8][CH:9]=2)[N:4]([CH3:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24].ClC1C2C(=CC(O)=CC=2)N(C)C=1C1C=CC(O)=CC=1N(CC)CC>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[N:4]([CH3:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[N:22]([CH2:23][CH3:24])[CH2:25][CH3:26]
Reactant: CCN(CC)c1cc(OC)ccc1-c1c(Cl)c2ccc(OC)cc2n1C
Agent: CCN(CC)c1cc(O)ccc1-c1c(Cl)c2ccc(O)cc2n1C
Product: CCN(CC)c1cc(OC)ccc1-c1c(Cl)c2ccc(O)cc2n1C
Yield: 37.9 %

Procedure:
Synthesized from [2-(3-chloro-6-methoxy-1-methyl-1H-indol-2-yl)-5-methoxyphenyl]diethylamine (96 mg) according to an analogous synthetic method to Example 364 described below, 3-chloro-2-(2-diethylamino-4-hydroxyphenyl)-1-methyl-1H-indol-6-ol (37 mg) and 3-chloro-2-(2-diethylamino-4-methoxyphenyl)-1-methyl-1H-indol-6-ol (35 mg) were obtained. 3-Chloro-2-(2-diethylamino-4-hydroxyphenyl)-1-methyl-1H-indol-6-ol: