Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:32][CH2:33][CH:34]1[CH2:36][CH2:35]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:30])[NH:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NCC1CC1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)NCC4CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and (aminomethyl)cyclopropane.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].O=[C:16]([CH2:22][CH3:23])[CH2:17][C:18]([O:20][CH3:21])=[O:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:22]([C:16]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=2)=[CH:2][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH3:23]
Reactant: O=C(CCl)c1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)OC
Reaction time: 2 h
Yield: 28.4 %

Procedure:
To a solution of 2-chloro-4′-(trifluoromethyl)acetophenone (50.9 g) and methyl 3-oxopentanoate (25 g) in toluene (500 mL) was added dropwise 1,8-azabicyclo[5.4.0]-7-undecene (28.7 mL) under ice-cooling over 30 min or longer. After the completion of the dropwise addition, and the mixture was stirred under ice-cooling for 30 min, and at room temperature for 2 hr. The resulting precipitate was filtered, and washed with toluene. The obtained toluene solution was passed through silica gel, and the silica gel was washed with ethyl acetate-hexane (1:1). The collected solution was concentrated under reduced pressure to remove ethyl acetate-hexane to give a toluene solution. To this toluene solution was added 4-toluenesulfonic acid monohydrate (7.2 g), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was washed with aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was collected, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 10% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (16.3 g, 29%) as a white solid.
Reaction SMILES: [Cl:1][C:2]12[C:15]([Cl:17])([Cl:16])[C:5]([Cl:18])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[C:8]([CH3:13])[C:7]3=[O:14])[C:4]([Cl:19])=[C:3]2[Cl:20].CO>N1C=CC=CC=1>[Cl:1][C:2]12[C:15]([Cl:16])([Cl:17])[C:5]([Cl:18])([C:6]3[C:7]([OH:14])=[C:8]([CH3:13])[CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:19])=[C:3]2[Cl:20]
Reactant: CC1=CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc(O)c2c(c1O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
30 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-6-methyl-1,4-methanonaphthalene-5,8-dione, prepared according to Example 45, were suspended in 150 ml. of methanol. 2 ml. of pyridine were added and the mixture was refluxed for 4 hours. Upon cooling in an ice-water bath, a crude white solid formed. This solid was recrystallized from methanol and white crystals were obtained. m.p. 159°-161° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C[O-].[K+].[H][H]>[Ru]>[CH2:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: [Ru]
Agent: C[O-]
Agent: [K+]
Product: NC1CCC(CC2CCCCC2)CC1
Temperature: 290 °C

Procedure:
In a steel autoclave fitted with a stirring apparatus and a product draw off system retaining the catalyst in the reactor can be placed 200 parts of 4-aminodiphenylmethane as described in British Patent 764,633 and 100 parts of a finely divided 5% ruthenium on an alumina support and 15 parts of potassium methoxide. The mixture within the autoclave can then be heated to 290°C with stirring and hydrogen added to maintain a pressure of 290 atmospheres for 20 minutes. The resulting mixture can then be freed of catalyst by filtration and distilled to strip off solvent. Final distillation under vacuum can then be used to provide the desired product, 4-aminodicyclohexylmethane, which is a colorless viscose liquid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]([SH:14])[CH2:9]1.Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1>CN(C=O)C.O>[CH3:7][C:8]1([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]([S:14][C:17]2[N:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)[CH2:9]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC1(C)CCCC(S)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CCCC(Sc2ccc(C#N)cn2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add potassium tert-butoxide (777 mg, 6.94 mmol) to a solution of 3,3-dimethylcyclohexanethiol (1 g, 6.94 mmol) in DMF (10 mL) and stir at room temperature for 10 min. Add 6-chloro-nicotinonitrile (547 mg, 3.96 mmol) and warm the solution to 60° C. for 18 h. Cool the mixture, dilute with water (100 mL) and extract with EtOAc (50 mL). Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate as a clear oil that solidifies on standing to a white solid (0.37 g, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]2=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(SCCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
A solution of 3-methoxybenzenethiol (1.52 mL, 12.2 mmol), N-(3-bromopropyl)phthalimide (3.28 g, 12.2 mmol), and potassium carbonate (2.53 g, 18.3 mmol) in acetone (50 mL) was heated to reflux for 88 hours. The solvent was removed in vacuo and the residue partitioned between water (50 mL) and methylene chloride (50 mL). The layers were separated and the aqueous layer washed with methylene chloride (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow oil. The crude product was purified by column chromatography (0→50% ethyl acetate/hexane) to provide the title compound as a clear oil.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[Cl:6][C:7]1[N:12]=[CH:11][C:10](O)=[CH:9][N:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:6][C:7]1[N:12]=[CH:11][C:10]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:9][N:8]=1
Reactant: OCC1CC1
Reactant: Oc1cnc(Cl)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ncc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of cyclopropylmethanol (276 mg), 2-chloropyrimidin-5-ol (500 mg) and triphenylphosphine (1.51 g) in toluene (20 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (659 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.21-0.49 (2H, m), 0.49-0.69 (2H, m), 1.07-1.46 (1H, m), 4.00 (2H, d, J=7.2 Hz), 8.53 (2H, s).
Reaction SMILES: Cl[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:17]1([N:23]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:25][C:24]2=[O:32])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>CC(=O)CC>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([N:29]1[CH2:28][CH2:27][C:26]2([N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:24](=[O:32])[CH2:25]2)[CH2:31][CH2:30]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)C(Cl)c1ccccc1
Reactant: O=C1CC2(CCNCC2)N1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(c1ccccc1)C(c1ccccc1)N1CCC2(CC1)CC(=O)N2c1ccccc1
Reaction time: 4 h
Yield: 89.3 %

Procedure:
A suspension of 2-chloro-1,2-diphenyl-ethanone (0.23 g, 1 mmol), 1-phenyl-1,7-diazaspiro[3.5]nonan-2-one (0.2 g, 0.9 mmol) and sodium bicarbonate (0.23 g) in 2-butanone was boiled for 4 h with stirring. The mixture was cooled, the solvent was removed in vacuo and the residue was purified by chromatography on silica gel with ethylacetate/hexane (1:2) to yield 0.33 g (87%) of the title compound. MS: m/e=411.3 (M+H+).
Reaction SMILES: [Na+].[Cl-].[CH2:3]([C:10](=[C:13]=[CH2:14])[CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>ClCCCl.CCOCC>[CH2:3]([C:10](=[C:13]=[CH2:14])[CH:11]=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C=C(CO)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCCl
Product: C=C=C(C=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
Fe(NO3)3.9H2O (20.3 mg, 0.05 mmol), 1,2-dichloroethane (DCE, 4 mL), 2,2,6,6-tetramethylpiperidinyloxy (TEMPO, 15.6 mg, 0.10 mmol) and NaCl (5.8 mg, 0.10 mmol) were added to a 10 mL-three-necked flask and were stirred for 5 mins at room temperature under oxygen atmosphere. 2-benzylbuta-2,3-dienol (160.6 mg, 1.0 mmol) was dissolved in DCE (1 mL) and then added to the reaction solution dropwise, and the reaction was monitored by TLC till it was complete. Then the reaction solution was diluted with ether (30 mL), dried over anhydrous MgSO4, filtered by a short pad of silica gel, and then concentrated to yield the crude products. Further purification by column chromatography on silica gel (petroleum ether:ethyl acetate=20:1) afforded the target product 2-benzylbuta-2,3-dienal (114.5 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 9.61 (s, 1H), 7.31-7.15 (m, 5H), 5.28 (t, J=2.4 Hz, 2H), 3.52 (t, J=2.6 Hz, 2H); 13C NMR (75.4 MHz, CDCl3) δ 222.50, 191.41, 138.52, 128.84, 128.35, 126.41, 110.62, 80.83, 30.84; IR (neat) 2827, 2728, 1955, 1928, 1677, 1602, 1495, 1454, 1426, 1227, 1144, 1071, 1030 cm−1; MS (EI) m/z 158 (M+, 5.25), 129 (100); HRMS: calcd. for C11H10O (M+): 158.0732. found: 158.07333.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:29].Cl.[CH3:31][NH2:32].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(O)C>[ClH:28].[CH3:31][NH:32][C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CNC(=N)c1cccc(COc2cc(C)cc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl)methoxy]-5-methylphenyl ester (414 mg, 1.0 mmol), as prepared in step (a) of Example 6, in methylene chloride (10 mL) was added 37% HCl in ethanol (15 mL) at 0° C. The mixture was allowed to stand at 0° C. for 3 days. The solvent was evaporated and the residue was concentrated in vacuo from methylene chloride several times. The residue was dissolved in ethanol (10 mL), treated with methylamine hydrochloride (270 mg, 4.0 mmol) and Na2CO3 (212 mg, 2.0 mmol), and then stirred at room temperature for 2 days. The reaction mixture was partitioned between methylene chloride (150 mL) and 10% K2CO3. The organic phase was washed with 10% K2CO3 (50 mL) and dried over K2CO3. After removing the solvent in vacuo, HCl in methanol (30 mL) was added and the solvent was removed in vacuo. The residue was then purified by flash column chromatography (10% methanol/methylene chloride) and crystallized from methanol/ethyl acetate to give the title compound as white crystals (145 mg, 30%). 1H-NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3 H), 3.01 (s, 3 H), 5.10 (s, 2 H), 6.53 (s, 1 H), 6.56 (s, 1 H), 6.87 (s, 1 H), 7.58 (t, 1 H, J=7.0 Hz), 7.63 (t, 1 H, J=7.6 Hz), 7.73 (m, 2 H), 7.86 (m, 3 H), 7.94 (d, 1 H, J=4.0 Hz), 9.05 (br S, 1 H), 9.55 (br s, 1 H), and 9.94 (br s, 1 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C22H21N2O4SCl: 445.1 (M+H). Found: 445.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][N:12]([C:17]([O:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:18])[CH2:13]2)[CH2:9]1)C1C=CC=CC=1.[O:25]1C[CH:26]1[CH2:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([O:29][CH2:28][CH:26]([OH:25])[CH2:1][N:8]2[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][N:12]([C:17]([O:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:18])[CH2:11]3)[CH2:15]2)=[CH:31][CH:32]=1)#[N:35]
Reactant: CC(C)(CO)OC(=O)N1CC2CC(CN(Cc3ccccc3)C2)C1
Reactant: N#Cc1ccc(OCC2CO2)cc1
Product: CC(C)(CO)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3)C2)C1
Yield: 88 %

Procedure:
2-Hydroxy-1,1-dimethylethyl 7-benzyl-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate (from step (c) above) was debenzylated according to the method described in Example E(b) above and subsequently reacted with 4-(2-oxiranylmethoxy)benzonitrile (see Example A above) in accordance with the method described in Example 2 above to give the title compound in an overall yield of 88%.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:13]([Br:29])=[CH:12][C:11]=1[OH:30].C([O-])([O-])=O.[K+].[K+]>C(O)C>[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:13]([Br:29])=[CH:12][C:11]=1[O:30][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCOc1cc(Br)c(O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCOc1cc(Br)c(OCc2ccccc2)cc1Br
Temperature: 50 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
Benzyl bromide (3.8 ml, 0.031 mol) was added drop wise to a stirred solution of 2,5-dibromo-4-dodecyloxy phenol (a) (6.95 g, 0.015 mol) and anhydrous K2CO3 (3.28 g, 0.023 mol) in 700 ml of absolute ethanol at 40-50° C. The reaction mixture was stirred for 10 h at 50° C., progress of the reaction was monitored using TLC, cooled to RT and evaporated to remove the solvent. An equal volume of distilled water was added to the residue and the mixture was stirred for one hour at 0° C. The resulting precipitate was collected by filtration, washed with water, and dried in vacuum. Recrystallization was done in methanol to get 80% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH:30][NH2:31].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]2[C:9]([CH:8]=1)=[N:31][N:30]([CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[C:13]=2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2ccccc2)c(Cl)c1
Reactant: NNCc1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)c1ccc2c(Cc3ccccc3)n(Cc3cccs3)nc2c1
Yield: 36 %

Procedure:
The reaction was performed according to example 1 using 156.4 mg 3-chloro-4-phenylethynyl-benzoic acid tert-butyl ester, 164.7 mg thiophen-2-ylmethyl-hydrazine hydrochloride (2.0 equiv.) and 488.7 mg Cs2CO3 (3.0 equiv.) with a reaction time of 5 hours at 110° C. This afforded 72.8 mg (36%) of the title compound. 1H-NMR (DMSO-d6) δ 1.56 (s, 9H), 4.58 (s, 2H), 5.86 (s, 2H), 6.93 (dd, 1H, J=5.1, 3.5 Hz), 7.04 (dd, 1H, J=3.5, 1.0 Hz), 7.16 (d, 2H, J=7.4 Hz), 7.20-7.29 (m, 3H), 7.42 (dd, 1H, J=8.8, 1.2 Hz), 7.44 (dd, 1H, J=5.0, 1.2 Hz), 7.55 (dd, 1H, J=8.7, 0.7 Hz), 8.20 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[N:22]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([NH:20][C:21]2[CH:25]=[CH:24][N:23]([CH2:26][C:27]([OH:29])([CH3:28])[CH3:30])[N:22]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
A solution of (S)-3-cyclohexyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (1.3 g, 4.87 mmol) in dichloromethane (25 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 830 mg, 5.36 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (2.60 g, 5.84 mmol) and triethylamine (1.48 g, 14.61 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 80 g; 0% to 10% methanol/dichloromethane) to afford (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (1.0 g, 51%) as a heavy yellow oil: LR-ES-MS m/z calculated for C21H32N4O4 [M]+ 404, observed [M+H]+ 405.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[NH:17][C:16]5[N:24]=[CH:25][CH:26]=[CH:27][C:15]=5[N:14]4[C:28]=3[C:29]3[CH:34]=[CH:33][C:32]([C:35]4([NH:39]C(=O)OC(C)(C)C)[CH2:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.Cl.O1CCOCC1>CO>[NH2:39][C:35]1([C:32]2[CH:33]=[CH:34][C:29]([C:28]3[N:14]4[C:15]5[CH:27]=[CH:26][CH:25]=[N:24][C:16]=5[NH:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:13]4=[N:12][C:11]=3[C:9]3[CH:8]=[CH:7][C:6]4[C:2](=[O:1])[O:3][CH2:4][C:5]=4[CH:10]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc5c(c4)COC5=O)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccc5c(c4)COC5=O)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reaction time: 23 h
Yield: 94.7 %

Procedure:
tert-Butyl (1-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (39 mg, 0.064 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at r.t for 23 hours. The mixture was concentrated, then sat.NaHCO3 aq. was added. The mixture was extracted with CH2Cl2+MeOH (×2), dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (CH2Cl2/MeOH=10:1) to afford the desired product (31 mg, 94%) as a pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.62 (s, 1H), 8.10 (dd, J=5.2 Hz and 1.7 Hz, 1H), 7.98 (dd, J=8.0 Hz and 1.7 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.55 (dd, J=8.6 Hz and 1.1 Hz, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.37 (td, J=8.0 Hz and 1.7 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.13 (td, J=8.0 Hz and 1.1 Hz, 1H), 6.91 (dd, J=8.0 Hz and 1.1 Hz, 1H), 6.75 (dd, J=8.0 Hz and 4.6 Hz, 1H), 5.39 (s, 2H), 2.45-2.41 (m, 2H), 2.23-2.18 (m, 2H), 2.10-2.02 (m, 1H), 1.77-1.70 (m, 1H). LCMS: 512 [M+H].
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].Cl[CH2:22][C:23]#[N:24]>C(#N)C>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:22][C:23]#[N:24])[CH2:3][CH2:2]2)=[N:8]1
Reactant: N#CCCl
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#CCN1CCN(c2n[nH]c3ccccc23)CC1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a stirred suspension of 3-piperazin-1-yl-1H-indazole (6.0 g, 29.7 mmol) and NaHCO3 (2.7 g, 32.7 mmol) in dry acetonitrile (125 ml) was added chloroacetonitrile (2.1 ml, 31.2 mmol) at room temperature, under nitrogen. The suspension was warmed to reflux for 17.5 hours, cooled to room temperature, and subsequently filtered. The remaining solids were washed with dichloromethane and the combined filtrates were concentrated. The resulting brown oil was purified via flash column chromatography (silica gel, 0-50% EtOAc/DCM) to give 4.0 g of product as an off-white solid, m.p. 121-123° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:19][CH:20]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:19][CH:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(N)Cc1cccc(O)c1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cccc(O)c1)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and methyl 2-amino-3-(3-hydroxyphenyl)propionate (prepared from 2-amino-3-(3-hydroxyphenyl)propionate (Biosynth AG, Switzerland) and methanol using General Procedure H), the title compound was prepared as a solid (mp=155-159° C.). The reaction was monitored by tlc (Rf=0.4 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent.