Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]([O:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:31]([O-:33])=[O:32])[N:19]2[C:22]([O:24]CCC(C)(C)C)=[O:23])=[CH:15][CH:14]=1)=[O:11])([CH3:6])[CH3:5].CO.O>C1COCC1>[CH3:3][C:4]([O:24][C:22]([N:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:10](=[O:11])[CH2:9][CH2:8][O:7][C:4]([CH3:3])([CH3:6])[CH3:5])[CH:21]=2)[CH:17]=[C:18]1[C:31]([OH:33])=[O:32])=[O:23])([CH3:6])[CH3:5]
Reactant: CC(C)(C)CCOC(=O)n1c(C(=O)[O-])cc2ccc(NC(=O)CCOC(C)(C)C)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OCCC(=O)Nc1ccc2cc(C(=O)O)n(C(=O)OC(C)(C)C)c2c1
Temperature: 50 °C
Yield: 162.7 %

Procedure:
Lithium hydroxide (0.037 g, 1.55 mmol) was added to a solution of 1-(1,1-dimethylethyl)2-ethyl 6-({3-[(1,1-dimethylethyl)oxy]propanoyl}amino)-1H-indole-1,2-dicarboxylate (0.067 g, 0.155 mmol) in THF:methanol:water/3:1:1 (3 mL). The mixture was heated at 50° C. for 1 hr. The solvent was evaporated and the residue was dissolved in water, acidified with 1N aqueous HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the title compound (0.051 g, 108%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (br. s., 1H), 9.82 (s, 1H), 7.94 (s, 1H), 7.44 (d, 1H), 7.04 (d, 1H), 6.85 (s, 1H), 3.57 (t, 2H), 2.33-2.48 (m, 2H), 1.09 (s, 9H). ES MS: m/z 305 (M+1).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[C:20](/[CH3:27])=[CH:21]\[C:22]([O:24]CC)=[O:23])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[C:20](/[CH3:27])=[CH:21]\[C:22]([OH:24])=[O:23])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C(/C)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Solvent: CCO
Product: C/C(=C/C(=O)O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Reaction time: 1 h

Procedure:
3.4 ml of 15N sodium hydroxide solution are added to 9.1 g (23.6 mmol) of ethyl 3-(2-benzenesulphonamidoindan-5-yl)-crotonate in 100 ml of ethanol and the mixture is boiled for 1 hour. The sodium salt is precipitated on cooling. It is filtered off with suction and dissolved in water. The free acid is precipitated by adding hydrochloric acid and is recrystallised from isopropanol.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:24])=O>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][Cl:24])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Cn2c(CO)nc3ccccc32)cc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(Cn2c(CCl)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2.2 g 1-(4-nitrobenzyl)-2-hydroxymethylbenzimidazole in 30 mL of chloroform was added 3.3 mL of thionyl chloride. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was taken up in water, neutralized with K2CO3 to a pH of 10 and extracted into methylene chloride. The organic layer was dried over Na2SO4 and concentrated to give 2 g of 1-(4-nitrobenzyl)-2-chloromethylbenzimidazole as a yellowish solid.
Reaction SMILES: CN(C)C(=O)C.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([O:22][CH3:23])(=[O:21])[C:15]#[C:16][C:17]([O:19][CH3:20])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(=O)C>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]1[C:14]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1[nH]c2ccccc2c1C(=O)OC
Temperature: 115 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
A 300 mL RBF was charged with N,N-Dimethylacetamide (DMA) (144 ml) and Acetic Acid (48.1 ml) was degassed with O2 for 5 min. To this was added aniline (2.94 ml, 32.2 mmol), dimethyl but-2-ynedioate (3.96 ml, 32.2 mmol), and Pd(OAc)2 (0.723 g, 3.22 mmol) and the reaction was heated to 115° C. under an atmosphere of O2. After 18 h, the reaction was cooled to ambient temperature, filtered through a pad of celite, diluted with EtOAc and washed with H2O. The organic was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes: 120 g SiO2) to afford dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol, 39.9% yield) as a yellow solid. The indole was dissolved in DMF (50 mL), treated with Cs2CO3 (6.30 g, 19.33 mmol), 4-Fluorobenzyl chloride (1.929 ml, 16.11 mmol) and KI (5.35 g, 32.2 mmol) and heated to 90° C. After 2 h, the reaction mixture was cooled to ambient temperature and partitioned between EtOAc and sat. aq. NH4Cl. The organic layer was washed with water (5×), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on ISCO (0-100% EtOAc-hexanes) to afford dimethyl 1-(4-fluorobenzyl)-1H-indole-2,3-dicarboxylate (3.79 g, 11.10 mmol, 34.5% yield) as a yellow solid. LCMS (m/z) ES+=342 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25](Br)=[CH:24][C:23]=1[CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O>[CH2:14]([O:21][C:22]1[C:23]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:24][C:25]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c(C2CCCC2)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1cc(C2CCCC2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 45.4 %

Procedure:
Diethyl malonate (1059 mg, 1.0 mL, 6.6 mmol) was added dropwise to a suspension of NaH (265 mg, 6.6 mmol) in DMSO (3.3 mL). The reaction mixture was warmed to 60° C. for 30 min. A solution of 1-benzyloxy-4-bromo-2-cyclopentyl-5-nitro-benzene (995 mg, 2.6 mmol) in DMSO (3 mL) was added dropwise and the reaction mixture heated at 100° C. for 2 h. The cooled solution was poured into ice water, and the aqueous layer extracted with dichloromethane (3×20 mL). The organic layer was dried down to an orange residue. Purification by silica gel chromatography (0-40% ethyl acetate/hexane) provided diethyl 2-(4-(benzyloxy)-5-cyclopentyl-2-nitrophenyl)malonate as a yellow oil (538 mg, 45% yield). LC/MS m/z 456.2 [M+H]+.
Reaction SMILES: Cl.[N+](C1C=CC([O:11][C:12](=O)[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[C:29]4[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:23][N:22]([CH3:32])[CH2:21]3)[CH:15]=2)=CC=1)([O-])=O.[NH2:34][CH2:35][CH2:36][OH:37]>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][CH:20]2[C:16]1[CH:15]=[C:14]([NH:13][C:12]([NH:34][CH2:35][CH2:36][OH:37])=[O:11])[CH:19]=[CH:18][CH:17]=1
Reactant: NCCO
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)C1
Agent: Cl
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)NCCO)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
509 mg (1,0 mmol) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic-acid 4-nitro-phenyl-ester-Hydrochloride (example 151, intermediate 1) were dissolved in 15 ml DMF and at 0° C. a solution of 67,2 mg (1,1 mmol) of 2-Aminoethanol in 10 ml DMF was added. After stirring for 3 h at room temperature the solvent was removed i. vac. The residue was dissolved in ethylacetate and washed with sat. NaHCO3-solution. The organic layer was separated and the aqueous layer was extracted twice with ethylacetate. The combined organic layers were washed with sat. NaCl-solution, dried (MgSO4) and concentrated. Purification by silica gel chromatography (dichloromethane/methanol) yielded 265 mg of the title compound.
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:12][C:13]1[CH:14]=[C:15](I)[CH:16]=[C:17]([F:19])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([CH:10]([NH2:11])[C:6]2([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8][CH2:9]2)[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: Fc1cc(F)cc(I)c1
Reactant: N#CC1(N2CCCC2)CCC1
Product: NC(c1cc(F)cc(F)c1)C1(N2CCCC2)CCC1

Procedure:
The title compound, yellow oil, MS: m/e=267.2 [(M+H)+], was prepared in accordance with the general method of intermediate K from 1-pyrrolidin-1-yl-cyclobutanecarbonitrile (intermediate F) and 3,5-difluoro-iodobenzene.
Reaction SMILES: [H-].[Na+].[C:3]([N:22]1[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]1=[O:29])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:30]([C:33]1[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[C:35]([CH:42]([CH3:44])[CH3:43])[C:34]=1[S:45](Cl)(=[O:47])=[O:46])([CH3:32])[CH3:31].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[CH:30]([C:33]1[CH:38]=[C:37]([CH:39]([CH3:40])[CH3:41])[CH:36]=[C:35]([CH:42]([CH3:44])[CH3:43])[C:34]=1[S:45]([O:28][C:25]1[CH:26]=[CH:27][N:22]([C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:23](=[O:29])[N:24]=1)(=[O:47])=[O:46])([CH3:31])[CH3:32]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: O=c1ccn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)Oc2ccn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(=O)n2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 52.6 %

Procedure:
Sodium hydride (0.494 g, 12.3 mmol) was added to a stirred solution of 1-tritylpyrimidine-2,4(1H,3H)-dione (1.75 g, 4.9 mmol) in dry THF (75 mL) at RT. After stirring the mixture at RT for 45 min, 2,4,6-triisopropylbenzene-1-sulfonyl chloride (2.99 g, 9.9 mmol) was added and stirring continued at RT for 2 h. The reaction mixture was poured into a stirred mixture of EtOAc and saturated ammonium chloride solution. The organic layer was dried (MgSO4), concentrated and the residue was subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient) to afford 2-oxo-1-trityl-1,2-dihydropyrimidin-4-yl 2,4,6-triisopropylbenzenesulfonate 4A (1.6 g, 52% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.[F:30][C:31]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[CH:42][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:30][C:31]1[CH:45]=[C:44]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]4[C:19]5=[N:20][C:21]([C:24]6[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=6)=[CH:22][N:23]=[C:18]5[N:17]=[N:16]4)[CH2:9]3)=[N:6][CH:7]=2)[CH:43]=[CH:42][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6ccc(OCCN7CCOCC7)c(F)c6)cn5)CCO4)c3n2)cn1
Temperature: 105 °C
Reaction time: 4 h
Yield: 39.3 %

Procedure:
(S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine 15 mg (0.033 mmol) was dissolved in dioxane 1 ml, and 4-(2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenoxy)ethyl)morpholine 17 mg (0.049 mmol) and 1M sodium carbonate 98.4 ul (0.098 mmol) were added. Pd(PPh3)4 2 mg (0.0016 mmol) was added, and the mixture was purged with N2 (g), followed by stirring at 105° C. for 4 hours. When the reaction was completed, the reaction mixture was extracted with ethyl acetate and brine, and the organic layer was dried over Na2SO4. Prep LC with 4% MeOH/MC gave a product 7.8 mg (40%).
Reaction SMILES: B.CSC.[C:5]([C-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)(=[O:8])[CH2:6][CH3:7].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]>O1CCCC1>[OH:8][C@@H:5]([C-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[CH2:6][CH3:7].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]
Reactant: CCC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: B
Agent: c1cc[cH-]c1
Solvent: CSC
Solvent: C1CCOC1
Product: CC[C@@H](O)[c-]1cccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.5 ml (25 mmol) of borane-dimethyl sulphide adduct were added dropwise at 200C to a solution of 10.0 g (41.3 mmol) of propionylferrocene and 2.5 ml (2.5 mmol, 0.06 eq) of catalyst (S)-III (R6 =CH3) in 30 ml of tetrahydrofuran over a period of 30 minutes. After 1 hour at 20°-25° C., the reaction mixture was poured while stirring vigorously onto about 200 ml of ice/water and stirred for 0.5 hours. The aqueous phase was subsequently extracted three times with 200 ml each time of tert-butyl methyl ether, the combined organic phases were dried over magnesium sulphate and evaporated in a high vacuum. This gave 10.7 g (106%) of the crude title compound. This crude product can be used without further purification for the further reactions.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][C:5]([CH2:8][S:9][C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:7]=1.[OH-].[K+].[CH3:27]I.O>CS(C)=O>[CH3:27][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:10]1[S:9][CH2:8][C:5]1[CH:4]=[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: CI
Reactant: Cc1cnc(CSc2cc3ccccc3[nH]2)cc1N1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cnc(CSc2cc3ccccc3n2C)cc1N1CCCCC1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
2-[(5-Methyl-4-piperidino-2-pyridyl)methylthio]indole (80 mg, 0.24 mmol) was added to a suspension of potassium hydroxide (finely ground) (62 mg) in dimethylsulfoxide (0.5 ml), and the mixture was stirred for 30 minutes. Methyl iodide (34 mg, 0.24 mmol) was then added to the mixture and the stirring was continued at room temperature for further 30 minutes. Then, water (20 ml) was added to the reaction solution and the mixture was extracted with ethyl ether. The ether layer so separated was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (eluent: chloroform), yielding the titled compound (75 mg) as an oil. Yield: 90%.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:30][C:31]3[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Product: Cn1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccc(C(F)(F)F)o3)c2c1=O

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 2-(bromomethyl)-5-(trifluoromethyl)furan. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.51-7.61 (m, 1H) 7.39-7.47 (m, 2H) 7.32-7.39 (m, 1H) 7.08-7.15 (m, 1H) 6.65-6.73 (m, 1H) 6.43-6.51 (m, 1H) 5.94-6.00 (m, 1H) 5.75-5.91 (m, 2H) 5.26 (s, 1H) 3.63 (s, 3H) 0.96 (s, 9H); LC/MS (m/z) ES+=537 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][C@@H:22]5[CH2:25][N:26](C(OCC)=O)[CH2:27][C@H:21]45)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=[CH:3]1.[OH-].[K+]>CC(O)=O.Cl.O>[N:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:7]4[C:2](=[O:1])[CH:3]=[CH:4][CH:5]=[N:6]4)=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[CH2:24][CH2:23][C@@H:22]2[CH2:25][NH:26][CH2:27][C@H:21]12
Reactant: CCOC(=O)N1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1cccnn1-c1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Temperature: 100 °C

Procedure:
The product from Example 85A (0.110 g, 0.256 mmol) was dissolved in 3 mL of a 1:1 mixture of HOAc and 12 M aqueous HCl, and heated at 100° C. for 16 hours in a sealed vessel. The mixture was cooled to 0° C., diluted with 15 mL of water, and the pH was adjusted to ˜10 by the dropwise addition of 20% (w/v) aqueous KOH. The mixture was extracted three times with 25 mL of 5% n-propanol in CHCl3 and the combined extracts were dried over Na2SO4, filtered, and absorbed on silica gel. The crude material was chromatographed, eluting with 0-5% aqueous NH4OH in MeCN/MeOH (9:1), to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.91 (dd, J=3.7, 1.7 Hz, 1H), 7.64 (s, 4H), 7.52 (d, J=8.8 Hz, 2H), 7.21-7.27 (m, 1H), 7.07 (dd, J=9.5, 1.7 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H), 4.10-4.19 (m, 1H), 3.56-3.67 (m, 1H), 3.23-3.35 (m, 1H), 2.91-3.22 (m, 5H), 2.15-2.32 (m, 1H), 2.12 (br s, 1H), 1.87 (ddd, J=12.9, 7.5 Hz, 1H), MS (ESI+) m/z 359 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH:26](B1OC(C)(C)C(C)(C)O1)=[CH2:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]([C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1)=[CH2:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Br
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C

Procedure:
A suspension of tert-butyl N-[(1S,2S)-2-{[3-bromo-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (650 mg, 1.53 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS number 75927-49-0; 942 mg, 6.11 mmol), tetrakis(triphenylphosphine)palladium (177 mg, 0.15 mmol) and potassium carbonate (845 mg, 6.11 mmol) in 1,4-dioxane (5 ml) and water (0.8 ml) was subjected to microwave irradiation at 120° C. for 1 hour. The reaction was partitioned between ethyl acetate (10 ml) and water (10 ml). The aqueous layer was further extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine (20 ml), filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH:10]=O)=[C:8]([CH3:12])[N:7]=[C:6]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:2]([CH3:4])[CH3:3].[C:23]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(O)C>[C:36]1([CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]2[CH2:31][CH2:32][N:33]([CH2:10][C:9]3[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)=[N:7][C:8]=3[CH3:12])[CH2:34][CH2:35]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)n(CC(C)C)c1C=O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)n(CC(C)C)c1CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 8 h
Yield: 35.5 %

Procedure:
A solution of 1-isobutyl-2-(4-trifluoromethylphenyl) -4-methyl-5-formylimidazole (1.6 g), N-(diphenylmethyl) -piperazine (1.3 g), and titanium tetraisopropoxide (2 ml) were stirred for 1 hour at room temperature. Ethanol (10 ml) was added, and the resultant solution was stirred for a further 30 minutes. Sodium cyanoborohydride (330 mg) was then added, and the mixture stirred overnight. The solvent was removed under reduced pressure, and the residue partitioned between methylene chloride/water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel, eluting with ethyl acetate/n-heptane (1/2), to yield 1.0 g of 1-diphenylmethyl-4-[(l-isobutyl-2-(4-trifluoromethyl -phenyl)-4-methylimidazol-5-yl)methyl)piperazine. Treatment with anhydrous hydrochloric acid in ethanol converted the base to its trihydrochloride salt, m.p. 200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:32][C:28]5[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=5)[CH:3]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(NCc2cccnc2)c1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a stirred mixture of 7-(3-aminophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (0.100 g, 0.285 mmol), 3-pyridinecarboxaldehyde (32.3 ml, 0.342 mmol), and acetic acid (65.5 ml, 1.14 mmol) in anhydrous methanol (4 ml) under nitrogen was added sodium cyanoborohydride (21.5 mg, 0.342 mmol) and the mixture was stirred for 3 h. The mixture was quenched with saturated aqueous K2CO3 (0.5 ml) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2Cl2) to give 0.1162 g (93%) of the title compound as a yellow solid; mp 284-287° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.13 (3H, s), 4.34 (2H, d, J 6.1 Hz), 6.39 (1H, t, J 6.1 Hz), 6.64-6.68 (3H, m), 7.17 (1H, t, J 7.7 Hz), 7.35 (1H, dd, J 7.9, J′4.9 Hz), 7.42 (2H, d, J9.0 Hz), 7.77 (1H, dt), 8.11 (2H, d, J 9.0 Hz), 8.44 (1H, m), 8.51 (1H, s), 8.61 (1H, s), 12.34 (1H, br s); MS (ES+) m/z 442/444[MH]+, 221/222[(M2H)/2]+. Anal. found: C, 67.08; H, 4.50; N, 15.54. C25H20ClN5O.0.3H2O requires: C, 67.13; H, 4.64; N, 15.66%.