Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].B(F)(F)F.CCOCC.[CH3:20][C:21]1([CH:27]=[CH2:28])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1>O1CCOCC1.CCOCC>[CH3:20][C:21]1([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:27][CH2:28][C:4]2[C:3](=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=2[CH3:9])[O:10]1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: C=CC1(C)CCC(=O)O1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cc(C)c2c(c1C)OC(C)(CCC(=O)O)CC2
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 2,3,5-trimethylphenol (0.01 mol) and boron trifluoride diethyl etherate (0.016 mol) in dioxane (10 mL, dried on sodium) in a flask was added γ-methyl-γ-vinylbutyrolactone (0.016 mol) in dioxane (5.0 mL) via syringe pump over 50 min at 110° C. (oil bath, reflux) under nitrogen. The reaction mixture was cooled to room temperature and diluted with ether (200 mL), then washed with water (100 mL, 2×50 mL) and dried over sodium sulfate. Ether was then removed in vacuum. The residue was dissolved in methanol (30 mL), and solvent was removed in vacuum. The reaction mixture was purified by flash column chromatography on silica gel (eluent ethyl acetate/hexane, 1:1). Fractions containing the desired chroman were pooled, solvent was removed, and the compound was crystallized from ethyl acetate/hexane to afford a white crystalline product in a yield of 40%. M.P.: 148-149° C.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[C:15]([NH:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1)(=[O:17])[CH3:16].N1CCCC1.O>C(O)C>[CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=[C:23]1[C:22]2[C:26](=[CH:27][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[CH:20][CH:21]=2)[NH:25][C:24]1=[O:28])([CH3:3])[CH3:2]
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Solvent: O
Solvent: CCO
Solvent: C1CCNC1
Product: COc1cc(C)c(C=C2C(=O)Nc3cc(NC(C)=O)ccc32)cc1C(C)C
Reaction time: 12 h

Procedure:
A mixture of 5-isopropyl-4-methoxy-2-methylbenzaldehyde (0.25 g, 1.3 mmol), 6-acetamido-2-oxindole (0.25 g, 1.3 mmol) and pyrrolidine (0.54 ml, 6.5 mmol) in ethanol (4 ml) was held in a sealed tube at 100° C. for 12 hours. The reaction was cooled and then poured into water (100 ml). The solid which formed was removed by filtration, washed with water and then dissolved in ethyl acetate (200 ml). The ethyl acetate solution was dried over magnesium sulfate and concentrated. The resulting solid was triturated with dichloromethane/hexanes to .afford 0.33 g (70%) of N-[3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide as a brownish yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of diisopropylamine (7.7 mL, 54.88 mmol) in dry tetrahydrofuran (23 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (22.0 mL, 54.88 mmol). The reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of 4-bromophenylacetic acid (5.62 g, 26.13 mmol) in dry tetrahydrofuran (23 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL). The reaction mixture turned dark in color and was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (5.76 g, 27.44 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified using a 10% aqueous hydrochloric acid solution. The resulting aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid (3.88 g, 50%) as a light yellow solid: mp 91-93° C.; EI-HRMS m/e calcd for C14H17BrO2 (M+) 296.0412, found 296.0417.
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][C@@H:6]1[O:10][CH2:9][C@@H:8]([S:11]C(=O)C)[CH2:7]1)=[O:3].C[O-].CO.Cl.C(O)(C)C>O1CCCC1>[C:2]([O:4][CH2:5][C@H:6]1[CH2:7][C@H:8]([SH:11])[CH2:9][O:10]1)(=[O:3])[NH2:1]
Reactant: CC(=O)S[C@@H]1CO[C@@H](COC(N)=O)C1
Agent: C[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CO
Product: NC(=O)OC[C@H]1C[C@H](S)CO1

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.109 g of product from Example 7, 120 microliter of 25% methoxide/methyl alcohol, 1.75 ml of tetrahydrofuran, 280 microliter of 1.86N hydrochloric acid/isopropyl alcohol to give the desired product as a white solid.
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:9]C1C=CC=CC=1)[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]>C(O)=O.Cl.C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]
Reactant: C=CC(C)(C)C(=CCl)Oc1ccccc1
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Product: C=CC(C)(C)C(=O)CCl
Temperature: 40 °C
Yield: 85.8 %

Procedure:
57 g (0.256 mol) of 1-chloro-3,3-dimethyl-2-phenoxy-1,4-pentadiene in a mixture of 250 ml of formic acid and 50 ml of concentrated hydrochloric acid were heated to 40° C. in the course of 1 hour. The mixture was then diluted with 400 ml of methylene chloride and ice, and was extracted three times by shaking with 2N sodium hydroxide solution. After the methylene chloride phase had been dried over sodium sulphate, the solvent was removed. 36 g of product (96% of theory) remained and were distilled. 32.2 g (86% of theory) of 5-chloro-3,3-dimethylpent-1-en-4-one of boiling point 81° to 84° C./24 mm Hg were obtained. ##STR27##
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][OH:7])[CH2:2]1.C(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.[CH3:21][CH:22]1[CH:27]([N:28]([CH3:48])[C:29]2[C:30]3[CH:37]=[CH:36][N:35]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[C:31]=3[N:32]=[CH:33][N:34]=2)[CH2:26][CH2:25][CH:24]([CH2:49][S:50](Cl)(=[O:52])=[O:51])[CH2:23]1>CN(C=O)C>[CH3:21][CH:22]1[CH:27]([N:28]([CH3:48])[C:29]2[C:30]3[CH:37]=[CH:36][N:35]([S:38]([C:41]4[CH:42]=[CH:43][C:44]([CH3:45])=[CH:46][CH:47]=4)(=[O:39])=[O:40])[C:31]=3[N:32]=[CH:33][N:34]=2)[CH2:26][CH2:25][CH:24]([CH2:49][S:50]([N:1]2[CH2:5][CH2:4][C@H:3]([CH2:6][OH:7])[CH2:2]2)(=[O:52])=[O:51])[CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCC(CS(=O)(=O)Cl)CC4C)ncnc32)cc1
Reactant: OC[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCC(CS(=O)(=O)N5CC[C@H](CO)C5)CC4C)ncnc32)cc1
Reaction time: 1 h

Procedure:
A mixture of (S)-pyrrolidin-3-ylmethanol (0.150 g, 1.5 mmol), CHCl3 (5 mL) and DIEA (0.5 mL, 3 mmol) was treated with a mixture of (3-methyl-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonyl chloride (0.208 g, 0.41 mmol), CHCl3 (3.0 mL), and DMF (1.5 mL). After 1 h, the mixture was concentrated and the resulting residue was chromatographed using 0→8% MeOH in CH2Cl2. The product fractions were pooled and concentrated to give ((3S)-1-((3-methyl-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methylsulfonyl)pyrrolidin-3-yl)methanol (0.126 g (54%). MS for C27H37N5O5S2 (ESI) (MH)+ m/z=576.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:26][O:25][C:19]1[CH:20]=[C:21]([O:23][CH3:24])[N:22]=[C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:18]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(OC)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 52 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4,6-dimethoxypyrimidine, using potassium carbonate as a base. The title compound was isolated in a yield of 52%. MS ISP (m/e): 342.1 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.70-7.55 (m broad, 2H), 7.35-7.20 (m broad, 3H), 7.04 (s broad, 1H), 3.92 (s broad, 6H), 3.81 (s broad, 3H), 2.14 (s broad, 3H).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:4]([SiH](C)C)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Br[C:16]1CC2C(C=1)=CC=CC=2.Cl[Si:26](Cl)([CH3:28])C>O1CCCC1>[Cl:2][C:3]1[CH:28]([SiH3:26])[C:6]2[C:5]([C:4]=1[CH3:16])=[C:10]([CH3:11])[CH:9]=[CH:8][CH:7]=2
Reactant: C[SiH](C)C1C(Cl)=Cc2ccccc21
Reactant: C[Si](C)(Cl)Cl
Reactant: BrC1=Cc2ccccc2C1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1=C(Cl)C([SiH3])c2cccc(C)c21
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Under nitrogen flow, 50 ml of THF (tetrahydrofuran) and 2.5 g (41 mmol) of magnesium was placed in a 1 liter 3-necked flask, to which 0.1 ml of 1 2-dibromoethane was added and stirred for 30 minutes to activate magnesium. After stirring, solvent was withdrawn and 50 ml of THF was newly added. To this, 5.0 g (25.6 mmol) of 2-bromoindene in THE (200 ml) solution was dropped in 2 hours. Then the solution was stirred at room temperature for 2 hours and cooled down to −78 ° C., to which 3.1 ml (25.6 mmol) of dichlorodimethylsilane in THF (100 ml) solution was dropped in one hour, followed by stirring for 15 hours and the solvent was distilled off. The residue was extracted by 200 ml of hexane and by distilling off the solvent, 6.6 g (24.2 mmol) of 2-chloro-dimethyl-silylindene was obtained (yield 94%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15]C)[CH:10]=3.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:26]=[N:25][CH:24]=[N:23][CH:22]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3
Reactant: COc1cc2c(=O)c(Cc3cncnc3)cn3c4cc(Br)ccc4c(c1)c23
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cc2cncnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
9-bromo-2-methoxy-5-(5-pyrimidylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (260 mg) produced in Example 125 was suspended in anhydrous methylene chloride (16 ml), and boron tribromide (3.7 ml) was added dropwise at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was poured into ice water and saturated aqueous solution of sodium hydrogencarbonate was added thereto until the termination of foaming. The crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with ethanol and ether in succession to obtain the title compound (250 mg, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][C@H:26]([C:32]3[CH:33]=N[CH:35]=[C:36]([OH:38])[CH:37]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40](=O)([O-])[O-].[Cs+].[Cs+].[C:46]1([CH3:69])[CH:51]=[CH:50][C:49]([S:52]([O:55][CH2:56][CH2:57]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:54])=[O:53])=[CH:48][CH:47]=1>CN(C)C=O>[CH3:31][O:30][C:28](=[O:29])[CH2:27][C@H:26]([NH:25][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH2:19]1)=[O:39])[C:32]1[CH:33]=[CH:40][CH:35]=[C:36]([O:38][CH2:57][CH2:56][O:55][S:52]([C:49]2[CH:48]=[CH:47][C:46]([CH3:69])=[CH:51][CH:50]=2)(=[O:53])=[O:54])[CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(OCCOS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 4e, 80 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (20 mL). Cesium carbonate (120 mg, 0.37 mmol) and ethylene glycol bis-p-toluenesulfonate (81 mg, 0.22 mmol) were added. The mixture was stirred at room temperature for 2 hours, quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate in dichloromethane 60%) to yield 67 mg of tert-butyl 4-{3-[(3R)-3-({(1S)-3-methoxy-1-[3-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylat.
Reaction SMILES: [Li].Br[CH:3]1[CH:7]2[CH2:8][CH2:9][CH:4]1[CH2:5][CH2:6]2.[C:10](=[O:12])=[O:11].O1CCC[CH2:14]1>>[CH:7]12[CH:3]([CH2:14][C:10]([OH:12])=[O:11])[CH:4]([CH2:9][CH2:8]1)[CH2:5][CH2:6]2
Reactant: C1CCOC1
Reactant: O=C=O
Reactant: BrC1C2CCC1CC2
Agent: [Li]
Product: O=C(O)CC1C2CCC1CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Lithium metal (78 mg, 11.2 mmol) was scraped under a tetrahydrofuran solution to remove the coating and then added to a solution of 4,4′-tertbutyl biphenyl (2.67 g, 10.02 mmol) in tetrahydrofuran (15 mL) under argon. The mixture was cooled to 0° C. and a blue-green color appeared over time. After 3 h, all the lithium metal was dissolved and the mixture was cannulated into a −78° C. mixture of 7-bromo-bicyclo[2.2.1]heptane (1.0 g, 5.71 mmol) in tetrahydrofuran (5 mL). The mixture turned colorless and then developed a red color and stirred at −78° C. for 30 min. The mixture was then quickly poured over freshly crushed dry ice. The resulting yellow mixture was allowed to warm to 25° C. and concentrated in vacuo. The residue was dissolved in diethyl ether (30 mL) and extracted with a 1N aqueous sodium hydroxide solution (2×15 mL). The combined aqueous extracts were acidified with concentrated hydrochloric acid and extracted with diethyl ether (3×10 mL). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo to afford bicyclo[2.2.1]hept-7-yl-acetic acid (554 mg, 63%)
Reaction SMILES: C(O[C:6]([NH:8][NH:9][C:10](=[S:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O)(C)(C)C.[CH3:19][O:20][C:21]1[C:22]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])=[C:23]([CH:26]=[CH:27][CH:28]=1)C=O.CCN(C(C)C)C(C)C.[F:49][C:50]1[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[C:51]=1[C:52](Cl)=[O:53].Cl>C(Cl)Cl.CCOC(C)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[S:18][CH:6]([C:28]3[CH:27]=[CH:26][CH:23]=[C:22]([O:29][Si:30]([CH:31]([CH3:32])[CH3:33])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:38])[CH3:39])[C:21]=3[O:20][CH3:19])[N:8]([C:52]([C:51]3[C:50]([F:49])=[CH:58][C:57]([F:59])=[CH:56][C:55]=3[F:60])=[O:53])[N:9]=2)=[CH:12][CH:13]=1
Reactant: COc1cccc(C=O)c1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CC(C)(C)OC(=O)NNC(=S)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 0.5 h

Procedure:
N′-(4-fluoro-thiobenzoyl)-hydrazinecarboxylic acid tert-butyl ester (1.23 mmol) is dissolved in 5 mL of CH2Cl2 at room temperature in a dry round bottom flask. Removal of the ester group is accomplished adding TFA (2 mL) to the solution at room temperature. The reaction is complete after 30 minutes as determined by LC/MS. Solvent is removed in vacuo. The resultant oil is dried on the vacuum line for 30 minutes and dissolved in 1 mL of dry CH2Cl2. This solution is added to a mixture of 3-methoxy-2-triisopropylsilanyloxy-benzaldehyde (1.23 mmol) and DIEA (4.9 mmol) in 1 mL of dry CH2Cl2. The mixture is allowed to stand at room temperature in the presence of molecular sieves for 5 minutes. 2,4,6-Trifluorobenzoyl chloride (1.6 mmol) is added and the reaction mixture is kept at room temperature for 16 hours. HCl (1 M) (10 mL) is added to the mixture to quench the reaction. The mixture is diluted with EtOAc (50 mL), washed with HCl (1 M) (2×10 mL) and brine (50 mL) and dried over anhydrous Na2SO4. Purification is accomplished by silica flash chromatography (5% EtOAc/hexane) to give [5-(4-fluoro-phenyl)-2-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J1=8.8 Hz, J2=5.3 Hz, 2H), 7.51 (s, 1H), 7.04 (t, J=8.6 Hz, 2H), 6.95 (t, J=7.8 Hz, 1H), 6.87 (t, J=8.8 Hz, 2H), 6.77 (t, J=7.9 Hz, 2H), 4.03 (s, 3H), 1.27-1.36 (m, 3H), 1.14 (dd, J1=J2=6.3 Hz, 18H); LC/MS (ES+): (M+1) 309.2. Rf=0.4 (5% EtOAc/hexanes).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH3:29])=[CH:23][CH:22]=1)#[N:14].C(N(CC)CC)C>C(O)C.O>[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][N:28]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=2)[CH3:29])=[CH:25][CH:26]=1)#[N:14]
Reactant: CNCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCc1cc(Cl)n2nccc2n1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCc1cc(N(C)Cc2ccc(-c3ccccc3C#N)cc2)n2nccc2n1

Procedure:
1.8 g (10 mmol) of the chloro compound of Step B and 2.2 g (10 mmol) of the amine of Step C were dissolved in 60 ml ethanol and heated with reflux for 4 h. After addition of 3 ml triethylamine the heating was continued for an additional hour. The mixture was diluted with water and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, evaporated in vacuo, and the title compound obtained as an oil after purification by column chromatography on silica gel using ethyl acetate/hexane 9:1 as eluent,
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH3:13][O:14][CH2:15][CH2:16][O:17][C:18]1[C:22]2[CH:23]=[N:24][C:25]([NH2:27])=[CH:26][C:21]=2[N:20]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:19]=1.N1C=CN=C1.[NH2:52][C@@H:53]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:54]1([OH:58])[CH2:57][CH2:56][CH2:55]1>O1CCCC1>[OH:58][C:54]1([C@H:53]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[NH:52][C:6]([NH:27][C:25]2[N:24]=[CH:23][C:22]3[C:18]([O:17][CH2:16][CH2:15][O:14][CH3:13])=[N:19][N:20]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:21]=3[CH:26]=2)=[O:7])[CH2:55][CH2:56][CH2:57]1
Reactant: COCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(N)ncc12
Reactant: N[C@@H](c1ccccc1)C1(O)CCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: COCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@@H](c3ccccc3)C3(O)CCC3)ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
CDI (36.0 mg, 0.222 mmol) was added to a stirred, room temperature mixture of 3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine 32B (50 mg, 0.111 mmol) and imidazole (30.2 mg, 0.444 mmol) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for overnight. The mixture turned from light yellow slurry to clear solution. (S)-1-(amino(phenyl)methyl)cyclobutanol (19.67 mg, 0.111 mmol) was added to mixture and the resultant mixture was kept stirring at room temperature for overnight. The residue was purified (24 g silica, eluting with 50% EtOAc/isohexane) to give (S)-1-((1-hydroxycyclobutyl)(phenyl)methyl)-3-(3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (54 mg, 74% yield) as a white solid. MS: [M+H]+ m/z 654.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[NH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:3][CH2:2]1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24]([OH:27])(=[O:26])=[O:25].[CH3:28]COCC>>[CH3:28][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH2:15][CH2:14][CH2:23][C:5]1=2.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24]([OH:27])(=[O:26])=[O:25].[CH2:2]1[CH:1]([NH2:4])[CH2:3]1
Reactant: CCOCC
Reactant: c1ccc2[nH]c(NC3CC3)cc2c1
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Product: Cn1c2c(c3ccccc31)CCC2
Product: NC1CC1

Procedure:
A 0.75 g portion of the cyclopropylaminoindole compound was dissolved in 75 ml Et2O and stirred while a solution of 0.69 g of 2-naphthalene sulfonic acid in 50 ml Et2O was added slowly. A white precipitate formed which was filtered under N2, washed with 2×50 ml Et2O and dried to afford 1.04 g of 4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-3-cyclopropylamine 2-naphthalene sulfonate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[N:20]=[CH:21][N:22]([C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)[CH:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[CH3:18][C:19]1[N:20]=[CH:21][N:22]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:15](=[O:17])[CH2:14][C:11]3[CH:10]=[CH:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:13][CH:12]=3)=[N:28][CH:29]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Reactant: Cc1cn(-c2ccc(N)nc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(-n4cnc(C)c4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 26-3 (22 mg, 0.1 mmol), 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine 143-3 (18 mg, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (40 mg, 0.1 mmol) in DMF (1 mL) was added DIEA (52 μL, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by reverse phase HPLC to give N-(5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 143. MS m/z 384.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.91 (s, 1H), 8.58 (dd, 1H), 8.43 (d, 1H), 8.10 (m, 2H), 7.99 (m, 1H), 7.77 (d, 2H), 7.51 (s, 1H), 7.43-7.40 (m, 4H), 3.75 (s, 2H), 2.46 (s, 3H), 2.10 (s, 3H).