Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:20]1[CH:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1ccc2ccccc2c1
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: COCCOC
Product: COC(=O)c1c(O)c2ccc(-c3ccc4ccccc4c3)cc2sc1=O
Yield: 46.9 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) (220 mg, 0.70 mmol) in dimethoxyethane (DME) (3.1 mL) was added naphthalen-2-yl-boronic acid (144 mg, 0.84 mmol), Pd(PPh3)4 solid (64 mg, 0.06 mmol) and then 2M aqueous Na2CO3 solution (0.86 mL). The resulting mixture was purged with nitrogen gas for 1 min and heated to reflux for 3 h. After cooling, the reaction mixture was diluted with water (100 mL) and acidified using 1 N HCl to pH 3-4. The precipitate was collected by filtration, rinsed with CH2Cl2 and the solid dried to provide 4-hydroxy-7-naphthalen-2-yl-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (119 mg). MS ESI(+) m/e: 363.19 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:31](O)CCC>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH3:31])[CH2:26][CH2:27]3)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCCCO
Reactant: COc1ccc(Nc2nc(Cl)cc(-c3ccccc3)n2)cc1Cl
Reactant: CN1CCNCC1
Product: CCN1CCN(c2cc(-c3ccccc3)nc(Nc3ccc(OC)c(Cl)c3)n2)CC1

Procedure:
The title compound was prepared by treating (3-chloro-4-methoxy-phenyl)-(4-chloro-6-phenyl-pyrimidin-2-yl)-amine (0.5 g, 1.4 mmol) with N-methyl piperazine in n-butanol at refluxing temperature.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:12]([CH:14]=[CH2:15])=[O:13].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]1(=[O:11])[N:5]([CH2:15][CH2:14][CH:12]=[O:13])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: C=CC=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Product: O=CCCN1C(=O)c2ccccc2C1=O

Procedure:
3-Phthalimidopropanal was prepared by addition of phthalimide to acrolein in the presence of tetrabutylammonium hydroxide according to the procedure described by R. O. Atkinson & F. Poppelsdorf, J Chem. Soc. (1952) 2448. 1H-NMR (CDCl3, 400 MHz): δ 9.82 (t, 1H, J=2); 7.85 (m, 2H); 7.72 (m, 2H); 4.04 (t, 2H, J=7); 2.88 (dt, 2H, J=2, 7). 13C-NMR (CDCl3, 100 MHz): δ 199.36, 167.98, 134.10, 131.95, 123.36, 42.35, 31.67.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][C:5]=1[CH3:20].ClC1C=[CH:30][C:26]([C:27](O)=[O:28])=[C:25](C)[CH:24]=1.Cl.C[O:35][C:36](=[O:50])[C@H:37]([CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([OH:49])[CH:47]=2)[NH:42][CH:41]=1)[NH2:38]>>[CH:14]1([N:13]2[C:7]3[CH:6]=[C:5]([CH3:20])[C:4]([C:3]([OH:2])=[O:21])=[CH:9][C:8]=3[N:10]=[C:30]2[C:26]2[CH:25]=[CH:24][O:28][CH:27]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH:14]1([N:13]2[C:7]3[CH:6]=[C:5]([CH3:20])[C:4]([C:3]([NH:38][C@@H:37]([CH2:39][C:40]4[C:48]5[C:43](=[CH:44][CH:45]=[C:46]([OH:49])[CH:47]=5)[NH:42][CH:41]=4)[C:36]([OH:35])=[O:50])=[O:21])=[CH:9][C:8]=3[N:10]=[C:30]2[C:26]2[CH:25]=[CH:24][O:28][CH:27]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC2CCCCC2)cc1C
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(O)cc12
Agent: Cl
Product: Cc1cc2c(cc1C(=O)N[C@@H](Cc1c[nH]c3ccc(O)cc13)C(=O)O)nc(-c1ccoc1)n2C1CCCCC1
Product: Cc1cc2c(cc1C(=O)O)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
1-Cyclohexyl-2-furan-3-yl-6-methyl-1H-benzimidazole-5-carboxylic acid was prepared from 4-cyclohexylamino-2-methyl-5-nitrobenzoic acid methyl ester (Example 151) as described for the 4-methyl derivative (Example 151). The acid was coupled to 5-hydroxy-(S)-tryptophan methyl ester hydrochloride in the usual manner and following saponification of the methyl ester and purification by preparative C18 reversed-phase HPLC, the title compound of example 154 was obtained.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[CH:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(Br)C#C>CCCCCC.O1CCCC1>[CH2:3]([C:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]#[CH:1]
Reactant: [Li]CCCC
Reactant: O=C(O)C1CCCCC1
Agent: C#CCBr
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCC1(C(=O)O)CCCCC1
Temperature: -20 °C

Procedure:
300 cm3 of dry tetrahydrofuran (THF) and 267 cm3 of 1.47 M solution of butyl-lithium in hexane were introduced into a 1 liter three-necked flask, which was kept under a nitrogen atmosphere. 40 g of anhydrous diisopropylamine and then 25.6 g (0.2 mole) of cyclohexylcarboxylic acid, dissolved in 50 cm3 of THF, were added to the mixture, which had been cooled to -20° C. The mixture was heated at 60° C. for 2 hours. 23.6 g of propargyl bromide were then added to the solution which had been cooled to -70° C. When the mixture had warmed to ambient temperature, it was concentrated under reduced pressure and the resulting product was taken up in water. The aqueous solution was washed with hexane and then treated with dilute hydrochloric acid. The expected 1-propargyl-1-cyclohexyl-carboxylic acid, which was in the form of a colourless liquid, was extracted with ether and then distilled in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)C(OC)=O)=[CH:4][CH:3]=1.[CH3:21][Mg]Br.[Cl-].[NH4+].CC[O:28][CH2:29][CH3:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[C:29]([CH3:30])([OH:28])[CH3:21])=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: C[Mg]Br
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(O)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl 2,3-bis(4-chlorophenyl)propionate (2.6 g, 8.4 mmol) in ether (20 mL) was added methylmagnesium bromide (3 M in ether, 8.4 mL, 25 mmol) at −10° C., and the reaction was allowed to warm to room temperature over 2 h. The reaction mixture was poured into saturated aqueous ammonium chloride (100 mL), and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.17 (ABq, 4H), 7.06 (d, 2H), 6.93 (d, 2H), 3.32 (dd, 1H), 2.94 (dd, 1H), 2.84 (dd, 1H), 1.20 (s, 3H), 1.16 (s, 3H).
Reaction SMILES: [C:1](O)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]([C:10]1C=N[CH:13]=[CH:14][CH:15]=1)#[N:9].[NH4+:16].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O>O.C(OCC)(=O)C.[N+]([O-])([O-])=O.[Ag+]>[C:2]([C:1]1[N:16]=[C:10]([C:8]#[N:9])[CH:15]=[CH:14][CH:13]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: N#Cc1cccnc1
Reactant: CC(C)(C)C(=O)O
Reactant: [NH4+]
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
Silver nitrate (4.43 g, 28.8 mmol) was added to a suspension of pivalic acid (1.96 g, 19.2 mmol), 3-cyanopyridine (2.00 g, 19.2 mmol) and ammonium peroxodisulfate (6.58 g, 28.8 mmol) in water (40 mL). The mixture was stirred at room temperature for 10 min and then stirred at an external temperature of 80° C. for 2 hr. After cooling, the reaction mixture was diluted with ethyl acetate and the resulting insoluble matter was removed by filtration through Celite (registered trademark). The aqueous layer was separated from the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=4:1) to afford 6-tert-butylpyridine-2-carbonitrile as a yellow oil (2.71 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([OH:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C.CCOC(C)=O>[Si:22]([O:12][CH:8]1[CH2:7][CH2:6][CH2:5][C:4]2[N:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]1=2)([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: OC1CCCc2nc(Cl)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCCc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A solution of 2-chloro-5,6,7,8-tetrahydroquinolin-5-ol (500 mg, 2.72 mmol) in DMF (10 mL) was treated with imidazole (260 mg, 3.81 mmol). After complete dissolution TBDMS-Cl was added and the resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (40 mL) and was washed with brine (5×). The organic layer was collected, dried with Na2SO4, filtered, and the solvent was evaporated at reduced pressure yielding the titled compound as an oil. Amount 760 mg. Yield 94%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][N:26]([C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1)C(=O)OC(C)(C)C>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:37]4[CH:36]=[N:35][C:34]([NH:26][CH3:25])=[CH:39][CH:38]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNc1ccc(-c2ccc3c(c2)-c2nc(C(=O)N(CCO)C(C)C)sc2CCO3)cn1
Yield: 2.5 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (52.9 mg, 0.129 mmol) and tert-butyl methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)carbamate (51.6 mg, 0.154 mmol) were reacted to give 282, purified by HPLC (1.4 mg, 2.5% yield, M+1 439.1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:26](=[O:31])N(OC)C)[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=3[CH:25]=2)=[C:5]([CH3:32])[O:4][N:3]=1.[C:33]1([Mg]Cl)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:26]([C:9]1[C:10]2[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[C:11]=2[CH:25]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:32])[CH:8]=1)(=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CCOc1nc2c(C(=O)N(C)OC)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOc1nc2c(C(=O)c3ccccc3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(methoxy(methyl)carbamoyl)-1H-benzo[d]imidazole-1-carboxylate was dissolved in THF (3 mL). To the solution was added a solution of phenyl magnesium chloride (2M in THF, 0.508 mmol, 0.254 mmol) at −78° C. after the addition, the reaction was allowed to warm up to room temperature. The reaction was stirred for 17 hat the same temperature. The reaction mixture was quenched with water (30 mL). The whole was extracted with AcOEt (30 mL×3). Organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give the crude product. The crude product was purified by a silica gel column chromatography (hexane:EtOAc, 7:1 to 3:1) to give tert-butyl 4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15](=O)[NH:16][CH2:17][C:18]1[N:19]=[C:20]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]2=[N:22][CH:23]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.CCOC(C)=O>O1CCOCC1.C(O[Hg]OC(=O)C)(=O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])[CH2:4][CH:3]1[C:15]1[N:19]2[C:20]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=4)(=[O:28])=[O:29])[C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CN(C(=O)OC(C)(C)C)CCC4C)cnc32)cc1
Agent: CC(=O)O[Hg]OC(C)=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C4CN(C(=O)OC(C)(C)C)CCC4C)n23)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (44 g, 83 mmol, Example #13, Step H) in 1,4-dioxane (500 mL) was added Lawesson's reagent (20.2 g, 50.0 mmol). The reaction was heated at about 80° C. for about 1 h. The reaction was allowed to cool to ambient temperature followed by the addition of diacetoxymercury (26.6 g, 83.0 mmol). After about 1 h, additional diacetoxymercury (13.3 g, 42.0 mmol) was added. After about 15 min, the reaction was poured into stirred EtOAc (2 L). After about 15 min the reaction was filtered through Celite® and the filtrate was concentrated under reduced pressure. The resulting residue was triturated with EtOAc (500 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (330 g column) eluting with a gradient of 10-50% EtOAc in heptane to provide tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (19 g, 44%) as a white solid: LC/MS (Table 2, Method a) Rt=2.57 min; MS m/z: 510 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:19][C:20]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][C:21]=1[CH2:22][N:23]([CH2:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:26][CH2:25][CH2:24][N:23]([CH2:22][C:21]3[CH:42]=[CH:43][CH:44]=[C:45]([C:46]([F:47])([F:48])[F:49])[C:20]=3[Cl:19])[CH2:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2cccc(O)c2)CC1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirring solution of 1-(3-hydroxyphenyl)-piperidine-4-carboxylic acid ethyl ester (0.19 g, 0.77 mmol) in 10 mL of anhydrous toluene was added 3-[(2-chloro-3-(trifluoromethyl)-benzyl)-(2,2-diphenyl-ethyl)-amino]-propan-1-ol (0.41 g, 0.92 mmol). Polymer bound triphenyphosphine (0.41 g, 1,23 mmol, 3 mmol/g, Fluka Chemie) was then added, and the mixture was reacted for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (0.2 g, 0.96 mmol) was added in a dropwise fashion. After stirring at RT overnight, the crude reaction mixture was filtered and the solid was washed with EtOAc. After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 10% EtOAc: hexane as eluent to afford 0.32 g (62%) of the title compound as an oil: MS(ESI) 679.0 (M+H+).
Reaction SMILES: C([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)C=C.[O-:36][Mn](=O)(=O)=O.[K+].[CH3:42][C:43]([CH3:45])=[O:44]>O>[Cl:13][C:11]1[C:12]2[N:4]([CH2:42][CH:43]([OH:44])[CH2:45][OH:36])[CH:5]=[C:6]([C:14]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[N:24]=[CH:23]4)([OH:19])[C:15]([F:18])([F:16])[F:17])[C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CC(C)=O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Agent: [K+]
Solvent: O
Product: OCC(O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Reaction time: 3 h
Yield: 44 %

Procedure:
To a room temperature solution of 1-(5-allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol (245 mg, 0.5 mmol, 1 equiv.) in 4 mL of acetone and 2 mL of water was added a solution of KMnO4 in 1 mL of water and 2 mL of acetone. After 3 hours, the mixture was filtered and the filter cake washed with acetone. The filtrate was concentrated and the residue diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by HPLC (5-85% CH3CN/water 0.1% TFA). The desired peaks were combined and made basic with saturated aqueous sodium bicarbonate. The CH3CN was removed and the aqueous was extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to provide 116 mg (44%) of the title compound as a white solid. MS m/z 536.10 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[Li]CCCC>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:10]([OH:11])[C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)c1ccccn1

Procedure:
31 (1.3 g, 6.54 mmol), 2-bromopyridine (0.70 ml, 7.19 mmol), n-BuLi (1.6M) (4.5 ml, 7.19 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[CH3:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH3:12])=[C:6]1[CH3:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2ccc(Br)cc2c1C
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccccc2)c2ccc(Br)cc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 5-bromo-2,3-dimethyl-1H-indole (1.793 g, 8 mmol) was reacted with k-t-butoxide (0.943 g, 8.4 mmol) and benzyl bromide (1.442 g, 8.4 mmol) in DMF (20 ml) to give the product (1.872 g, 5.958 mmol, 74%) as a pink solid. 1H NMR (DMSO-d6) δ 2.18 (s, 3H), 2.26 (s, 3H), 5.38 (s, 21), 6.94 (d, J=7.3 Hz, 2H), 7.12 (dd, J=1.8, 8.6 Hz, 1H), 7.20 (t, J=7.2 Hz, 1H), 7.27 (t, J=7.2 Hz, 2H), 7.32 (d, J=8.7 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H); [EI], m/z 313/315 (M)+.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[CH2:3][CH3:4].Cl[C:8](OC1C=CC([N+]([O-])=O)=CC=1)=[O:9].Br.[CH3:21][O:22][CH2:23][CH2:24][N:25]1[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:26]1=[NH:32]>C1COCC1.C(N(CC)C(C)C)(C)C>[CH3:1][C:2]([NH:6][C:8](/[N:32]=[C:26]1\[S:27][C:28]([CH3:31])=[C:29]([CH3:30])[N:25]\1[CH2:24][CH2:23][O:22][CH3:21])=[O:9])([CH3:5])[CH2:3][CH3:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: CCC(C)(C)N
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)(C)NC(=O)/N=c1\sc(C)c(C)n1CCOC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1,1-dimethylpropylamine (174 mg, 2.0 mmole) in 19 mL of THF and 1 mL of N,N-diisopropylethyl amine was added 4-nitrophenyl chloroformate (403 mg, 2.0 mmole). The solution was irradiated in a sealed tube placed in a single node microwave at 70° C. for 300 sec (maximum power 300 W) with stirring. The resulting solution was cooled to room temperature and 3-(2-methoxyethyl)-4,5-dimethyl-3H-thiazol-2-ylideneamine hydrobromide (587 mg, 2.2 mmole) from Example 12A was added. The sealed tube was irradiated at 120° C. for 1800 sec with stirring. The mixture was cooled and the volatile components were removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The phases were separated and organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 0-70% ethyl acetate/hexanes gradient) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.76 (t, J=7 Hz, 3H) 1.20 (s, 6H) 1.66 (d, J=7 Hz, 2H) 2.06 (s, 3H) 2.11 (s, 3H) 3.30 (s, 3H) 3.55 (t, J=5 Hz, 2H) 4.06 (t, J=5 Hz, 2H) 6.13 (s, 1H)), MS (DCI/NH3) m/z 300 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O-:5])([CH3:4])[CH3:3].[K+].[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:10]([OH:11])[C:9]=1[OH:15].[C:16]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](=[O:31])[CH2:29]Br)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:2]([O:5][C:21]([C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](=[O:31])[CH2:29][O:11][C:10]1[CH:12]=[CH:13][CH:14]=[C:8]([CH3:7])[C:9]=1[O:15][CH2:29][C:28]([N:24]1[CH2:25][CH2:26][CH2:27][C@@H:23]1[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[O:31])=[O:20])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)CBr
Reactant: Cc1cccc(O)c1O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reaction time: 0.04 h
Yield: 65 %

Procedure:
To a solution of 236 mg (2.1 mmol) potassium tert-butylate in 2 ml dimethylformamide at room temperature was added dropwise a solution of 124 mg (1.0 mmol) 3-methylcatechol in 2 ml dimethylformamide. Stirring was continued for 2-3 min and a solution of 584 mg (2.0 mmol) (R)-(1) -bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml dimethylformamide was added within 1-2 min. The reaction mixture was stirred for additional 3 h at room temperature. The solvent was removed in vacuo and the residue purified by flash-chromatography to yield 356 mg (65%) of the title compound as a colorless oil. MS m/e (%): 547 (M+H+, 100), 491 (14), 435 (17).