Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12][C:13](=[O:17])[C:14]([OH:16])=[O:15])[CH:3]=1.C(N(CC)CC)C>C1COCC1>[OH:17][C@H:13]([CH2:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)[C:14]([OH:16])=[O:15]
Reactant: Cc1cc(CC(=O)C(=O)O)cc2c1OCCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](O)C(=O)O)cc2c1OCCO2
Temperature: -35 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a solution of 15.1 g (47.0 mmol) (1R)—B-chlorodiisopinocampheylborane in 50 mL THF was added dropwise within 15 min to a solution of 9.2 g (38.9 mmol) 3-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxo-propionic acid and 5.4 mL (39.0 mmol) triethylamine in 100 mL THF cooled to −35° C. and the reaction mixture was stirred for 1 h at RT. After the end of the reaction the reaction solution was evaporated down i.vac., combined with 200 mL 1 M NaOH and 150 mL TBME, stirred, the aqueous phase was separated off, acidified with 2 M HCl and extracted twice with 250 mL EtOAc. The combined organic phases were dried, filtered through activated charcoal and evaporated down i.vac.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:16][O:15][C:14]2[C:5](=[CH:6][C:7]3[C:8]([C:21]([F:24])([F:23])[F:22])=[CH:9][C:10]([O:17][CH:18]([CH3:20])[CH3:19])=[N:11][C:12]=3[CH:13]=2)[N:4]1[CH2:25][C:26]([F:29])([F:28])[F:27].[H-].[Na+].I[CH2:33][CH2:34][CH3:35]>C1COCC1>[CH:18]([O:17][C:10]1[CH:9]=[C:8]([C:21]([F:22])([F:23])[F:24])[C:7]2[CH:6]=[C:5]3[N:4]([CH2:25][C:26]([F:28])([F:29])[F:27])[CH:3]([CH2:2][O:1][CH2:33][CH2:34][CH3:35])[CH2:16][O:15][C:14]3=[CH:13][C:12]=2[N:11]=1)([CH3:20])[CH3:19]
Reactant: CCCI
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(CO)N3CC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCOCC1COc2cc3nc(OC(C)C)cc(C(F)(F)F)c3cc2N1CC(F)(F)F
Yield: 49.5 %

Procedure:
This compound was prepared according to General Method 16 (EXAMPLE 30) from (±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (EXAMPLE 28) (11 mg, 0.026 mmol), NaH (5.0 mg, 0.12 mmol) and 1-iodopropane (21 mg, 0.12 mmol) in 1.0 mL THF to afford 6 mg (50%) of (±)-2,3-dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a yellow oil, after flash chromatography (5:1 hexanes:EtOAc). Data for (±)-2,3-dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: Rf0.57 (5:1 hexanes: EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 7.13 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.44 (dd, 1H, J=10.9, 1.8), 4.17 (dd, 1H, J=11.0, 2.5), 4.00-4.20 (m, 2H), 3.71 (broad t, 1H, J=6.8), 3.54-3.64 (m, 2H), 3.40 (broad t, 2H, J=6.6), 1.52-1.62 (m, 2H), 1.38 (d, 6H, J=6.2), 0.91 (t, 3H, J=7.4).
Reaction SMILES: [Al].[Li].[C:3]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](=[O:24])[CH3:23])=[CH:14]1)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].CCCCCC>O1CCCC1.CCOCC>[C:3]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]([OH:24])[CH3:23])=[CH:14]1)([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: CC(=O)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Agent: [Al]
Agent: [Li]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Lithium aluminum hydrode (1.2 g, 32 mmol) was suspended in tetrahydrofuran (100 ml) and cooled to -78° C. N-Carbobenzoxy-3-acetyl indole (19.3 g, 66 mmol) dissolved in tetrahydrofuran (200 ml) was added over 0.5 hr. and the reaction mixture was allowed to stir at -78° C. for 0.5 hr and then at 0° C. for 0.5 hr. Ether (300 ml) was added and the mixture was quenched with 1.2 ml H2O, 1.2 ml 2N NaOH, adn 3.6 ml and H2O. The mixture was filtered through celite, dried over MgSO4 and evaporated leaving a solid. The solid was dissolved in 50 ml hot ether and then hexane was added (300 ml). The resulting crystals were collected to afford 12.5 g (64% yield): mp 79°-80° C., which was identical with the material prepared above in procedure A.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[C:18]1([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CNCCNC.CC(C)([O-])C.[Na+]>[Cu](I)I.C1(C)C(C)=CC=CC=1>[C:25]1([N:24]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[C:4](=[CH:3][C:2]([Br:1])=[CH:14][CH:13]=4)[C:5]([CH3:17])([CH3:16])[C:6]=3[CH:7]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(I)cc21
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: I[Cu]I
Agent: CC(C)(C)[O-]
Agent: CNCCNC
Solvent: Cc1ccccc1C
Product: CC1(C)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Yield: 69.9 %

Procedure:
Charged under Ar atmosphere were 2-bromo-7-iodo-9,9-dimethylfluorene 20.0 g, diphenylamine 8.46 g, copper iodide 0.476 g, N,N′-dimethylethylene-diamine 0.441 g, sodium t-butoxide 7.21 g and xylene 50 ml, and the mixture was refluxed for 24 hours under heating. After cooled down to room temperature, the mixture was extracted with toluene, and the insoluble matter was filtered. The filtrate was concentrated, and then the concentrate was refined by silica gel chromatography to obtain 15.4 g of a yellow solid matter of 2-(N,N-diphenylamino)-7-bromo-9,9-dimethylfluorene.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][C:25]4[N:26]=[C:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[S:28][CH:29]=4)=[CH:20][CH:21]=3)[C:16]([CH2:36][C:37](O)=[O:38])=[C:15]2[CH3:40])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[C:30]1([C:27]2[S:28][CH:29]=[C:25]([CH2:24][O:23][C:19]3[CH:18]=[C:17]4[C:22](=[CH:21][CH:20]=3)[N:14]([CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:15]([CH3:40])=[C:16]4[CH2:36][CH2:37][OH:38])[N:26]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1c(CC(=O)O)c2cc(OCc3csc(-c4ccccc4)n3)ccc2n1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(CCO)c2cc(OCc3csc(-c4ccccc4)n3)ccc2n1Cc1ccccc1
Reaction time: 1 h
Yield: 55 %

Procedure:
To a slurry containing lithium aluminum hydride (0.10 g, 2.6mmol) in tetrahydrofuran (40 mL), is added slowly at 23° C. a solution of the ester of Example 40 (1.0 g, 2.0 mmol) in tetrahydrofuran (10 mL). After stirring for 1 hour, the excess lithium aluminum hydride is quenched with ethyl acetate (5.0 mL), poured into saturated sodium chloride (200 mL) and extracted with ether (200 mL, 2×). The ether layer is washed with brine, dried over MgSO4, and concentrated to give crude product (0.8 g). Crystallization of the solid from ethyl acetate affords 0.5 g of title compound as a white solid in 55% yield, m.p. 114°-116° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1>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>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[N:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:28]=[N:27]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)Nc1cnc(Oc2ccnc(Cl)c2)cn1
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: CC(=O)Nc1cnc(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a degassed solution of N-(5-((2-chloropyridin-4-yl)oxy)pyrazin-2-yl)acetamide (0.25 g, 0.945 mmol) in dioxane (6 mL) was added a solution of K2CO3 (0.261 g, 1.889 mmol) in water (1.5 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.255 g, 1.228 mmol), and Pd(PPh3)4 (0.109 g, 0.094 mmol). The mixture was stirred at 80° C. for 3 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×80 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (MeOH/DCM) to afford N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrazin-2-yl)acetamide (240 mg, 82%) product as white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 8.97 (d, J=1.4 Hz, 1H), 8.43 (dd, J=5.6, 0.5 Hz, 1H), 8.40 (d, J=1.4 Hz, 1H), 8.27 (s, 1H), 7.98 (d, J=0.7 Hz, 1H), 7.40 (m, 1H), 6.92 (dd, J=5.6, 2.4 Hz, 1H), 3.85 (s, 3H), 2.12 (s, 3H); MS (ESI) m/z: 311.1 (M+H+).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:26]3[C:31]4[S:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[C:30]=4[CH:29]=[CH:28][CH:27]=3)[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3.C[O:40][B:41](OC)[O:42]C.Cl>O1CCCC1>[CH:29]1[C:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[S:32][C:31]=2[C:26]([N:17]2[C:16]3[CH:15]=[CH:14][C:13]([B:41]([OH:42])[OH:40])=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:27][CH:28]=1
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
An excess of 1.6M n-BuLi in hexane (14 mL, 22.3 mmol) was added to a solution of 3-bromo-9-(diberizo[b,d]thiophen-4-yl)-9H-carbazole (8.7 g, 20.3 mmol) in 100 ml dry tetrahydrofuran at −78° C. under N2. The reaction mixture was then maintained at 0° C. for 1 h before cooling to −78° C. Trimethylborate (2.8 g, 26.4 mmol) was added dropwise; the solution was then warmed slowly to room temperature and stirred for 24 h. 2N HCl (50 ml) was added and then the mixture was stirred for a further 1 h. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum, and the residue was crystallized from n-hexane to give the 9-(dibenzo[b,d]thiophen-4-yl)-9H-carbazol-3-ylboronic acid 4.7 g (59%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([O:20]CC)=[O:19])=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.CO.O.[OH-].[Li+]>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:18]([OH:20])=[O:19])=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(C2CCC3(CC2)OCCO3)ccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ccc(C2CCC3(CC2)OCCO3)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 3-amino-6-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine-2-carboxylate (Compound 232E, 228 mg, 0.744 mmol) was taken up in THF (1.0 mL) and MeOH (1.0 mL, 25 mmol). This was treated with a solution of Lithium hydroxide, monohydrate (156 mg, 3.72 mmol) in H2O (1.0 mL) and allowed to stir at rt for 4 hours. The THF was removed in vacuo and treated, dropwise with 1N HCl until a pH of ˜5 was achieved. This aqueous solution was extracted with EtOAc (3×50 mL) and saturated with salt and stirred with ˜100 mL DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to a crude yellow oil which was used without further purification. MS (ES+): m/z=278.86 [MH+]. HPLC: tR=2.39 min (ZQ3, polar—5 min).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[N:9]2)[CH2:5][NH:4][CH2:3][CH2:2]1.[C:31](O)(=[O:35])[CH2:32][CH2:33][CH3:34]>>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH:6]3[CH2:7][O:1][CH2:2][CH2:3][N:4]([C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH2:5]3)[N:9]=[C:10]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[C:11]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNCCOC1
Reactant: CCCC(=O)O
Product: CCCC(=O)N1CCOCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1

Procedure:
1-(1,4-oxazepan-6-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine is coupled with butyric acid under basic condition to afford title compound in good yield.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[CH3:23][S:24]([O:27][CH:28]([CH2:38][CH2:39][CH2:40][OH:41])[CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:26])=[O:25].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:23][S:24]([O:27][CH:28]([CH2:38][CH2:39][CH:40]=[O:41])[CH2:29][O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)OC(CCCO)COCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC(CCC=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
440 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one (Dess-Martin Periodinane) was added to a solution of 200 mg of 1-benzyloxy-5-hydroxypentan-2-yl methanesulfonate in 2 mL of dichloromethane, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 100 mg of Dess-Martin Periodinane was added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the reaction mixture was added to a mixture of 50 mL of ethyl acetate and 30 mL of a saturated sodium hydrogen carbonate aqueous solution, and the obtained mixture was then filtrated with Celite. The organic layer was fractionated. The obtained organic layer was washed with 30 mL of a sodium thiosulfate aqueous solution twice, and then with 30 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/2 to 1/1), so as to obtain 141 mg of 1-benzyloxy-5-oxopentan-2-yl methanesulfonate in the form of a colorless oily product.
Reaction SMILES: [C:1]([O:6][OH:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].OC([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)(C)C.S(=O)(=O)(O)O>O>[C:1]([O:6][O:7][C:12]([C:13]1[CH:12]=[CH:17][CH:16]=[C:15]([C:18]([O:21][O:21][C:18]([CH2:15][CH3:14])([CH3:20])[CH3:19])([CH3:19])[CH3:20])[CH:14]=1)([CH3:17])[CH3:13])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)OO
Reactant: CC(C)(O)c1ccc(C(C)(C)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(C)(C)OOC(C)(C)c1cccc(C(C)(C)OOC(C)(C)CC)c1

Procedure:
1,4-Bis(2-t-amylperoxy-2-propyl)benzene (para III) was prepared by reacting 28.1 grams (0.231 mole) of aqueous 85.7% t-amyl hydroperoxide diluted with 3.2 grams of water with 20.4 grams (0.105 mole) of 1,4-bis(2-hydroxy-2-propyl)benzene in the presence of 44.1 grams (0.316 mole) of 70% sulfuric acid according to the procedure of Example VII. The stripped product was a yellow liquid which remained liquid at 15° C. The product weighed 32.0 grams.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:17]1[CH:22]=[C:21]([N:23]([CH:31]2[CH2:33][CH2:32]2)C(=O)OCCCC)[N:20]2[N:34]=[CH:35][C:36]([CH:37]=[O:38])=[C:19]2[N:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[CH:31]1([NH:23][C:21]2[N:20]3[N:34]=[CH:35][C:36]([CH:37]=[O:38])=[C:19]3[N:18]=[C:17]([NH:5][C:4]3[CH:3]=[C:2]([F:1])[CH:8]=[C:7]([F:9])[CH:6]=3)[CH:22]=2)[CH2:32][CH2:33]1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CCCCOC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=Cc1cnn2c(NC3CC3)cc(Nc3cc(F)cc(F)c3)nc12
Reaction time: 1 h
Yield: 79 %

Procedure:
3,5-Difluoroaniline (29 mg, 0.22 mmol), Cs2CO3 (67 mg, 0.21 mmol) were added to Ten-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (50 mg, 0.15 mmol) dissolved in 1,4-dioxane (1 mL). Racemic BINAP (6 mg, 0.06 mmol) and palladium(II) acetate (4 mg, 0.04 mmol) were then added. The mixture was sealed and irradiated at 110° C. for 20 min in the microwave. Et2O (3 mL) was added and the solution was filtered. The filtrate was concentrated in vacuo. The crude residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). After 1 h, the solution was concentrated under a stream of air. The residue was triturated with 20% 2-propanol/hexanes. The product was filtered to yield 7-(cyclopropylamino)-5-(3,5-difluorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (39 mg, 80%). LCMS (M+1=330)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[OH-].[K+].[CH3:15]I>CC(C)=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1ccc2cc([N+](=O)[O-])ccc21
Yield: 92.3 %

Procedure:
To a solution of 5-nitro-1H-indole (2.0 g, 12.3 mmol) in acetone (20 ml), powdered potassium hydroxide (3.4 g, 60.7 mmol, 5 eq) was added followed by the addition methyl iodide (2.61 g, 18.5 mmol, 1.5 eq) at 0° C. The reaction mixture was heated to reflux for 10 hr. The solvent was evaporated and water was added. The compound was extracted with ethyl acetate, dried over anhydrous sodium sulphate, filtered and the organic layer was concentrated to dryness to yield 1-methyl-5-nitro-1H-indole (2.0 g, 92%). The crude compound was used in the next stage without purification.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.CS(C)=O.[H-].[Na+].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[CH:26][CH:25]=1>C(O)(=O)C.O>[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=[C:17]2[C:6]3[N:5]4[CH:1]=[CH:2][N:3]=[C:4]4[C:9](=[O:10])[NH:8][C:7]=3[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]2=3)=[CH:26][CH:25]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]c2c3ccccc3c(=Cc3ccnc4ccccc34)c2n2ccnc12
Yield: 80.1 %

Procedure:
The procedure is performed as in Example 28, but starting with 3 g of 5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one, 60 ml of dimethyl sulphoxide, 0.96 g of 80% sodium hydride and 3.18 g of 4-quinolincarboxaldehyde. After treating with water and acetic acid, the suspension obtained is filtered and the solid thus isolated is washed with 2×30 ml of water and then 4×30 ml of acetone and dried at 100° C. under vacuum (2 mmHg; 0.26 kPa). 3.9 g of 10-(4-quinolylmethylene)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one are obtained, in the form of an orange solid melting above 260° C. (Analysis % calculated C: 76.23, H: 3.89, N: 15.46, O: 4.41, % found C: 75.9, H: 4.2, N: 15.4).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][C:63]([F:66])([F:65])[F:64])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][C:63]([F:66])([F:65])[F:64])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)(F)F)c2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)(F)F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 105 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethoxy-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 99 mg light yellow viscous oil (66%). MS (ISP) 495.5 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:25][C:24]2[N:20]([CH:21]=[N:22][N:23]=2)[C:19]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:18]=2[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>O1CCCC1>[C:9]([O:13][C:14]([N:16]1[CH2:25][C:24]2[N:20]([C:21]([Br:1])=[N:22][N:23]=2)[C:19]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:18]=2[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2cnnc2C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2c(Br)nnc2C1
Yield: 84.8 %

Procedure:
N-Bromosuccinimide (4.50 g, 24.0 mmol) was added to 8-chloro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester (7.00 g, 21.8 mmol) in tetrahydrofuran (140 ml). The mixture was stirred in boiling tetrahydrofuran for 2 hours. The solvent was removed in vacuo and the residue was purified by chromatography (50 g silica gel, heptane: ethylacetate 1:9 to 1:0) to yield 7.39 g (85%) 1-bromo-8-chloro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester as white solid. MS m/e: 401 (M+H+).
Reaction SMILES: C([O:8][C@H:9]([C@H:11]([N:23]1[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]1)[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH3:10])C1C=CC=CC=1.C[Si](I)(C)C>C(Cl)(Cl)Cl>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[O:14][CH2:13][CH2:12][C@@H:11]([N:23]1[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]1)[C@@H:9]([OH:8])[CH3:10]
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCOc1ccc(Cl)c(Cl)c1)n1cnc(C(N)=O)c1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: C[C@H](O)[C@@H](CCOc1ccc(Cl)c(Cl)c1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 84.8 %

Procedure:
To an ice cooled solution of 1-[(2S,3R)-2-benzyloxy-5-(3,4-dichlorophenyloxy)-3-pentyl]imidazole-4-carboxamide (59.5 mg, 0.133 mmol) in chloroform (5 ml) was added trimethylsilyl iodide (34.5 mg, 0.173 mmol). After 3 minutes, the ice bath was removed, and then stirred at room temperature overnight. The reaction was quenched by addition of methanol. This mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (2.5 g) chromatography eluting with chloroform/methanol (50:1 to 10:1) to give 1-[(2S,3R)-5-(3,4-dichlorophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide (4) (40.4 mg, 85.0%) as a white amorphous solid.