Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].C(O[C:8]([N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:19])[CH:16]=2)[CH2:11]1)=O)(C)(C)C>O1CCCC1>[CH3:8][N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:19])[CH:16]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1Cc2ccc(N)cc2C1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
166 e) To a cooled solution of 2.0 M of lithium tetrahydroborate in tetrahydrofuran (13 mL, 26 mmol) at 5° C. was added dropwise a solution of 5-amino-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (1.0 g, 4.3 mmol) in tetrahydrofuran (50 mL). Gas evolution was noted. The mixture was stirred for 1 hour at 5° C. then warmed to room temperature and stirred for 24 hours. The mixture was cooled to 5° C. in a ice/water bath and the reaction was quenched by addition of sodium sulfate decahydrate (3 g). Gas evolution noted. The mixture was stirred for 2 hours at room temperature. The suspension was filtered through a plug of diatomaceous earth and rinsed with tetrahydrofuran. The filtrate was dried over magnesium sulfate, filtered and evaporated. The residue was purified via flash chromatography (silica gel column and 0%→20% methanol: dichloromethane). 2-Methyl-2,3-dihydro-1H-isoindol-5-ylamine was isolated as an orange solid (0.271 g, 43%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 6.82 (d, J=7.9 Hz, 1H), 6.41 (s, 1H), 6.37 (d, J=8.1 Hz, 1H), 4.86 (br s, 2H), 3.64 (s, 2H), 3.62 (s, 2H), 2.42 (s, 3H). MS=149 (MH)+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[NH:31][C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O.O>CN(C)C=O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@H:27]6[N:31]([CH2:43][C:44]([F:47])([F:46])[F:45])[C@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5CC(F)(F)F)cn3)nc2n1C1CCCC1
Temperature: 80 °C
Yield: 64.1 %

Procedure:
A sample of 7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (60 mg, 0.123 mmol) was combined with 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.035 ml, 0.246 mmol) in dimethylformamide (1 mL) and heated to (80° C.) overnight. The reaction was then poured into water and extracted with ethyl acetate. The aqueous was washed with ethyl acetate. The organics were combined, dried over sodium sulfate, filtered and concentrated which gave a crude material that was purified by silica gel column chromatography which gave 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-4-oxo-9-(2,2,2-trifluoroethyl)-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (45 mg) in 64% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.51 (d, J=9.09 Hz, 1H), 8.22 (s, 1H), 8.15 (d, J=2.53 Hz, 1H), 7.52 (dd, J=8.84, 2.78 Hz, 1H), 6.46 (s, 1H), 4.80 (t, J=8.59 Hz, 1H), 4.23 (d, J=13.64 Hz, 1H), 3.47 (m, 3H), 3.16 (s, 6H), 3.06 (m, 3H), 2.83 (dd, J=15.66, 7.07 Hz, 1H), 2.57 (dd, J=12.13, 8.59 Hz, 2H), 2.04 (m, 6H), 1.70 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:13](=[O:28])[N:12]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:49])([F:48])[O:40][C:41]1[CH:42]=[C:43]([OH:47])[CH:44]=[CH:45][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:13](=[O:28])[N:12]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:11]=2[N:10]=[C:9]1[O:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([O:40][C:39]([F:38])([F:48])[F:49])[CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of 7-benzyl-8-chloro-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (4.7 g, 8.58 mmol, intermediate 18) in DMF (15 mL) was added 3-(trifluoromethoxy)phenol (1.83 g, 10.28 mmol) and potassium carbonate (2.4 g, 17.39 mmol). The mixture was stirred at 80° C. overnight. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7-benzyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (5.3 g, 89.3% yield) as yellow oil. LCMS retention time 3.974 min; LCMS M+Na 713.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[CH:10][C:9]=1[N:18]1[CH:26]([O:27][C:28](OC2C=CC=CC=2)=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:37].C(=O)(O)[O-].[Na+]>C(#N)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:28]([O:27][CH:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:37])[N:18]2[C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[N:16][CH:15]=[CH:14][CH:13]=3)[N:8]=2)=[O:29])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2cccnc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3cccnc3n2)CC1
Temperature: 20 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
4-Methylpiperazine (8 g.) is added all at once to a suspension of 2-(1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (5.6 g.) in acetonitrile (100 cc.). The solution obtained is stirred for 6 hours at a temperature of about 20° C. The reaction mixture is poured into a suspension of ice (100 g.) in methylene chloride (300 cc.). An 8% aqueous solution of sodium bicarbonate (200 cc.) is added to the suspension obtained. The organic phase is decanted and the aqueous phase is extracted with methylene chloride (400 cc.). The combined organic phases are dried over anhydrous potassium carbonate (10 g.) and concentrated to dryness. The oily residue (8 g.) is taken up in refluxing diisopropyl ether (100 cc.). On cooling the solution, crystals are deposited and are filtered off. 3-(4-Methylpiperazin-1-yl)carbonyloxy-2-(1,8-naphthyridin-2-yl)isoindolin-1-one (2.9 g.), which melts at 183° C., is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[O:26][CH2:27][CH2:28]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][O:26][C:25]2[CH:24]=[C:23]([O:22][CH3:21])[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=2)=[CH:7][CH:6]=1
Reactant: COc1cc(OCCO)cc(OC)c1OC
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(3,4,5-trimethoxyphenoxy)ethanol (1.8 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material form dichloromethane extraction was purified by HPLC (dichloromethane-diethyl ether, 50:1) and crystallized from dichloromethane-hexane to provide 1 g of 4-[[2-(3,4,5-trimethoxyphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 82°-83° C. Analysis Calculated for C20H22O8 : C, 61.53; H, 5.68. Found: C, 60.82; H, 5.71.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.[CH3:11][NH:12][NH2:13]>C(O)C>[CH3:11][N:12]1[C:9]([NH2:10])=[C:6]([C:7]#[N:8])[C:4]([CH3:5])=[N:13]1
Reactant: CCOC(C)=C(C#N)C#N
Reactant: CNN
Solvent: CCO
Product: Cc1nn(C)c(N)c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
To a solution of 1-ethoxyethylidene malononitrile (27.2 g, 0.2 mol) in ethanol (50 ml) was added methyl hydrazine (9.4 g, 0.2 mol). The reaction mixture was stirred at room temperature for 3 hours and the product was collected by filtration to afford 23.6 g (87%) of 1,3-dimethyl-5-amino-1H-pyrazole-4-carbonitrile as white crystals, m.p. 193°-195° C. when dried in high vacuum.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[C:23]([OH:24])=[C:22]2[C:17]([CH:18]=[N:19][C:20]([Cl:25])=[N:21]2)=[CH:16][CH:15]=1.O[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:13][C:14]1[C:23]([O:24][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[C:22]2[C:17]([CH:18]=[N:19][C:20]([Cl:25])=[N:21]2)=[CH:16][CH:15]=1
Reactant: Oc1c(Br)ccc2cnc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Cl)nc23)CC1
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A solution of DEAD (404 mg, 2.32 mmole) in THF (0.5 mL) was added to a solution of 7-bromo-2-chloroquinazolin-8-ol (400 mg, 1.54 mmole), tert-butyl 4-hydroxypiperidine-1-carboxylate (621 mg, 3.09 mmole) and PPh3 (610 mg, 2.32 mmole) in THF (5.5 mL) at RT. After 1.5 hours, silica gel was added to the reaction which was evaporated to dryness and loaded onto a flash column. The product was eluted with 25% EtOAc/hexane to give tert-butyl 4-(7-bromo-2-chloroquinazolin-8-yloxy)piperidine-1-carboxylate in 80% yield (545 mg, 1.23 mmole).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N+:18]([O-])=O)=[C:14]([CH:17]=2)[NH:15][CH3:16])[CH:6]=[C:5]([CH3:21])[N:4]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:17]=[C:14]([NH:15][CH3:16])[C:13]([NH2:18])=[CH:12][CH:11]=2)[CH:6]=[C:5]([CH3:21])[N:4]=1
Reactant: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1N
Yield: 100.3 %

Procedure:
The reaction and post-treatment were carried out according to Example (1b) using 5-[(2-methoxy-6-methylpyridin-4-yl)oxy]-N-methyl-2-nitroaniline produced in Example (17b) (4.87 g, 16.8 mmol), iron powder (4.70 g, 84.2 mmol), ammonium chloride (0.45 g, 8.42 mmol), ethanol (80 mL) and water (40 mL) to obtain the title compound (4.37 g, 99%) as a brown oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:17]3[C:12](=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29](I)[CH3:30]>CN(C=O)C.O>[CH2:29]([N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][N:9]2[C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1)[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:30]
Reactant: CCI
Reactant: CSc1nccc(-n2ccc3c(NS(C)(=O)=O)cccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1cccc2c1ccn2-c1ccnc(SC)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
N-[1-(2-Methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yl]-methanesulfonamide (0.4 g) in DMF (2 mL) was treated with K2CO3 (0.83 g) followed by EtI (0.2055 g), stirred at RT overnight, diluted with water, the solid filtered, washed with water and dried at 50° C. in vacuo overnight to yield N-ethyl-N-[1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yl]-methane-sulfonamide (0.4 g).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[N:9]([CH2:10][C:11]#[C:12][CH3:13])[C:8]([C:14]([O:16]CC)=O)=[C:7]([CH:19]=O)[N:6]=1.C(O)(=O)C>C(O)C>[Br:4][C:5]1[N:9]([CH2:10][C:11]#[C:12][CH3:13])[C:8]2[C:14](=[O:16])[NH:3][N:2]=[CH:19][C:7]=2[N:6]=1
Reactant: CC#CCn1c(Br)nc(C=O)c1C(=O)OCC
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC#CCn1c(Br)nc2cn[nH]c(=O)c21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6.31 ml (0.126 mol) hydrazine hydrate were added drop-wise at ambient temperature to a solution of 35.0 g (0.117 mol) ethyl 2-bromo-3-(but-2-ynyl)-5-formyl-3H-imidazole-4-carboxylate in 400 ml of ethanol. After 30 min stirring 27 ml (0.472 mol) concentrated acetic acid were added and the solution was then stirred for 1 h at 100° C. After cooling the precipitated solid was suction filtered, washed with ethanol and diethyl ether and dried. The solid was further purified by re-crystallization from EtOH.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:3]=1
Reactant: CCOC(=O)CCl
Reactant: Ic1n[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(I)c2cccnc21
Yield: 83.1 %

Procedure:
To a mixture of 3-iodo-1H-pyrazolo[3,4-b]pyridine (9.8 g, 40 mmol, 1 equiv) and potassium carbonate (27.6 g, 5 equiv) in 15 mL of DMF at 90° C. was added ethyl chloroacetate (8.5 mL, 40 mmol, 1 equiv). Two hours later, the reaction mixture was diluted with ethyl acetate followed by washing with saturated aqueous NaHCO3. The organic layer was dried and concentrated to provide the crude product. Purification of the crude product by flash chromatography gave ethyl (3-Iodo-pyrazolo[3,4-b]pyridin-1-yl)-acetate (11 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[O:26][C:27]=1[CH3:28])[CH:11]=[C:10]2[CH3:16])[CH3:2]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]cc(C)c2c1)OCC
Product: CCOC(=O)C(Cc1ccc2c(c1)c(C)cn2Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), rac-2-ethoxy-3-(3-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 4) was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole to give rac-2-ethoxy-3-{3-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless oil.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[NH:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=1)=[O:7])(C)(C)C.C([O:30][CH:31]=[C:32]([C:38](OCC)=O)[C:33]([O:35][CH2:36][CH3:37])=[O:34])C>FC(F)(F)C(O)=O>[CH2:19]([C:18]1[N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[C:6]([OH:5])=[O:7])=[CH:15][CH:14]=2)[C:31](=[O:30])[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][N:23]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(=N)NCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(C(=O)OCC)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound is prepared form N-(2'-t-butoxycarbonylbiphen-4-yl)methylvaleramidine and diethyl ethoxymethylenemalonate (Aldrich) similarly to that in Example 7. The t-butyl ester is hydrolyzed in neat trifluoroacetic acid to give the title compound.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH2:39][CH:40]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:40][CH2:39][CH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CCC=O)CC2)cc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: O
Product: COC=CCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reaction time: 1 h

Procedure:
A suspension of 6.4 g of methoxymethyl-triphenylphosphonium chloride in 80 ml of t-butyl methyl ether was treated within 3 minutes with 2.1 g of potassium t-butylate while gassing with argon at 0° C. and the mixture was stirred for a further 1 hour at 0°-5° C. The mixture was then treated dropwise within 5 minutes at 0° C. with a solution of 3.0 g of 3-[trans-4-(p-cyanophenyl)cyclohexyl]propionaldehyde in 20 ml of t-butyl methyl ether and the resulting mixture was stirred for a further 2 hours at room temperature. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. The residue was dissolved in 15 ml of ethyl acetate and the clear solution was treated with 250 ml of petroleum ether. After leaving to stand for 10 minutes at -20° C. the precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the residue (5.5 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 2.95 g (88%) of p-[trans-4-(4-methoxy-3-butenyl)cyclohexyl]benzonitrile as colourless crystals.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10](F)=[CH:9][N:8]=1)[CH3:2].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([OH:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[N:31]1>O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10]([O:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[N:39]=[CH:38][N:37]=[C:36]3[NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(COc1ncc(F)cn1)OCC
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(COc1ncc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)cn1)OCC
Temperature: 190 °C
Reaction time: 14 h
Yield: 37.6 %

Procedure:
2-(2,2-Diethoxyethoxy)-5-fluoropyrimidine (168 mg, 0.73 mmol) and potassium tert-butoxide (93 mg, 0.83 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (80 mg, 0.33 mmol), and stirred at 190° C. for 14 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Moritex, acetone:hexane=1:2) to obtain 6-{[2-(2,2-diethoxyethoxy)pyrimidin-5-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (56 mg, yield: 37%) as a pale brown amorphous solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[C:17]([N:18]=[C:19]4[CH2:25]CC[CH2:22][CH2:21][C:20]=24)=[CH:16][CH:15]=[N:14]3)=[CH:8][CH:7]=1.N1N2C(N=C3C(=C2C2C=CC(O)=CC=2)CCC3)=CC=1.BrCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[C:17](=[CH:16][CH:15]=[N:14]3)[N:18]=[C:19]3[C:20]=2[CH2:21][CH2:22][CH2:25]3)=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Agent: ClCCCBr
Agent: Oc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1
Product: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1

Procedure:
Using the method described for the preparation of 10-[4-(3-chloro-propoxy)-phenyl]-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 4-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-phenol and 1-bromo-3-chloropropane provided the title compound.
Reaction SMILES: O=[O+][O-].Cl[C@@H:5]1[N:8](C(=O)C(OCOC(=O)C(C)(C)C)=O)[C:7](=[O:22])[C@H:6]1[C:23]([OH:26])([CH3:25])[CH3:24].[C:27]([CH2:30][C:31](=[O:33])[CH3:32])(=[O:29])[CH3:28].CO.C[O-].[Na+]>ClCCl.CCCCCC.C(OCC)(=O)C>[C:27]([CH:30]([C:31](=[O:33])[CH3:32])[C@@H:5]1[NH:8][C:7](=[O:22])[C@@H:6]1[C:23]([OH:26])([CH3:24])[CH3:25])(=[O:29])[CH3:28]
Reactant: CC(C)(C)C(=O)OCOC(=O)C(=O)N1C(=O)[C@@H](C(C)(C)O)[C@@H]1Cl
Reactant: CC(=O)CC(C)=O
Agent: C[O-]
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)C(C(C)=O)[C@@H]1NC(=O)[C@@H]1C(C)(C)O
Temperature: -10 °C

Procedure:
A solution of 1.5 g (4 mMol) of pivaloyloxymethyl [3R,4S]-2-[4-chloro-3-(1-hydroxyisopropyl)-2-oxoazetidin-1-yl]-2-isopropylidenylacetate in 50 ml of dichloromethane is stirred at -78° C., to which is introduced ozone for 15 minutes. Consumption of the starting material is cofirmed by means of thin-layer chromatography. Introduction of nitrogen gas into the reaction mixture for 30 minutes gives a solution containing pivaloyloxymethyl [3R,4S]-2-[4-chloro-3-(1-hydroxyisopropyl)-2-oxoazetidin-1-yl]-2-oxoacetate. This solution is stirred at -10° C., to which are added 800 mg (8 mMol) of acetylacetone, then 20 ml of methanol dissolving 216 mg (4 mMol) of sodium methylate. The solvent is distilled off under reduced pressure, and the residue is stirred vigorously together with 20 ml of ethyl acetate, 1 ml of 1 N-hydrochloric acid and 10 ml of a saturated aqueous solution of sodium chloride. The organic layer is separated, dried over magnesium sulfate, and concentrated. The resulting reaction product is subjected to silica-gel column-chromatography (n-hexane-ethyl acetate 1:1-1:4). The fractions containing the desired product are combined and concentrated to give 80 mg of the titled compound as crystals, m.p. 109°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:18]2[C:26]3[C:21](=[C:22]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)([CH2:16][CH3:17])[C:9]([NH:11][C:12](=[N:14]O)[CH3:13])=[O:10])=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:18]2[C:26]3[C:21](=[C:22]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)([C:9]2[O:10][N:14]=[C:12]([CH3:13])[N:11]=2)[CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCC(C(=O)NC(C)=NO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)cc1)(c1nc(C)no1)n1ccc2c(NS(C)(=O)=O)cccc21

Procedure:
A solution of 2-(4-chlorophenyl)-N-(1-(hydroxyimino)ethyl)-2-(4-(methylsulfonamido)-1H-indol-1-yl)butanamide (148 mg, 0.32 mmol) in THF (5 mL) was heated at 70° C. for 2 days. Then the solvent was removed in vacuo to afford the crude product. The product was purified by column chromatography (50% EtOAc/hexanes), then by chiral separation following the conditions below provided the title compound as a single enantiomer.