Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([CH3:18])=[C:14](Br)[N:15]=2)[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][C:13]([CH3:18])=[C:14]([NH:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:32]=3)[N:15]=2)[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Cc1nc2c(nc1Br)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc2c(nc1Nc1cccc(S(C)(=O)=O)c1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Temperature: 110 °C
Reaction time: 21.5 h

Procedure:
A mixture of 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (0.110 g, 0.25 mmol), 3-methanesulfonyl-phenylamine (0.086 g, 0.5 mmol), tris(dibenzylideneacetone)dipalladium (0.011 g, 0.0125 mmol), racemic BINAP [rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl](0.023 g, 0.038 mmol) and sodium tert-butoxide (0.060 g, 0.63 mmol) in toluene (2.5 mL), under an argon atmosphere, was heated and stirred in a sealed vessel at 110° C. for 21.5 h. The cooled reaction mixture was diluted with ethyl acetate, washed once with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica, 75% ethyl acetate in hexanes) gave 0.107 g of slightly impure 2-(3-methanesulfonyl-phenylamino)-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a yellow glass. The reaction was repeated as above, and the combined slightly impure products were purified further by chromatography (silica, 33% ethyl acetate in hexanes) to give 2-(3-methanesulfonyl-phenylamino)-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (0.169 g, 64%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.07 (s, 9H), 0.85 (t, J=8.2 Hz, 2H), 1.30 (s, 9H), 2.64 (s, 3H), 3.19 (s, 3H), 3.54 (t, J=8.2 Hz, 2H), 5.59 (s, 2H), 7.49 (m, 1H), 7.56 (m, 1H), 7.62 (s, 1H), 7.96 (m, 1H), 8.05 (m, 1H), 8.16 (s, 1H), 8.74 (s, 1H). MS (EI/CI) m/z: 532 [M+H].
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:19][C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([NH:15][C:14](=O)[C:13]3=O)=[C:8]2[CH2:7][CH2:6]1)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:19][C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([NH:15][CH:14]=[CH:13]3)=[C:8]2[CH2:7][CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1CCc2c(ccc3c2NC(=O)C3=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)C1CCc2c(ccc3cc[nH]c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of 7-di-n-propylamino-6,7,8,9-tetrahydro-1H-benzo[g]indole-2,3-dione, 2a, (Chart 1) (22.0 g, 73.2 mmol) in dry diethyl ether (100 mL) was added dropwise to a suspension of lithiumaluminum hydride (9.0 g, 237 mmol) in dry diethyl ether (600 mL). After stirring overnight at ambient temperature, water (9.0 mL), 15% sodium hydroxide (9 mL) and water (27 mL) were consecutively added. The mixture was stirred for 20 minutes followed by filtration of inorganic material. The solution was dried (sodium sulfate), filtered and evaporated to yield 17 g of a blue off, which was purified on silica (acetone/methanol, 20:1) to yield 7.4 g (37%) of the pure material. For analytical and biological purposes, the fumarate salt (1/2 fum) was prepared which was recrystallized from ethanol/diethyl ether. m.p. 201°-205° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-])=O)[CH2:6]1)(=[O:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.C(OC(=O)C)C.[Fe]>[C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1Cc2cccc([N+](=O)[O-])c2C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)OC1Cc2cccc(N)c2C1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-nitro-2,3-dihydro-1H-inden-2-yl acetate (100 mg, 0.45 mmol) and ammonium chloride (100 mg) in ethanol (6 ml) and water (3 ml) was added iron powder (300 mg) portionwise at room temperature. The mixture was stirred at 90° C. for 1 hour, and after cooled to room temperature, the mixture was diluted with ethylacetate. The mixture was filtered through a pad of celite, and the filtrate was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 4-amino-2,3-dihydro-1H-inden-2-yl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NCCO
Product: COc1ccc(C(=O)NCCO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 2-aminoethanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[Br:21][C:22]1[CH:23]=[C:24]2[CH2:30][C:29](=[O:31])[NH:28][C:25]2=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]2[C:30](=[CH:19][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[C:7](=[O:18])[C:6]=4[C:2]=3[CH3:1])[C:29](=[O:31])[NH:28][C:25]2=[N:26][CH:27]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: O=C1Cc2cc(Br)cnc2N1
Product: Cc1c(C=C2C(=O)Nc3ncc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 37 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (35 mg, 37.0%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:13][CH2:14][C:6]3=[CH:5][C:4]=2[CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][O:17][C:15]([C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:13][CH2:14][C:6]3=[CH:5][C:4]=2[CH:3]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)C1Cn2c(cc3cc(Br)ccc32)CN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)cc1n2CC(C(=O)OC(C)(C)C)NC1
Temperature: 25 °C

Procedure:
A solution of 2-5 (3.0 g, 8.5 mmol) in MeOH (60 mL) and DMSO (20 mL) was treated with triethylamine (3.55 mL, 25.5 mmol), 1,3-Bis(diphenylphosphino)propane (1.75 g, 4.25 mmol) and palladium (II) acetate (0.952 g, 4.25 mmol). Carbon monoxide was bubbled through the solution while it was heated to reflux for 2 hours. The reaction was heated at reflux overnight under a balloon atmosphere of carbon monoxide. Additional 1,3-Bis(diphenylphosphino)propane (0.8 g, 2.12 mmol) and palladium acetate (0.476 g, 2.12 mmol) were added and the reaction was heated at reflux for 48 hours under a balloon atmosphere of carbon monoxide. The reaction was cooled to room temperature, the residue was partitioned between water and EtOAc. The water layer was extracted with EtOAc, the organic layers were combined, washed with water, brine, dried with MgSO4, filtered and evaporated. The residue was chromatographed (25% EtOAc/hexanes) to give 2-6 as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C@H:12]([CH2:20][OH:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(N(CC)CC)C>[C:14]1([CH2:13][CH:12]([NH:11][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[Cl:1])[CH2:20][OH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NC(CO)Cc1ccccc1)c1cccnc1Cl

Procedure:
10.0 g of chloronicotinic acid were reacted with 9.7 g of phenylalaninol in 250 ml of CH2Cl2 in the presence of 13.0 g of EDC, 2.9 g of HOBT and 9.6 g of triethylamine analogously to Example 1c, 17.3 g (94%) of the product being obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH2:10][CH2:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)=[O:2].[F:39][C:40]([Si](C)(C)C)([F:42])[F:41].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:24][C:17]([O:16][C:15]1[CH:25]=[CH:26][C:12]([CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]([OH:2])[C:40]([F:42])([F:41])[F:39])=[CH:8][N:7]=2)[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[CH:13][CH:14]=1)([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C=O)cn2)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C(O)C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A solution of ethyl 2-[4-(2-{(5-formylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (400 mg; 0.75 mmol) in 5 ml of dry THF was treated in an ice bath, under nitrogen, with trifluoromethyltrimethylsilane (128 mg; 0.90 mmol), followed by tetrabutylammonium fluoride (0.075 ml of a 1M solution in THF; 0.075 mmol). The reaction mixture was allowed to warm to rt and stirred overnight. Additional trifluoromethyltrimethylsilane (128 mg; 0.90 mmol) and tetrabutylammonium fluoride (0.075 ml) were added. After 6 hours the previous reagents were added again in the same amounts. After stirring at rt overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. Purification by radial chromatography using ethyl acetate-hexane mixtures (5–40% gradient) afforded ethyl 2-methyl-2-[4-(2-{[5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate (247 mg; 55% yield).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[C:25]([O:29][C:30](=[O:47])[NH:31][CH2:32][CH2:33][NH:34][S:35]([C:38]1[CH:43]=[C:42](Br)[C:41]([F:45])=[CH:40][C:39]=1[F:46])(=[O:37])=[O:36])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:47])[NH:31][CH2:32][CH2:33][NH:34][S:35]([C:38]1[CH:43]=[C:42]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)[C:41]([F:45])=[CH:40][C:39]=1[F:46])(=[O:36])=[O:37])([CH3:28])([CH3:26])[CH3:27]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(Br)c(F)cc1F
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (675 mg, 2 mmol) and [2-(5-bromo-2,4-difluoro-benzenesulfonylamino)-ethyl]-carbamic acid tert-butyl ester (1080 mg, 2.6 mmol) according to general procedure II. Obtained as a yellow solid (670 mg, 50%). MS (ISP) 572.0 [(M+H)+]; mp 203–204° C. (dec.).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/[C:25](C)=[O:26])=N\O.COC1C=CC(C=O)=CC=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:26][CH3:25])=[CH:16][CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: CC(=O)/C(C)=N/O
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: COc1ccc(C=O)cc1
Product: COc1ccc(-c2nc(CI)c(C)o2)cc1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 4-methoxybenzaldehyde gave 4-iodomethyl-2-(4-methoxyphenyl)-5-methyloxazole.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[N:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[I-].[Na+]>C(#N)C>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[N:14][C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=2)[CH2:32][CH2:33]1
Reactant: ClCCCOc1cnc2c(n1)CCCC2
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(N2CCN(CCCOc3cnc4c(n3)CCCC4)CC2)nc1
Yield: 78.9 %

Procedure:
227 mg (1 mmol) of 2-(3-chloropropoxy)-5,6,7,8-tetrahydroquinoxaline was dissolved in 10 ml of acetonitrile. To the resultant solution were added 208 mg (1.5 mmol) of potassium carbonate, 196 mg (1.2 mmol) of 1-(2-pyridyl)piperazine and 149 mg (1 mmol) of sodium iodide, and the resultant mixture was heated under reflux for 15 hours. Then, the mixture was subjected to filtration to filter off insoluble substances, which were then washed with acetonitrile, to thereby obtain a filtrate. The solvent of the filtrate was distilled off in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was charged in a column of 20 g of silica gel (Art7734, manufactured and sold by E. Merck, Darmstadt) and eluted with chloroform-methanol (100:1), to thereby obtain 279 mg of 2-[3-{4-(2-pyridyl)-1-piperazinyl}propoxy]-5,6,7,8-tetrahydroquinoxaline (yield: 79%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[C:16]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=2[O:14][CH:13]=1)=O)C.[OH-].[Na+]>C1COCC1>[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([CH2:10][OH:9])=[CH:13][O:14][C:15]=2[CH:20]=1
Reactant: CCOC(=O)c1coc2cc(F)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1coc2cc(F)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
1M LiAlH4-solution in THF (75.9 ml, 75.9 mmol) is diluted with 100 ml of THF and cooled to 0° C. 110 (7.9 g, 37.9 mmol) is dissolved in 100 ml of THF and added dropwise within 30 min. After completed addition the mixture is allowed to stir at rt for 2 h. Then the reaction mixture is cooled to −15° C. and 10 ml of a 1M NaOH solution is added very slowly. The mixture is filtrated over celite and evaporation under reduced pressure gave 5.3 g of a yellow oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[N:14]([C:39]4[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=4)[C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC4(CC2)OCCO4)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 55 %

Procedure:
The title compound was synthesized in analogy to example 66, from (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 196), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (55%).
Reaction SMILES: [CH:1]1([N:4]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=2[OH:14])[CH3:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:24][C:25](=[O:27])[CH3:26]>CC(C)=O>[CH:1]1([N:4]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=2[O:14][CH2:24][C:25](=[O:27])[CH3:26])[CH3:5])[CH2:2][CH2:3]1
Reactant: CN(c1cc(F)c(F)cc1O)C1CC1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1cc(F)c(F)cc1N(C)C1CC1

Procedure:
53 mg of 2-(N-cyclopropyl-N-methylamino)-4,5-difluorophenol, 44 mg of potassium carbonate, 6.4 mg of potassium iodide and 0.03 ml of chloroacetone are mixed in 1 ml of acetone and are heated at reflux for 20 h. The mixture is then evaporated and the residue is taken up in diethyl ether and washed with water. The organic phase is dried with magnesium sulfate and evaporated to dryness, and the residue is purified by flash chromatography. 1-[2-(N-Cyclopropyl-N-methylamino)-4,5-difluorophenoxy]propan-2-one is thus obtained as a yellow oil.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:15](=[O:17])[N:14]4[C:18]([CH3:21])=[N:19][N:20]=[C:13]4[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:11]=3[N:10]=[C:9]2N2C=NC=N2)=CC=1>FC(F)(F)C(O)=O>[CH3:21][C:18]1[N:14]2[C:15](=[O:17])[C:16]3[NH:8][C:9]([N:14]4[CH:13]=[N:20][N:19]=[CH:18]4)=[N:10][C:11]=3[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]2=[N:20][N:19]=1
Reactant: CCCCCn1c2nc(-n3cncn3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Solvent: O=C(O)C(F)(F)F
Product: CCCCCn1c2nc(-n3cnnc3)[nH]c2c(=O)n2c(C)nnc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
A mixture of 6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(1H-1,2,4-triazol-1-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (53 mg, 0.12 mmol) in trifluoroacetic acid (10 mL) was stirred at 60° C. overnight. The mixture was concentrated and purified by preparative LC-MS to give the desired product (20 mg, 52%). LCMS calculated for C14H18N9O(M+H): 328.2; found: 328.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1.[O:36]([CH2:43][CH2:44]Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:1][CH2:44][CH2:43][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:4][CH:5]=2)[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]1[CH2:12][CH2:13]2
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(CO)cc1)C2
Product: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(COCCOc3ccccc3)cc1)C2

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (1RS,2RS,3RS,5SR)-3-(4-hydroxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate [Example 86 (eee)] with phenoxy-ethyl bromide there was obtained tert-butyl (1RS,2RS,3RS,5SR)-2-(naphthalen-2-ylmethoxy)-3-[4-(2-phenoxy-ethoxymethyl)-phenyl]-8-aza-bicyclo[3.2.1]octane-8-carboxylate as a colourless oil; MS: 611 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[NH4+].[Cl-].O.[CH2:18]1COCC1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](=[O:13])[CH3:18])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 30 %

Procedure:
At −78° C., to a solution of 2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl chloride (2.45 g, 10 mmol) in dry THF (50 mL) was added MeMgCl THF solution (3.0 M, 4 mL, 12 mmol) slowly and the reaction mixture was allowed to stir at −78° C. for 45 min. Sat. aq. NH4Cl (2 mL) and water (4 mL) were added. The aqueous layer was extracted with EtOAc (2×10 mL), and the combined extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica chromatography eluting with EtOAc/hexanes (1/9) to give to give 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (675 mg, 30% yield). LC-MS m/z 225 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.86 (s, 1H), 2.65 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]([NH2:14])[CH3:13].[CH:15]([C:18]([CH3:25])([CH:22]([CH3:24])[CH3:23])[C:19](Cl)=[O:20])([CH3:17])[CH3:16]>O1CCCC1>[CH:15]([C:18]([CH3:25])([CH:22]([CH3:24])[CH3:23])[C:19]([NH:14][CH:12]([C:8]1[O:7][CH:11]=[CH:10][CH:9]=1)[CH3:13])=[O:20])([CH3:17])[CH3:16]
Reactant: CC(C)C(C)(C(=O)Cl)C(C)C
Reactant: CC(N)c1ccco1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(NC(=O)C(C)(C(C)C)C(C)C)c1ccco1
Reaction time: 8 h
Yield: 45.5 %

Procedure:
In a 25 mL round bottom flask, fitted with magnetic stirrer, 15 mL of tetrahydrofuran, 2.1 mmol (1.5 eq.) of pyridine and 1.54 mmol (1.1 eq.) of 1-(furan-2-yl)ethanamine were added. 1.4 mmol of 2-isopropyl-2,3-dimethylbutanoyl chloride (prepared by hydrolysis of 2-isopropyl-N,2,3-trimethylbutanamide, WS-23 with NaNO2 in H2SO4 and subsequent acid chloride formation with SOCl2) were added and the mixture was stirred at room to temperature for 16 hours, overnight. The reaction mixture was extracted with MTBE and HCl (1N in water). The organic layer was washed with NaOH (1N in water) and brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography, obtaining 160 mg of a beige solid, mp 57-60° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N+](=[CH2:13])=[N-]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: O=C(O)c1cccc(F)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1cccc(F)c1
Temperature: 0 °C
Yield: 84.4 %

Procedure:
To an ice-cooled and stirred solution of m-fluorobenzoic acid (8.0 g, 57 mmol) in 50 ml of ether was added an excess solution of diazomethane in ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl m-fluorobenzoate (7.4 g, 48.1 mmol, yield 84.4%, b.p. 80°-82° C./16 mmHg), which was assigned the structure by the following data: