Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]#[N:5])[CH3:2].O=[C:7]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.O.[OH-].[NH4+]>P(Cl)(Cl)(Cl)=O>[CH2:26]([C:7]1[N:5]=[C:4]([S:3][CH2:1][CH3:2])[C:21]2[C:20]([C:8]=1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][CH3:29]
Reactant: CCSC#N
Reactant: CCCCC(=O)C(Cc1ccc(C(=O)OC)cc1)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1nc(SCC)c2ccccc2c1Cc1ccc(C(=O)OC)cc1
Reaction time: 10 h

Procedure:
0.4 ml of ethyl thiocyanate and 0.45 ml of stannic chloride were added to a solution of 1 g of methyl 4-(3-oxo-2-phenyl-heptyl) benzoate of Step C in 20 ml of phosphorous oxychloride and the mixture was stirred for 10 hours at reflux, then poured into ice-cooled water. The mixture was stirred for 15 minutes and alkalized with concentrated ammonium hydroxide. Extraction was carried out with ethyl acetate and the extracts were washed with water, dried and evaporated to dryness. The residue was chromatographed on silica (eluant: hexane--ethyl acetate (9-1)) to obtain 0.57 g of the desired product melting at 70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(CO)NCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-amino-2-methyl-1-propanol (18 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(2-hydroxy-1,1-dimethylethyl)aminomethyl]indol-2-yl)isoindolinone.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=O)=[CH:34][CH:33]=1>>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:38])=[CH:39][CH:40]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: COc1ccc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 4-methoxybenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(4-methoxybenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 500 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([N:20]3[CH2:23][CH:22]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([C:32]5[S:33][CH:34]=[CH:35][N:36]=5)=[O:31])[CH2:26][CH2:25]4)[CH2:21]3)=[O:19])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[S:33]1[CH:34]=[CH:35][N:36]=[C:32]1[C:30]([N:27]1[CH2:28][CH2:29][N:24]([CH:22]2[CH2:23][N:20]([C:18]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][NH:8][CH2:17][CH2:16]4)=[O:19])[CH2:21]2)[CH2:25][CH2:26]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)N3CC(N4CCN(C(=O)c5nccs5)CC4)C3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc2c(c1)CCNC2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.9 %

Procedure:
To a solution of compound 17c (826 mg, 1.61 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The mixture was extracted with CH2Cl2, and H2O after basifying the water layer to pH˜8 with 1N aqueous NaOH. The organic solution was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave Cpd 916 (675 mg). 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=3.3 Hz, 1H), 7.55 (d, J=3.3 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J=8.03 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 4.54 (br. s., 1H), 4.44 (br. s., 1H), 4.01-4.35 (m, 6H), 3.75-3.95 (m, 2H), 3.12-3.31 (m, 2H), 2.85 (t, J=5.8 Hz, 1H), 2.49 (br. s., 4H). MS m/z (M+H+) 412.0.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[CH:17]1([C:20]2[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=2)[CH2:19][CH2:18]1>C(O)CCC>[CH:17]1([C:20]2[NH:24][N:23]=[C:22]([NH:25][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)[N:3]=3)[CH:21]=2)[CH2:19][CH2:18]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1cnc(-c2ccccn2)nc1Cl
Solvent: CCCCO
Product: O=[N+]([O-])c1cnc(-c2ccccn2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Yield: 77325.3 %

Procedure:
To 4-chloro-5-nitro-2-(pyridin-2-yl)pyrimidine (1.42 g, 0.006 mmol, 1 equiv.) in BuOH (20 mL) was added 5-cyclopropyl-1H-pyrazol-3-amine (1.23 g, 0.01 mmol, 1.6 equiv.) After heating at 90° C. for 4 h. the reaction mixture was filtered to produce N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitro-2-(pyridin-2-yl)pyrimidin-4-amine (1.5 g, 79%). LC-MS (m/z)=324 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ0.74-0.77 (m, 2H), 0.97-1.02 (m, 2H), 1.93-2.00 (m, 1H), 7.00 (s, 1H), 7.60-7.63 (m, 1H), 8.03-8.06 (m, 1H), 8.43 (d, J=7.6 Hz, 1H), 8.84 (d, J=4.0 Hz, 1H), 9.37 (s, 1H), 10.24 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:13][O:14][CH3:15])[CH2:11][F:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]([N:13]([O:14][CH3:15])[C:30]([C:29]2[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=2)=[O:31])[CH2:11][F:12])=[CH:6][CH:7]=1
Reactant: CONC(CF)CCc1ccc(Cl)cc1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(CF)CCc1ccc(Cl)cc1
Temperature: 24 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
To a stirred solution of N-[3-(4-chlorophenyl)-1-fluoromethyl-propyl]-O-methyl-hydroxylamine (60 mg; 0.26 mmol), prepared as described in example P8c and triethylamine (0.05 ml; 0.31 mmol) in dichloromethane (1 ml) under nitrogen was added drop wise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (51 mg; 0.26 mmol). The reaction mixture was stirred at 24° C. for 16 hours under nitrogen. The mixture was washed with 1M sodium hydroxide (20 ml), 1M hydrochloric acid (20 ml) and brine (20 ml). Organics were dried over sodium sulfate and evaporated under reduced pressure. The crude was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10 to 70:30) to afford 67 mg (66% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [3-(4-chloro-phenyl)-1-fluoromethyl-propyl]-methoxy-amide as a clear oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:46])[C@@H:20]([NH:36][C:37](=[O:45])[C@@H:38]([NH:42][CH:43]=[O:44])[CH:39]([CH3:41])[CH3:40])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:23]=3)[NH:14]2)=[O:12])[CH:4]=1)=[CH2:2].[CH3:47][O:48][C@H:49]([CH2:55][CH2:56][CH:57]=[CH2:58])[C@@H:50](C)[C:51](O)=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>C(#N)C>[CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:46])[C@@H:20]([NH:36][C:37](=[O:45])[C@@H:38]([NH:42][C:43](=[O:44])[C@H:50]([CH3:51])[C@H:49]([O:48][CH3:47])[CH2:55][CH2:56][CH:57]=[CH2:58])[CH:39]([CH3:41])[CH3:40])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:31])[CH3:30])[CH:23]=3)[NH:14]2)=[O:12])[CH:4]=1)=[CH2:2]
Reactant: C=CCC[C@@H](OC)[C@@H](C)C(=O)O
Reactant: C=Cc1ccnc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC=O)C(C)C)N2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: C=CCC[C@@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCc2cc(C=C)ccn2)N1)C(C)C
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of crude (S)-1-[(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-((S)-2-formylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 4-vinyl-pyridin-2-ylmethyl ester (0.52 mmol) and (2R,3R)-3-methoxy-2-methylhept-6-enoic acid 10d (90 mg, 0.52 mmol) in acetonitrile (10 mL) was stirred at room temperature. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (140 mg, 0.73 mmol) and 1-hydroxybenzotriazole hydrate (containing 20% water, 85 mg, 0.52 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic extract was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:3 to neat ethyl acetate to afford the title compound (271 mg, 67%) as a gum. 1H NMR (300 MHz, CDCl3) δ 0.17 (s, 6H), 0.86-0.98 (m, 15H), 1.17 (d, J=7.1 Hz, 3H), 1.5-2.2 (m, 11H), 2.45-3.00 (m, 5H), 3.33-3.44 (m, 1H), 3.40 (s, 3H), 3.60 (d, J=10.9 Hz, 1H), 4.27-4.33 (m, 2H), 4.97 (dd, J=10.2, 1.7 Hz, 1H), 5.05 (dd, J=17.2, 1.7 Hz, 1H), 5.28 (d, J=7.3 Hz, 1H), 5.56 (d, J=10.7 Hz, 1H), 5.73-5.87 (m, 2H), 6.03 (d, J=17.6 Hz, 1H), 6.50 (d, J=8.2 Hz, 2H), 6.66-6.82 (m, 4H), 7.04-7.10 (m, 1H), 7.31 (s, 1H), 8.56 (d, J=5.1 Hz, 1H). LCMS (m/z) 778 [M+H], Tr=5.78 min.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6]3=[C:7]([CH:13]=[CH:14][N:5]3[CH2:4]1)[CH:8]=[CH:9][CH:10]=2.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[Si:15]([O:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6]3=[C:7]([CH:13]=[CH:14][N:5]3[CH2:4]1)[CH:8]=[CH:9][CH:10]=2)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1Cc2cccc3ccn(c23)C1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1Cc2cccc3ccn(c23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(hydroxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (47 mmol) in dichloromethane (143 mL) at 0° C. was added tert-butyldimethylsilyl chloride (7.63 g, 49.4 mmol), followed by triethylamine (7.92 mL, 56.4 mmol) and dimethylaminopyridine (0.58 g, 4.7 mmol). The reaction was allowed to warm to room temperature and stirred 2 hours. The reaction was quenched with water, extracted with dichloromethane and the combined organics dried over sodium sulfate. The organic phase was concentrated under reduced pressure to provide 5-(tert-butyldimethylsilyloxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline. This material was treated essentially as described in Preparation II to provide the title compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16](O)=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16]([Cl:23])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCc1cccc(C(=O)c2ccc(Cl)cc2)c1

Procedure:
6.96 g of 3-(3'-p-chlorobenzoyl-phenyl)-propionic acid and 70 ml of thionyl chloride were refluxed for 3 hours and then evaporated to dryness. The residue was taken up in 100 ml of benzene and evaporated to dryness to obtain 8.7 g of 3-(3'-p-chlorobenzoyl-phenyl)-propionyl chloride which was used as is.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.C1C(=O)N(Br)C(=[O:27])C1>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:23])[C:10]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:21])[CH3:22])=[N:18][N:19]=2)[N:16]=1)=[O:27]
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Product: CC(C)c1nnc2ccc(C(=O)C(=O)c3ccc(F)cc3F)nn12
Reaction time: 72 h
Yield: 72.8 %

Procedure:
To a round bottom flask was added 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (1.50 g, 4.74 mmol, Preparation #K.1) followed by DMSO (15 mL) and NBS (0.844 g, 4.74 mmol). The reaction mixture was stirred at about ambient temperature for about 3 d. The reaction mixture was partitioned between EtOAc and water. The layers were separated, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/EtOAc (gradient, 1:0 to 0:1) to give the title compound (1.14 g, 73%): LC/MS (Table 1, Method a) Rt=2.4 min; MS m/z: 331.1 (M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[C:28]5Br)=[O:23])[CH2:21][CH2:20]3)=[CH:18][C:13]=2[O:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[C:28]5[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:23])[CH2:21][CH2:20]3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccc2[nH]cc(Br)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Nc1ccc2[nH]cc(-c3ccccc3)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 130 °C

Procedure:
Phenyl boronic acid (24.6 mg, 0.204 mmol) was added to a solution of 1-(benzo[d][1,3]-dioxol-5-yl)-N-(3-bromo-1H-indol-5-yl)cyclopropanecarboxamide (39.9 mg, 0.100 mmol) in ethanol (1 mL) containing FibreCat 1001 (6 mg) and 1M aqueous potassium carbonate (0.260 mL). The reaction mixture was then heated at 130° C. in a microwave reactor for 20 minutes. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-phenyl-1H-indol-5-yl)cyclopropane carboxamide ESI-MS m/z calc. 396.2, found 397.3 (M+1)+. Retention time of 3.52 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (d, J=1.9 Hz, 1H), 8.66 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.65-7.61 (m, 3H), 7.46-7.40 (m, 2H), 7.31 (d, J=8.7 Hz, 1H), 7.25-7.17 (m, 2H), 7.03 (d, J=1.6 Hz, 1H), 6.98-6.87 (m, 2H), 6.02 (s, 2H), 1.43-1.39 (m, 2H), 1.06-1.02 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][O:9]2)[CH:7]=1.B(F)(F)F.CCOCC.[CH3:20][C:21]([CH3:23])=[O:22]>O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][O:9][C:21]([CH3:23])([CH3:20])[O:22]2)[CH:7]=1
Reactant: CC(C)=O
Reactant: Brc1cncc(C2CO2)c1
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: CC1(C)OCC(c2cncc(Br)c2)O1
Reaction time: 14 h
Yield: 54.2 %

Procedure:
To a solution of 3-bromo-5-(oxiran-2-yl)pyridine (1.00 g, 5.00 mmol) in acetone (25 mL) was added BF3.OEt2 (0.950 mL, 7.50 mmol) dropwise at ambient temperature and the reaction mixture was stirred for 14 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The resulting residue was purified by combiflash (REDISEP®, silica gel, 40 g, 25% EtOAc/hexanes) to obtain 3-bromo-5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (0.700 g, 54.2%) as a pale yellow liquid. LCMS (Condition 8): retention time 2.17 min, [M+2]=260.0. 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 3 H), 1.55 (s, 3 H), 3.72 (dd, J=7.6 Hz, J=8.4 Hz, 1 H), 4.36 (dd, J=6.4 Hz, J=8.4 Hz, 1 H), 5.08 (dd, J=6.4 Hz, J=7.6 Hz, 1 H), 7.85-7.86 (m, 1 H), 8.49 (d, J=1.6 Hz, 1 H), 8.62 (d, J=2.0 Hz, 1 H).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([OH:25])[CH2:20][O:21][CH2:22][CH2:23]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[OH:25][CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:10]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: C1COCCO1
Product: OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
82 g of 4,4-diphenylpiperidine, 50 g of diethylene glycol monochlorohydrin, 250 g of finely powdered potassium carbonate and 1 g of potassium iodide are heated at the boiling point under reflux, with vigorous stirring, in 1.2 l of a 1:1 mixture of dioxane and 1-butanol for 50 h. After cooling, the mixture is filtered and the filtrate is concentrated. The oily residue is taken up in ethyl acetate and the solution is filtered again. After the filtrate has been concentrated to constant weight (high vacuum), the title compound is obtained as a waxy viscous residue. Yield: 106 g. The hydrochloride is obtained with ethereal hydrochloric acid and is recrystallized from 2-propanol. M.p.: 120°-121° C.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C@@:6]12[O:13][C@@H:10]([CH2:11][CH2:12]1)[C:9](=[O:14])[CH2:8][C:7]2=[O:15].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH3:42])=[C:37]([Pb+3])[CH:36]=2)=[CH:31][CH:30]=1.Cl>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH3:42])=[C:37]([CH:8]3[C:9](=[O:14])[C@H:10]4[O:13][C@:6]([CH3:5])([CH2:12][CH2:11]4)[C:7]3=[O:15])[CH:36]=2)=[CH:33][CH:34]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 67.8 %

Procedure:
To a mixture of chloroform (2.0 ml) and toluene (0.5 ml) is added (1R*,5S*)-1-methyl-8-oxa-bicyclo[3.2.1]octane-2,4-dione (0.10 g, 0.6 mmol) and N,N-dimethylamino-pyridine (0.395 g, 3.2 mmol) under a nitrogen atmosphere with stirring. To this reaction mixture is added 4′-chloro-4-ethylbiphenyl-3-yllead triacetate (0.42 g, 0.70 mmol) in one portion, then the mixture is heated at 80° C. for 1-2 hours. The reaction mixture is cooled to room temperature, acidified with dilute aqueous hydrochloric acid then filtered through diatomaceous earth to remove inorganic residues (subsequent washing with dichloromethane). The aqueous fractions are extracted with dichloromethane (2×5 ml), all organic fractions are combined, dried over sodium sulfate then concentrated under vacuum to give the crude product which is purified by flash chromatography (hexane/ethyl acetate) to give (1R*,5S*)-3-(4′-chloro-4-ethylbiphenyl-3-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.150 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 79, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution) and stirred overnight at room temperature. Work-up afforded 48.0 mg (76%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:25][CH2:26][C@@H:27]1[CH2:31][C@@H:30]([O:32][Si](C(C)(C)C)(C)C)[CH2:29][N:28]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(OCC)(=O)C>CN(C)C(=O)C>[C:43]([O:42][C:40]([N:28]1[CH2:29][C@H:30]([OH:32])[CH2:31][C@H:27]1[CH2:26][CH2:25][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCl
Reactant: Oc1ccc(F)cc1CCc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)cc1
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
687 mg of 4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenol (prepared as described in Preparation 6) were dissolved in 12 ml of N,N-dimethylacetamide, and then 212 mg of potassium t-butoxide were added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred for 10 minutes, after which 687 mg of (2S,4R)-2-(2-chloroethyl)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine were added. The resulting mixture was then stirred at room temperature for 14 hours. At the end of this time, 135 mg of potassium t-butoxide were added to the reaction mixture, and the mixture was stirred at 40° C. for 4 hours, after which 300 ml of ethyl acetate were added. The resulting reaction mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. It was then concentrated by evaporation under reduced pressure. The resulting oily substance was purified by silica gel column chromatography, using a 2:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 571 mg (yield 74%) of the title compound as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Oc1cccc(Cl)c1
Product: Clc1cccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-chloro-phenol to give [1-(3-chloro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).