Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36]Br)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCBr)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Temperature: 80 °C

Procedure:
A suspension of 2.0 g of 5-benzyloxy-3-[5-(2-bromoethoxy)-1-tert-butoxycarbonyl-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester and of 498 mg of potassium iodide in 90 ml of acetonitrile is heated at 80° C. for 7 hours. 394 μl of morpholine, 150 mg of potassium iodide and 1.24 g of potassium carbonate are then added and the mixture is heated at 80° C. for 15 hours. The reaction mixture is cooled to ambient temperature and then filtered. The filtrate is evaporated under reduced pressure in a rotary evaporator to obtain 1.90 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:9]([C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+]>C(Cl)Cl>[CH2:1]([C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C@@H:9]([OH:10])[C@H:11]([CH:13]1[CH2:15][CH2:14]1)[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
2.83 g (8.77 mmol) tert-butyl [(1S,2R)-1-benzyl-2-(cyclopropylcarbonyl)-2-hydroxyethyl]carbamate were dissolved in 130 ml of methylene chloride, 3 ml of acetic acid were added thereto and the mixture was finally treated portionwise at 0°-10° C. with 0.332 g (8.78 mmol) of sodium borohydride. The reaction solution was stirred at 50 for a further 2 hours and was then partitioned between 2N sodium hydrogen carbonate solution and methylene chloride. The organic phase was separated, washed with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure. Crystallization of the residue from ether/hexane yielded 2.1 g of tert-butyl [(1S,2R,3S)-1-benzyl-3-cyclopropyl-2,3-dihydroxypropyl]carbamate as colourless needles, m.p. 83-85°.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[C:8]=2[CH3:12])[N:3]=1>O.C(O)(=O)C>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[C:8]=2[CH3:12])[NH:3]1
Reactant: Cc1ccc2c(C)c(F)ccc2n1
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)ccc2c1CCC(C)N2
Reaction time: 20 h

Procedure:
7.0 kg of 2,5-dimethyl-6-fluoroquinoline, 51.5 kg of glacial acetic acid and 350 g of 50% water-wet 5% platinum on carbon catalyst were combined and hydrogenated at 50 psi for 20 hours. Gas chromatography showed residual starting material so an additional 35 g of catalyst was added and the hydrogenation was continued for an additional 2 hours. The mixture was filtered to remove the catalyst and the solvent was then evaporated. The residue was dissolved in 10 gallons of cold water, and the resulting mixture was made basic with ammonium hydroxide to pH 11 while maintaining the temperature below 30° C. The resulting mixture was extracted with 8 gallons of 1,2-dichloroethane and the extract was dried through azeotropic distillation. The dried extract was treated with magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to give a dark oil, 2,5-dimethyl-6-fluoro-1,2,3,4-tetrahydroquinoline, which was used directly in the next step.
Reaction SMILES: O.[BH4-].[Na+].[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C@@:12]2([CH3:37])[C:16](=[O:17])[N:15]([CH2:18][C:19]([O:21]CC3C=CC=CC=3)=[O:20])[C:14](=[O:29])[N:13]2[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][CH:7]=1)=[O:5]>C(O)C>[OH:5][CH2:4][C:6]1[CH:11]=[CH:10][C:9]([C@@:12]2([CH3:37])[C:16](=[O:17])[N:15]([CH2:18][C:19]([OH:21])=[O:20])[C:14](=[O:29])[N:13]2[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:8][CH:7]=1
Reactant: C[C@]1(c2ccc(C=O)cc2)C(=O)N(CC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@]1(c2ccc(CO)cc2)C(=O)N(CC(=O)O)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
20 ml of water and then, at 0° C., 22 mg (0.6 mmol) of sodium borohydride were added to a solution of 500 mg (1.1 mmol) of 8.2 in 50 ml of ethanol. After stirring at 0° C. for 40 min, the reaction mixture was concentrated in vacuo, the residue was heated at 50° C. for 12 h in 30 ml of 6 N hydrochloric acid/THF (1:1) and the reaction mixture was allowed to stand overnight at room temperature. The mixture was extracted with dichloromethane and the organic phase was dried over sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was treated with water and freeze-dried. 440 mg of crude 8.3 were obtained, which was employed in the next synthesis step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:20]=[C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[C:16]([O:17][CH3:18])[C:11]2=[N:10]1.P(Br)(Br)([Br:23])=O>ClCCCl>[Br:23][C:13]1[C:12]2=[CH:20][N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:10]=[C:11]2[C:16]([O:17][CH3:18])=[CH:15][N:14]=1
Reactant: COc1c[n+]([O-])cc2cn(-c3c(Cl)cccc3Cl)nc12
Reactant: O=P(Br)(Br)Br
Solvent: ClCCCl
Product: COc1cnc(Br)c2cn(-c3c(Cl)cccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
To a cooled (0° C.) solution of 2-(2,6-dichlorophenyl)-7-methoxy-2H-pyrazolo[4,3-c]pyridine 5-oxide (1.3 g, 4.2 mmol) in DCE (30 mL) under nitrogen was added phosphorous oxybromide (2.4 g, 8.4 mmol). The reaction mixture was stirred for 30 minutes, warmed to room temperature, and stirred for a further 4 hours. Further phosphorous oxybromide (1.8 g, 6.3 mmol) was added and the reaction mixture was stirred for a further 16 hours. The temperature was raised to 80° C. and stirred for 2 hours. The resultant mixture was cooled, quenched with sodium carbonate (sat. aq.) and the layers were partitioned. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (30-40% ethyl acetate in cyclohexane) to afford the title compound as a white solid (143 mg, 9% yield). LCMS (Method D): RT=3.52 min, m/z: 372 [M+H+].
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][CH2:22][CH:23]([CH3:33])[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[CH2:16]1)=O)(C)(C)C.[C:34]1([CH2:40]C=O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)(=O)C>[CH2:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][CH2:22][CH:23]([CH3:33])[C:24]([NH:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH2:16]1)[CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(CCC1CCCN(C(=O)OC(C)(C)C)C1)C(=O)Nc1ccccc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(CCC1CCCN(CCc2ccccc2)C1)C(=O)Nc1ccccc1

Procedure:
Trifluoroacetic acid (0.38 mL, 4.99 mmol) in CH2Cl2 (0.38 mL) was added dropwise to a 0° C. stirring solution of 101 in CH2Cl2 (0.40 mL). When the reaction was judged complete by TLC, the solvent and excess trifluoroacetic acid were removed in vacuo. The crude residue was dissolved in DMF (1.54 mL, 0.18M), then phenylacetaldehyde (0.10 mL, 0.832 mmol), acetic acid (0.078 mL), and Na(OAc)3BH (0.118 g, 0.555 mmol) were added sequentially. When the reaction was judged complete by TLC, saturated aqueous K2CO3 was added. The organic layer was removed, and 5% aqueous HCl was added. The organic layer was discarded, and the aqueous layer was basified with saturated aqueous NH4OH. The organic layer was removed, dried with Na2SO4, and concentrated in vacuo. Purification by silica gel chromatography (98:2::CH2Cl2:2N NH3 in EtOH) provided (1-phenethylpiperidine-3-ylethyl)-N-phenylpropionamide (102). 13C NMR: 173.64, 142.77, 140.45, 129.82, 128.84, 128.50, 128.45, 127.95, 126.13, 61.08, 60.03, 54.27, 47.06, 33.89, 33.46, 32.57, 30.86, 28.00, 25.31, 9.74 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[N:23]1([C:29]2[CH:30]=[C:31]([CH:35]=[C:36]([S:38]([F:43])([F:42])([F:41])([F:40])[F:39])[CH:37]=2)[C:32](O)=[O:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[OH-].[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:32](=[O:33])[C:31]2[CH:35]=[C:36]([S:38]([F:43])([F:39])([F:40])([F:41])[F:42])[CH:37]=[C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:30]=2)=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: O=C(O)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.17 mmol) of the compound of Example 6A, 58 mg (0.17 mmol) of the compound of Example 18A and 79 mg (0.21 mmol) of HATU were dissolved in 1.0 ml of DMF, 38 μl (0.35 mmol) of 4-methylmorpholine were added and the mixture was stirred at RT for 16 h. 10 ml of 0.1 M aqueous sodium hydroxide solution were then added, and the mixture was stirred at RT for another 10 min. The precipitate formed was filtered off, washed with water and dried under high vacuum. This crude product was then purified by preparative HPLC (Method 29). The product fractions were concentrated under reduced pressure and the residue was taken up in ethyl acetate and with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. This gave 55 mg (53% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:21][CH2:20][CH2:19][O:18][CH3:17])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: COCCO
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COCCOc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, 2-methoxyethanol and DBU in DME. ES-MS m/e (%): 271 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][CH2:31][NH2:32]>C(O)(C)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:32][CH2:31][CH2:30][CH:26]4[CH2:27][CH2:28][CH2:29][N:25]4[CH3:24])[N:7]3[N:8]=2)=[CH:18][CH:19]=1
Reactant: CN1CCCC1CCN
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Solvent: CC(C)O
Product: CN1CCCC1CCNc1cccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn12
Temperature: 85 °C
Yield: 17 %

Procedure:
To a stirred solution of 7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (50 mg, 0.154 mmol) in 1 mL of isopropanol was added excess of 2-(1-methylpyrrolidin-2-yl)ethanamine (1 mL). The mixture was heated to reflux at 85° C. overnight. The mixture was evaporated to dryness and purified by preparative thin layer chromatography to give N-[2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridin-7-yl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]amine as peach solid in 17% yield (28.3% yield based on recovered starting material). 1H NMR (CDCl3): δ 8.58 (dd, 2H, J=1.4, 4.6 Hz), 7.59–7.62 (m, 2H), 7.25–7.32 (m, 3H), 7.04–7.14 (m, 3H), 6.83 (t, 1H, J=5.3 Hz), 5.98 (d, 1H, J=7.4 Hz), 3.40–3.55 (m, 2H), 3.13–3.19 (m, 1H), 2.43 (s, 3H), 2.36–2.43 (m, 1H), 2.20–2.29 (m, 1H), 1.66–2.20 (m, 6H); MS (ES+ve): 418 (10, M+3), 417 (20, M+2), 416 (60, M+1), 112 (100).
Reaction SMILES: BrCCCCC(O)=[O:7].C(O)C1C=CC=CC=1.[CH:17]([N:20]=[C:21]=[N:22][CH:23]([CH3:25])[CH3:24])([CH3:19])[CH3:18]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:18][CH:17]([CH3:19])[N:20]=[C:21]=[N:22][CH:23]([CH3:25])[CH3:24].[NH2:20][C:21]([NH2:22])=[O:7]
Reactant: O=C(O)CCCCBr
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: OCc1ccccc1
Product: NC(N)=O
Temperature: 25 °C

Procedure:
A solution of 5-bromopentanoic acid (1.00 g, 5.52 mmol) and benzyl alcohol (0.286 mL, 2.76 mmol) in methylene chloride (14 mL) was treated sequentially with N,N′-diisopropylcarbodiimide (0.523 g, 4.14 mmol) and 4-dimethylaminopyridine (43.9 mg, 0.359 mmol). The solution was allowed to stir at room temperature. A precipitate formed within 1 minute of the addition of the 4-dimethylaminopyridine. After −65 h, the reaction mixture was filtered, the solid was washed with CH2Cl2 and the filtrate was washed with 20 mL portions of 1N HCl, sat NaHCO3 and brine and dried over Na2SO4. The solution was filtered and concentrated to yield a nearly colorless liquid along with a solid (DIC urea). The material was taken up in 1/1 MTBE/heptane to yield a solution with a white precipitate. The mixture was filtered and concentrated and the crude material was purified by flash chromatography (75 g silica gel; 5-10% MTBE/hept) to yield the title compound (0.69 g, 92%) as a colorless liquid. HPLC purity>95% (ret. time, 4.73 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23])=[CH:16][CH:15]=3.Cl.[NH2:32]O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[O:25][N:32]=[C:22]([CH3:23])[CH:21]=1)=[CH:16][CH:15]=3
Reactant: CC(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: NO
Agent: Cl
Product: Cc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)on1

Procedure:
The process is carried out as indicated in Example 44 above, using 1-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]butane-1,3-dione from preparation 1.14 and hydroxylamine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].S(=O)(=O)(O)O.O.[CH3:21]O>>[OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:21])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1
Yield: 97 %

Procedure:
To a solution of (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid (3.0 g, 15 mmol) in methanol (30 mL) was added sulfuric acid (0.5 mL), and the mixture was heated under reflux for 12 hours. After the reaction solution was returned to room temperature, water was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure to give the title compound (3.1 g, yield 97%) as an oily matter. The obtained compound was used in the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:28]([C:38]([O:40][CH3:41])=[O:39])[CH:27]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.O>[Pd].C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:26]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C@H:28]([C:38]([O:40][CH3:41])=[O:39])[CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: COC(=O)[C@@H]1C=C(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1C(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
(2S)-1-tert-Butyl 2-methyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-2H-pyrrole-1,2(5H)-dicarboxylate (0.618 g, 1.1 mmol) and 10% palladium on carbon, 50% water (0.58 g) were combined in a flask and treated with nitrogen and 10 mL THF. The reaction mixture was stirred rapidly under H2 balloon for 48 h. The reaction mixture was flushed with nitrogen, filtered, rinsing with DCM and concentrated in vacuo. Purification by silica gel chromatography, 40 g, 0-30% EA/hexanes gave (2S,4R)-1-tert-butyl 2-methyl 4-(3-fluoro-4-(5-(1-phenyl-cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-1,2-dicarboxylate as a yellow foam. MS (ESI) m/z: Calculated: 573.2; Observed: 573.7 (M++1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:16]2[O:15][C:14]([CH3:18])([CH3:17])[O:13][C:12]=2[C:11]([C:19]([C:41]2[C:51]3[O:52][C:53]([CH3:56])([CH3:55])[O:54][C:50]=3[C:49]([C:57]([O:59]C)=[O:58])=[C:43]3[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=23)([C:21]2[C:31]3[O:32][C:33]([CH3:36])([CH3:35])[O:34][C:30]=3[C:29]([C:37]([O:39]C)=[O:38])=[C:23]3[O:24][C:25]([CH3:28])([CH3:27])[O:26][C:22]=23)[OH:20])=[C:10]2[C:6]=1[O:7][C:8]([CH3:62])([CH3:61])[O:9]2)=[O:4].[OH-].[Na+].O>CO.CO.O>[C:37]([C:29]1[C:23]2[O:24][C:25]([CH3:27])([CH3:28])[O:26][C:22]=2[C:21]([C:19]([C:11]2[C:12]3[O:13][C:14]([CH3:18])([CH3:17])[O:15][C:16]=3[C:5]([C:3]([OH:4])=[O:2])=[C:6]3[O:7][C:8]([CH3:61])([CH3:62])[O:9][C:10]=23)([C:41]2[C:51]3[O:52][C:53]([CH3:56])([CH3:55])[O:54][C:50]=3[C:49]([C:57]([OH:59])=[O:58])=[C:43]3[O:44][C:45]([CH3:47])([CH3:48])[O:46][C:42]=23)[OH:20])=[C:31]2[C:30]=1[O:34][C:33]([CH3:36])([CH3:35])[O:32]2)([OH:39])=[O:38]
Reactant: COC(=O)c1c2c(c(C(O)(c3c4c(c(C(=O)OC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)OC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c(c2C(=O)O)OC(C)(C)O3)O1
Reaction time: 12 h

Procedure:
The ester of Example 15, tris(8-methoxycarbonyl-2,2,6,6-tetramethyl-benzo[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methanol (0.30 g, 0.34 mmol) was dissolved in MeOH (10 mL), and NaOH (0.041 g, 1.02 mmol) dissolved in MeOH/H2O (2.32M NaOH solution) was added until pH reached 7. In total 0.44 mL of the basic solution was used. The MeOH was evaporated in vacuum due to solubility problems and THF (3.5 mL) was added. The reaction mixture cleared with this treatment. After 12 h the reaction mixture was turbid and a precipitate had formed. This precipitate dissolved with the addition of water (10 mL). The THF was evaporated under reduced pressure and water (10 mL) was added and the aqueous phase was extracted with ether (10 mL). The organic phase was separated and the aqueous phase was acidified (pH 3.5) with 2M HCl. A yellow precipitate was formed and the aqueous phase was extracted with ether (3×20 mL) and CH2Cl2 (30 mL). The organic phases were collected, dried (Na2SO4) and the solvent was evaporated to yield the product tris(8-carboxy-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methanol as a slightly tanned residue (0.25 g, 87%). The product contained a small impurity (appreciated to about 2% at the same extinction) according to HPLC (C18, ion pair (tetrabutyl-ammonium acetate) chromatography, CH3CN:H2O) with UV (254 nm) detection.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]4[CH:28]=[CH:29][O:30][C:26]=4[CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].CCOC(C)=O>CO>[ClH:32].[ClH:32].[ClH:32].[O:30]1[C:26]2[CH:25]=[CH:24][N:23]=[C:22]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:17][CH2:18]3)[C:27]=2[CH:28]=[CH:29]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Temperature: 25 °C

Procedure:
trans-{4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (2.9 g, 7 mmol) was treated with 1 N HCl in EtOAc (100 ml, 100 mmol) and MeOH (1.9 ml) and the resulting mixture was stirred over night at room temperature. A white precipitate was formed that was collected by filtration and washed with EtOAc. The solid was dried over night under high vacuum to yield trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride as a white powder (2.9 g, 96%), MS (ISP) m/z=329.1 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:17][C:18]([CH3:20])=O.[BH4-].[Na+]>C(O)(=O)C>[CH:18]([NH:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([CH3:20])[CH3:17]
Reactant: CC(C)=O
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)c2ccccc2)c(NC(C)C)c1
Temperature: 20 °C
Yield: 99 %

Procedure:
To a solution of 21.1 gms. of 2-amino-4-methylbenzophenone in 100 mls. of acetone is added 100 mls. of glacial acetic acid. The solution is cooled to 20° C. With stirring, and by portionwise addition, 10 gms. of sodium borohydride is added to the solution over a period of 70 minutes. After the addition, the solution is stirred for an additional 20 minutes at 20° C., and extracted with 100 mls. of chloroform and 50 mls. of water. The aqueous phase is extracted twice using 50 mls. of chloroform each time. All the chloroform solutions are then combined and treated with 150 mls. of 20% ammonium hydroxide. The chloroform phase is dried over magnesium sulphate, filtered and concentrated by distillation to a constant weight of 25 gms or a crude 99% yield of 2-(N-isopropylamino)-4-methylbenzophenone, providing an actual yield of pure material of at least 90%.