Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:26]=[C:25]([C:27]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=2)=[O:28])[CH:24]=[C:23]([O:36][C@@H:37]([CH3:40])[CH2:38][OH:39])[CH:22]=1)[C:14]([OH:16])=O.CN(C(ON1N=N[C:51]2[CH:52]=[CH:53][CH:54]=[N:55][C:50]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C.O>[F:10][C:11]1[CH:12]=[C:13]([C:14]([N:55]2[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]2)=[O:16])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:26]=[C:25]([CH:24]=[C:23]([O:36][C@@H:37]([CH3:40])[CH2:38][OH:39])[CH:22]=1)[C:27]([NH:29][C:30]1[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=1)=[O:28]
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCCCC3)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.7 %

Procedure:
DIPEA (0.36 mL, 1.95 mmol) was added to a suspension of 3-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)benzoic acid (209 mg, 0.49 mmol), HATU (390 mg, 1.02 mmol) and piperidine (0.19 mL, 1.95 mmol) in DMF (3 mL), and the mixture stirred at ambient temperature for 24 hours. Water (30 mL) was added and the mixture extracted with diethyl ether/ethyl acetate 4:1 (3×20 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-20% methanol in ethyl acetate, to give the desired compound (116 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC(=O)O)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 4 of Example 6, ethyl 2-{[1-chloro-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetate (0.477 g, 1.03 mmol) was hydrolyzed with potassium hydroxide (0.175 g, 3.12 mmol) in THF (10 mL) and water (10 mL). The title compound was obtained as a light yellow solid (0.249 g), mp 142-143° C. Mass spectrum (+ESI, [M+H]+) m/z 437. 1HNMR (500 MHz, DMSO-d6): δ13.0-13.5 (br, 1H), 8.5 (s, 1H), 8.25 (d, 1H, J=8.7 Hz), 8.1 (d, 1H, J=9.0 Hz), 8.05 (t, 2H, J=10.3 Hz), 7.75 (d,1H, J=8.0 Hz), 7.55 (d, 1H, J=9.2 Hz), 7.4-7.45 (m, 2H), 5.05 (s, 2H), 2.75 (t, 2H, J=7.2 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.75 ppm (t, 3H J=7.3 Hz). Elemental Analysis for C25H21ClO5: Calculated: C, 68.73; H, 4.84; N, 0.00. Found: C, 68.56; H, 4.60; N, 0.08.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.O>CO.O>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(C=O)s1
Solvent: O
Solvent: CO
Product: O=Cc1ccc(CCCO)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 69.1 %

Procedure:
To a solution of crude 5-(3-((t-butyldimethylsilyl)oxy)propyl)thiophene-2-carbaldehyde (ca. 871 mg, 3.06 mmol) in 32 mL of 9:1 methanol/water was added p-tosic acid monohydrate (58 mg, 0.31 mmol). The resulting mixture was stirred at room temperature for 45 minutes and poured into 100 mL water. Organics were extracted with ethyl acetate (2×75 mL) and ether (75 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (20-50% ethyl acetate in hexanes) to give 5-(3-hydroxypropyl)thiophene-2-carbaldehyde (360 mg, 69%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([C:24](=[O:33])[NH:25][CH2:26][C:27](=[O:32])[NH:28][CH:29]([CH3:31])[CH3:30])[CH:16]=2)[CH2:10][CH:9]1[CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([C:24](=[O:33])[NH:25][CH2:26][C:27](=[O:32])[NH:28][CH:29]([CH3:30])[CH3:31])[CH:16]=2)[CH2:10][CH:9]1[CH3:34])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)NC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)C(C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)NC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)C(C)C2)ccc1N
Yield: 100.5 %

Procedure:
4-{3-[(Isopropylcarbamoylmethyl)carbamoyl]-4-nitrophenyl}-2-methylperhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (100 mg, 0.209 mmol) and 10% Pd/C (10 mg, 0.209 mmol) in MeOH (5 mL) was stirred under 4 bar H2 (g) at room temperature overnight. The mixture was filtered through a pad of celite and the solvent removed in vacuo to afford 4-{4-amino-3-[(isopropylcarbamoylmethyl)carbamoyl]phenyl}-2-methylperhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE V.53) (94 mg, 0.210 mmol, 100%). This was used directly without purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4SC(C5C=CC=CC=5)=CN=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[F:64][C:65]([F:83])([F:82])[C:66]1[CH:71]=[CH:70][C:69]([C:72]2[CH:76]=C(C(OCC)=O)[O:74][N:73]=2)=[CH:68][CH:67]=1>>[CH3:38][CH:2]([CH3:1])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[O:74][N:73]=[C:72]([C:69]5[CH:70]=[CH:71][C:66]([C:65]([F:64])([F:82])[F:83])=[CH:67][CH:68]=5)[CH:76]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)no1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(-c5ccc(C(F)(F)F)cc5)no4)cc3)cc2C1=O
Yield: 62 %

Procedure:
The compound of example 619 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with ethyl 3-(4-(trifluoromethyl)phenyl)isoxazole-5-carboxylate.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.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.[C:54]([C:58]1[CH:63]=[CH:62][C:61](B(O)O)=[CH:60][CH:59]=1)([CH3:57])([CH3:56])[CH3:55]>C/C(/O)=C/C(C)=O.C=C.C=C.[Rh].O1CCOCC1.O>[C:54]([C:58]1[CH:63]=[CH:62][C:61]([CH:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]2)=[CH:60][CH:59]=1)([CH3:57])([CH3:56])[CH3:55]
Reactant: O=C1C=CCCC1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Rh]
Agent: C=C
Agent: CC(=O)/C=C(/C)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(C2CCCC(=O)C2)cc1
Temperature: 100 °C
Yield: 61.1 %

Procedure:
To a 40 mL microwave flask containing 10/1 dioxane/H2O (22 mL) was added cyclohexen-1-one (1.35 g, 14.0 mmol), acetylacetonatobis(ethylene)rhodium(I) (0.36 g, 1.40 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.88 g, 1.40 mmol) and 4-tert-butylphenylboronic acid (5.0 g, 28.0 mmol). The reaction mixture was heated in the microwave at 100° C. for 20 minutes. The material was poured into a separatory funnel and extracted with ethyl acetate (150 mL), washed with saturated aqueous NaHCO3 (75 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (20% EtOAc/hexanes) to afford the title compound (1.97 g, 61%) as a yellow oil. 1H NMR (CD3OD, 300 MHz) δ 1.30 (s, 9H), 1.68-2.17 (m, 4H), 2.32-2.38 (m, 3H), 2.64 (dt, J=1.01, 12.0 Hz, 1H), 2.91-3.01 (m, 1H), 7.11-7.20 (m, 2H), 7.31-7.36 (m, 2H); MS (DCI) m/z 248 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:34][CH2:35][CH3:36])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Li+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH2:34][CH2:35][CH3:36])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CCC)cccc1OCC(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CCC)cccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 45 (70 mg, 0.1395 mmol) and 279 μl of 1M lithium hydroxide was added to 2.0 ml of methanol, and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum and 2.0 ml of water was added, and the solution was acidified with 10% hydrochloric acid and then extracted three times with ethyl acetate. The extracts were combined and the solvent was removed under vacuum to give the product.
Reaction SMILES: F[B-](F)(F)F.[F:6]S(F)=[N+](CC)CC.F.F.F.C(N(CC)CC)C.[CH:24]1([C@@H:27]2[O:37][CH2:36][C:30]3=[N:31][O:32][C@@H:33]([CH2:34]O)[C@@H:29]3[CH2:28]2)[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:24]1([C@@H:27]2[O:37][CH2:36][C:30]3=[N:31][O:32][C@@H:33]([CH2:34][F:6])[C@@H:29]3[CH2:28]2)[CH2:26][CH2:25]1
Reactant: CC[N+](CC)=S(F)F
Reactant: OC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Agent: F
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(Difluoro-λ4-sulfanylidene)-N-ethylethanaminium tetrafluoroborate (XtalFluor-E, 766 mg, 3.35 mmol) was added to a solution of triethylamine trihydrofluoride (727 μL, 4.46 mmol) in dichloromethane (11 mL). rel-[(3R,3aR,5R)-5-Cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazol-3-yl]methanol (C37) (440 mg, 2.23 mmol) was added, and the reaction mixture was stirred for 2 hours at room temperature. Aqueous sodium bicarbonate solution was added, and the mixture was stirred for 15 minutes, then extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane) afforded the product as an oil. Yield: 180 mg, 0.904 mmol, 41%. 1H NMR (400 MHz, CDCl3) δ 4.63 (ddd, half of ABX pattern, J=47.4, 10.4, 3.5 Hz, 1H), 4.62 (br d, J=13.3 Hz, 1H), 4.54 (ddd, half of ABX pattern, J=46.7, 10.3, 4.2 Hz, 1H), 4.32 (dddd, J=20.2, 10.3, 3.9, 3.8 Hz, 1H), 4.10 (dd, J=13.4, 1.2 Hz, 1H), 3.28 (br ddd, J=11, 11, 6.5 Hz, 1H), 2.81 (ddd, J=11.0, 7.9, 1.9 Hz, 1H), 2.25 (ddd, J=12.8, 6.5, 1.7 Hz, 1H), 1.61-1.72 (m, 1H), 0.85-0.94 (m, 1H), 0.47-0.59 (m, 2H), 0.34-0.41 (m, 1H), 0.18-0.25 (m, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([F:32])([F:30])[F:31])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: O[C@@H](CNCC1CCN(CCC(F)(F)F)CC1)COc1cccc2[nH]c3ccccc3c12
Yield: 18.2 %

Procedure:
Prepared from 260 mg (1.09 mmol) of 4-[(2S)-oxiranylmethoxy]-9H-carbazole and 229 mg (1.09 mmol) of 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine according to the procedure used for Example 2 to give 0.089 g of the title compound as a white solid (Et2O, EtOAc/hexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([OH:36])(=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:15][O:16][C:17](=[O:36])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C@H:11]([CH2:13][O:14][C:17](=[O:36])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](CO)C1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1COC(=O)CCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound XIII-2 (351 mg, 71.7%) was obtained in the same manner as that in Reference Example 2, by using trans-3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.674 mmol) obtained by using the method described in WO2006/100036 and linoleic acid (Aldrich; 400 mg, 1.48 mmol)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c[nH]c23)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A154) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]2[CH:18]=[C:19]([CH:23]=[O:24])[N:20]([CH3:22])[CH:21]=2)=[O:16])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[K+].Cl.[Si](=O)=O.C(OCC)(=O)C>O.C1(C)C=CC=CC=1.C(O)(=O)C.C(O)C>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]2[CH:18]=[C:19]([CH:23]=[O:24])[N:20]([CH3:22])[CH:21]=2)=[O:16])=[CH:25][CH:26]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(OCCCCC(=O)c2cc(C=O)n(C)c2)cc1
Agent: Cl
Agent: O=[Si]=O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(C(=O)CCCCOc2ccc(C(=O)O)cc2)cc1C=O
Reaction time: 5 h

Procedure:
A mixture consisting of 17 (3.56 g, 0.01 mol), 2N potassium hydroxide and ethanol (95%; 35 ml) was stirred for 5 hrs. at 70° C. The resulting solution was diluted with water (70 ml), acidified with 12N hydrochloric acid, and extracted with ethyl acetate (3×20 ml). The collected organic extracts were washed with a saturated solution of sodium chloride to neutralization, dried on anhydrous sodium sulphate, and deprived of the solvent. A yellowish solid consisting of compound 18 was obtained (2.26 g; 69%). The product was found to be pure by thin-layer analysis (silicon dioxide-ethyl acetate:acetic acid 50:1). M.p. 181°-183° C. (via toluene). Anal. (C18H19NO5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11](/[CH:14]=[CH:15]/[N+:16]([O-])=O)=[CH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.Cl.CO>[Pd].C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH2:14][CH2:15][NH2:16])=[CH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])/C=C/c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1

Procedure:
2-(3,4-Dichlorophenyl)-5-((E)-2-nitrovinyl)furan (5.73 g, 20.2 mmol) was dissolved into the mixture of dry methanol (90 ml) and dry ethyl acetate (70 ml). Then, 14.3 ml of 10 w-% HCl-methanol and 2.4 g of 10% palladium on carbon were added. 2-(3,4-Dichlorophenyl)-5-((E)-2-nitrovinyl)furan was hydrogenated at 3 atm at RT for about 4 h. The catalyst was removed by filtrating through Celite®. Removal of solvent under reduced pressure gave a raw product which was purified by flash chromatography on silica gel using CH2Cl2/MeOH (98:2-80:20) as a gradient eluent. 1H NMR (400 MHz, DMSO-d6): 3.04 (2H, m), 3.14 (2H, m), 6.43 (1H, d), 7.07 (1H, d), 7.67 (2H, s), 7.93 (1H, s), 8.19 (3H, broad s).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:14]([CH3:25])[N:15]=[C:16]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:33]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:34]([NH2:36])=[O:35].O>CN(C)C=O>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([C:16]2[C:5]3[C:4]4[CH:3]=[C:2]([O:1][CH:33]([C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=5)[C:34]([NH2:36])=[O:35])[C:11]([O:12][CH3:13])=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:14]([CH3:25])[N:15]=2)=[CH:18][CH:19]=1)#[N:22]
Reactant: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1O
Reactant: NC(=O)C(Br)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OC(C(N)=O)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
4-(8-Hydroxy-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (97.7 mg, 296 μmol) is dissolved in N,N-dimethylformamide (3.7 ml). Potassium carbonate (102 mg, 738 μmol) and 2-bromo-2-(4-fluorophenyl)acetamide (170 mg, 733 μmol) are subsequently added. The reaction mixture is stirred at 120° C. for 18 h. When the reaction is complete, the mixture is poured into water (50 ml) and extracted three times with ethyl acetate (50 ml each time). The combined organic phases are dried over Na2SO4, filtered with suction and evaporated in vacuo. The residue is then suspended in a little 2-propanol, filtered off with suction and dried in a high vacuum, giving 2-[1-(4-cyanophenyl)-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yloxy]-2-(4-fluorophenyl)acetamide (68 mg, 141 μmol) as a solid having a melting point of 249.2° C. MS: 482.1 (M+H+), TLC (HPTLC): Rf=0.31 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10]1[O:11][C:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][N:14]=1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:21][N:22]([CH3:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:9][C:10]2[O:11][C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=2)[CH:4]=1)=[O:27]
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2cccnc2)o1
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1Nc1ncc(-c2cccnc2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-methyl-5-amino-phenyl)-(5-pyridin-3-yl-oxazol-2-yl)-amine (120 mg, 0.451 mmol) and 3-dimethylaminobenzoic acid (86 mg, 0.521 mmol) in DMF (6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (136 mg, 0.824 mmol), 1-hydroxybenzotriazole (84 mg, 0.622 mmol) and triethylamine (0.98 ml, 0.710 mmol). The mixture was stirred at room temperature for 4 h. After removal of the solvent, the residue was treated with saturated aqueous NaHCO3 (20 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated. 3-dimethylamino-N-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-benzamide was obtained after silica gel column chromatography (dichloromethane/ethanol:98/2) (113 mg, 58%) as yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]=[CH:17][C:18]([C:33]([F:36])([F:35])[F:34])([OH:32])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])([CH3:22])[CH3:21])[N:7]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO.O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:16][CH2:17][C:18]([C:33]([F:34])([F:35])[F:36])([OH:32])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])([CH3:22])[CH3:21])[N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(COC(C)=O)ccc12)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(COC(C)=O)ccc12)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution that consists of 170 mg (0.34 mmol) of 1-(2-(acetoxymethyl)quinolin-5-ylimino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol in 1.5 ml of methanol and 0.8 ml of tetrahydrofuran is mixed with 53 mg (1.38 mmol) of sodium borohydride. After 3 hours at room temperature, the reaction is halted by adding water. It is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried on sodium sulfate. After removal of the solvent and chromatography on silica gel with hexane-ethyl acetate (0-100%), 94 mg (55% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C@H:11]([CH3:24])[CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[C:7]([F:25])=[CH:6][C:3]=1[C:4]#[N:5]>C(O)C.O1CCCC1>[NH2:13][CH2:12][C@H:11]([NH:10][C:8]1[C:7]([F:25])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=1)[CH3:24]
Reactant: C[C@H](CN1C(=O)c2ccccc2C1=O)Nc1nc(Cl)c(C#N)cc1F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](CN)Nc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.9 %

Procedure:
Hydrazine•monohydrate (0.124 ml) was added to an ethanol/tetrahydrofuran (5 ml/1 ml) solution containing (R)-2-chloro-6-((1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)amino)-5-fluoronicotinonitrile (300 mg), followed by stirring at room temperature for 14 hours. Further, hydrazine•monohydrate (0.062 ml) was added, followed by stirring at room temperature for 8.5 hours. The solvent was distilled away under reduced pressure, chloroform was added, and insoluble matter was removed. Then, the solvent was distilled away under reduced pressure, and a yellow solid of (R)-6-((1-aminopropan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile (38 mg) was thus obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:16][N:17]([CH3:31])[C:18]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O)(=O)C>ClCCCl>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH:21]3[CH2:20][CH2:19][C:18]([N:17]([CH3:31])[CH3:16])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:22]3)[CH2:2][CH2:3]2)=[CH:8]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(N2CCC(c3c[nH]c4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-piperidine-4-yl-1H-indole (200 mg, 1 mmole) and 4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) were dissolved in dry 1,2-dichloroethane (20 ml). Glacial acetic acid (1 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which were separated by chromatography with methanol. The polar and the non-polar diastereoisomers were obtained in each case as a colourless oil in a yield of 90 mg (22%).