Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8]C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:22]([NH:24][CH2:25][C@@H:26]([C:48]([OH:50])=[O:49])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:45]([OH:47])=[O:46])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:23])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=O)C1C=CC=CC=1.O>C(OCC)(=O)C.[Pd]>[OH2:8].[C:48]([C@H:26]([CH2:25][NH:24][C:22](=[O:23])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:45]([OH:47])=[O:46])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:50])=[O:49]
Reactant: CS(=O)(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)CCCC1)C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N[C@@H](CCCCN)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
A solution of (S,S,S)-N-(1-[3-(N6-benzyloxycarbonyl-N2-mesyllysylamino)-2-carboxypropyl]-1-cyclopentylcarbonyl)tyrosine (see Preparation 9) (351 g) in ethyl acetate (1300 ml) was added to water (385 ml) and the two phase mixture hydrogenated at 414 kPa (60 psi) and room temperature over a 5% palladium-on-carbon catalyst (35 g) for 20 hours. The catalyst was filtered off, the aqueous phase separated and concentrated to low volume under reduced pressure. The viscous solution was poured into methanol (2.85 l) and stirred at room temperature for 18 hours during which time there was a slow precipitation of a solid. The solid was granulated at 5-10° C. for 2 hours, filtered, washed with methanol and dried to give the title compound as a white solid (178.1 g), m.p. 168-171° C. Found: C,51.37; H,7.47; N,9.06. C26H40N4O9S.χH2O (where χ=1) requires: C,51.81; H,7.02; N,9.30%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[C:25]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C:20]=3[NH:19][N:18]=2)=[O:16])[CH2:11][CH2:10]1.Cl>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[C:25]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[NH:19][N:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(F)ccc4Cl)CC3)n[nH]c2C1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2cc(F)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 179.5 %

Procedure:
To a solution of tert-butyl 3-(4-(2-chloro-5-fluorophenyl) piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (47, 57 mg, 0.12 mmol) in CH2Cl2 (2 mL) was added HCl (2N in Et2O, 2 mL). The mixture stirred for 18 h at ambient temperature. The reaction mixture was concentrated under reduced pressure to yield (4-(2-chloro-5-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (48) as a white solid (43 mg, 87%): 1H NMR (300 MHz, DMSO-d6) δ 9.42 (br s, 2H), 7.49 (dd, J=8.7, 5.4 Hz, 1H), 7.28 (dd, J=10.2, 3.0 Hz, 1H), 7.16-7.07 (m, 1H), 4.71-4.43 (m, 2H), 4.32-4.23 (m, 2H), 3.38-3.14 (m, 4H, overlaps with H2O), 2.91-2.72 (m, 3H), 1.89-1.73 (m, 2H), 1.69-1.50 (m, 2H), missing N—H pyrazole; ESI MS m/z 363 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][CH2:38][O:39][C:40]1[CH:46]=[C:45]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([CH:47]4[CH2:48][CH2:49][N:50]([CH2:53][CH2:54][CH3:55])[CH2:51][CH2:52]4)=[CH:46][C:40]=3[O:39][CH2:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCCN1CCC(c2ccc(N)c(OCC)c2)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5ccc(OCC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 130 °C
Yield: 62.2 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(2-ethyloxy)-4-(1-propyl-4-piperidinyl)aniline (Example 154, step E) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (82 mg, 0.112 mmol, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.32 (d, J=6.78 Hz, 1H), 8.40 (s, 1H), 8.26 (d, J=5.13 Hz, 1H), 8.05 (d, J=2.01 Hz, 1H), 7.72 (dd, J=8.70, 2.11 Hz, 1H), 7.64-7.71 (m, 2H), 7.40-7.45 (m, 1H), 7.32-7.40 (m, 1H), 7.24 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.91-6.97 (m, 2H), 6.76 (dd, J=8.24, 1.47 Hz, 1H), 6.61 (d, J=5.13 Hz, 1H), 4.24 (q, J=6.71 Hz, 2H), 4.08 (q, J=6.96 Hz, 2H), 2.93 (d, J=10.80 Hz, 2H), 2.38-2.45 (m, J=4.03 Hz, 1H), 2.16-2.27 (m, 2H), 1.91 (d, J=9.71 Hz, 2H), 1.67-1.75 (m, 2H), 1.64 (dd, J=12.00, 2.84 Hz, 2H), 1.38-1.46 (m, 5H), 1.26 (t, J=6.87 Hz, 3H), 0.84 (t, J=7.33 Hz, 3H). MS (ESI): 732 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:37])[NH:6][C:7]2[CH:35]=[CH:34][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH2:26][CH2:25][N:24](C(OCCCC)=O)[CH2:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:36])[CH:8]=2)[CH2:3][CH2:2]1.[ClH:38].CCOC(C)=O>CCOC(C)=O>[ClH:38].[ClH:38].[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:35]=[CH:34][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:36])[CH:8]=2)=[O:37])[CH2:3][CH2:2]1
Reactant: CCCCOC(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1)NC1CC1
Reaction time: 18 h
Yield: 101.8 %

Procedure:
To a suspension of 270 (996 mg, 1.90 mmol) in EtOAc (20 mL) was added 1N HCl-EtOAc (11.4 mL, 11.4 mmol). The reaction mixture was stirred for 18 hours, the precipitate was collected by filtration, washed with EtOAc (30 mL) and dried to afford title compound 271 (962 mg, 100% yield) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 9.22 (br, 2H), 9.03 (s, 1H), 8.58 (d, J=6.0 Hz, 1H), 7.74 (dd, J=13.5, 2.7 Hz, 1H), 7.70 (s, 1H), 7.38 (t, =9.0 Hz, 1H), 7.25-7.15 (m, 1H), 6.77 (d, J=6.0 Hz, 1H), 6.72 (s, 1H), 6.47 (s, 1H), 4.80-4.30 (br, 1H), 3.85-3.75 (m, 2H), 3.42-3.31 (m, 2H), 2.90-2.80 (m, 2H), 2.60-2.40 (m, 1H), 0.70-0.60 (m, 2H), 0.48-0.35 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:40]([O:43][CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:75])[C@H:49]([N:57]([C:59](=[O:74])[C@H:60]([NH:72][CH3:73])[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[CH3:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:42])[CH3:41].C(N(C(C)C)CC)(C)C>ClCCl>[C:40]([O:43][CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:75])[C@H:49]([N:57]([C:59](=[O:74])[C@H:60]([N:72]([C:13](=[O:15])[CH2:12][O:11][CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:17])[CH3:16])[CH3:73])[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[CH3:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)(=[O:42])[CH3:41]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCCCOC(C)=O
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a solution of (2-t-butoxycarbonylamino-2-methylpropoxy) acetic acid (504 mg, 2.0 mmol) in dichloromethane (10 ml) were added 1-hydroxy-7-azabenzotriazole (278 mg, 2.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (429 mg, 2.3 mmol) and the mixture was stirred for 30 min. 3-((2R)-2-(N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-propyl acetate (500 mg, 1.0 mmol) in dichloromethane (10 mL) was added followed by diisopropylethylamine (0.23 ml, 1.32 mmol) and the mixture was stirred overnight at room temperature. The mixture was washed with water (10 ml), aqueous sodium bicarbonate (10 ml), water (2×10 ml), brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (60 g) with ethyl acetate/heptane 4:1 to give 623 mg of 3-((2R)-2-(N-((2R)-2-(N-((2-(tert-butoxycarbonylamino)-2-methylpropoxy) acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate as an oil. The obtained product was taken up in 50% trifluoroacetic acid in dichloromethane (3 ml) and stirred for 10 min. Then saturated sodium bicarbonate was added until pH 8 and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The product was redissolved in water (30 ml) and the mixture was liophilized to give 434 mg of the title compound as an amorphous powder.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[OH-].[Na+].[O:12]1[C@H:14]2[CH2:15][C@H:16]3[C@:29]([CH3:31])([CH2:30][C@@H:13]12)[C@@H:28]1[C@H:19]([C@H:20]2[C@@:24]([CH2:26][C:27]1=[O:32])([CH3:25])[C@@H:23]([C:33]#[N:34])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3.O>C(O)CO>[OH:12][C@@H:14]1[C@@H:13]([N:5]2[CH2:6][CH2:7][O:8][C:3]([CH3:9])([CH3:2])[CH2:4]2)[CH2:30][C@@:29]2([CH3:31])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[C:27](=[O:32])[CH2:26][C@@:24]2([CH3:25])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:33]#[N:34])[CH2:15]1
Reactant: CC1(C)CNCCO1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C#N)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
2,2-Dimethylmorpholine hydrochloride (9.67 g) and sodium hydroxide (2.55 g) were added to a mixture (4:1) of (2α,3α,5α,17β)-2,3-epoxyandrostan-11-one-17-carbonitrile and its 3α,4α-epoxy isomer (5.0 g) (British patent 1,434,919) in 1,2-ethanediol (50 ml) and the mixture was heated in an atmosphere of nitrogen at 120° C. for 19 h and then at 150° C. for 4.5 h. The reaction mixture was poured into water (500 ml) and the precipitated solid was filtered off and dissolved in dichloromethane. After washing the solution with water and drying over sodium sulfate, the solvent was removed under reduced pressure and the residue (6.9 g) was chromatographed on silica gel. The purified product (4.3 g) was sequentially crystallised from ethanol and acetone-diethyl ether to give (2β,3α,5α,17β)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)androstan-11-one-17-carbonitrile (2.37 g). m.p. 206°-210° C.; [α]D +122.9° (c 0.8).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[CH:5]=1.[OH-].[Li+]>O1CCOCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][C:6]=1[O:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(Br)c(OCCc2cccc(C)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cccc(CCOc2cc(C(=O)O)ccc2Br)c1
Yield: 86.4 %

Procedure:
The compound of step 1 (0.50 g, 1.43 mmol) was dissolved in dioxane (5 ml), lithium hydroxide (7.1 ml of an aqueous 1 M (i.e. 1 mol per liter) solution) was added, and the mixture was reacted overnight. The mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase extracted with EA, and the organic extracts were dried over sodium sulfate, filtered and evaporated to dryness in vacuo to give 0.414 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15][N:16](C)C)[C:10]([O:12]CC)=O)=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[CH2:21]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([NH:36]N)=[N:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:10]([OH:12])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[O:19][CH3:20])[CH:15]=[N:16]2)=[N:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1OC
Product: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCc3ccccc3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 188 using ethyl 2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate and N-benzyl-6-hydrazinylnicotinamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.97 (s, 3 H) 4.53 (d, J=5.6 Hz, 2 H) 7.27 (d, J=3.8 Hz, 1 H) 7.36 (d, J=4.0 Hz, 5 H) 7.42-7.59 (m, 2 H) 8.47 (d, J=6.6 Hz, 1 H) 8.98 (s, 1 H) 9.28 (br. s., 1 H). MS m/z [M+H]+ 426.4.
Reaction SMILES: [Cl:1][C:2]1[C:20]([O:21]COC)=[CH:19][CH:18]=[C:17]([Cl:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.Cl>CO>[Cl:1][C:2]1[C:20]([OH:21])=[CH:19][CH:18]=[C:17]([Cl:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: COCOc1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: Cl
Solvent: CO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(O)c3Cl)c2n1
Reaction time: 0.08 h
Yield: 52.9 %

Procedure:
To a solution of 8-[2,6-dichloro-3-(methoxymethoxy)benzyloxy]-2-methylquinoline (1.57 g) in methanol was dropwise added conc. hydrochloric acid (2.7 ml) at 0° C., and the mixture was stirred for 5 minutes. The solvent was removed, and water was added thereto. The mixture was neutralized with saturated sodium bicarbonate solution, and the resulting participates were collected by filtration to give 8-(2,6-dichloro-3-hydroxybenzyloxy)-2-methylquinoline (734 mg) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH2:15])[CH2:4][CH2:3]1.[NH2:16][C:17]1[C:18]([CH3:27])=[CH:19][C:20]([F:26])=[C:21]([CH:25]=1)[C:22](O)=[O:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:16][C:17]1[C:18]([CH3:27])=[CH:19][C:20]([F:26])=[C:21]([CH:25]=1)[C:22]([NH:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:23]
Reactant: Cc1cc(F)c(C(=O)O)cc1N
Reactant: CN1CCN(c2ccccc2CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(F)c(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture comprising (2-(4-methylpiperazin-1-yl)phenyl)methanamine (413 mg, 2.010 mmol) and 5-amino-2-fluoro-4-methylbenzoic acid (step 2) (340 mg, 2.010 mmol) in DMF (3 ml) was treated with DIPEA (0.351 ml, 2.010 mmol) followed by HATU (764 mg, 2.010 mmol) and stirred at 25° C. for 24 hrs. The mixture was partitioned between water and EtOAc. The organic portion was washed with sat. aq. NaHCO3, 0.5 M LiCl and brine (each back extracted with EtOAc). The combined organic layers were dried (MgSO4), filtered and evaporated to dryness to give a pink oil. Purification by chromatography on silica eluting with 0-20% MeOH in DCM afforded the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.CN(C1C=CC=CN=1)C.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:26]([O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CN2CCC(O)CC2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCC(OC(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.4 %

Procedure:
0.52 g (0.0023 mol) of 1-(4-methoxy-benzyl)-piperidin-4-ol was dissolved in 25 ml of dimethylformamide and treated with 0.14 g (0.0012 mol) of dimethylaminopyridine and 0.28 g (0.0023 mol) of benzoic acid. The mixture was cooled to 0° and 0.490 g (0.0025 mol) of N-ethyl-N'-(3-dimethylamino-propyl)-carbodiimide hydrochloride was added. The mixture was warmed to room temperature and stirred for 18 hrs. The solvent was distilled off and the residue was taken up in ethyl acetate and treated with silica gel. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:3→1:2) as the eluent. 0.16 g (21%) of 1-(4-methoxy-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil. MS: me/e=326 (C20H24 NO3+).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:19][C:20]([O:22]CC)=[O:21])[C:13]=3[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:25][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:19][C:20]([OH:22])=[O:21])[C:13]=3[CH:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1cccc2c(-c3ccc(N(C)C)cc3)nccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1ccc(-c2nccc3c(CC(=O)O)cccc23)cc1
Yield: 76.4 %

Procedure:
Ethyl 1-(4-dimethylaminophenyl)isoquinoline-5-acetate (0.5 g) was heated for 1.5 hours with 40 ml of ethanol and 4 ml of a 5 N aqueous solution of sodium hydroxide. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and it was treated with activated carbon. Acetic acid was added to acidify the treated residue. Yellow crystals which precipitated were collected by filtration, dried, and then recrystallized from tetrahydrofuran-acetone to afford 0.35 g of 1-(4-dimethylaminophenyl)isoquinoline-5-acetic acid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([O:12][C:13]2[C:14]([C:19](=[O:21])[CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]2[C:4](=[C:5]([F:22])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23][Mg]Cl.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:22][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[C:11]([O:12][C:13]1[C:14]([C:19]([OH:21])([CH3:23])[CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:10]2
Reactant: CC(=O)c1ncccc1Oc1cc2cccc(F)c2nc1C
Reactant: C[Mg]Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2c(F)cccc2cc1Oc1cccnc1C(C)(C)O
Reaction time: 3 h

Procedure:
1.58 g of 1-[3-(2-methyl-8-fluoroquinolin-3-yloxy)-pyridin-2-yl]-ethanone were dissolved in 20 ml of dehydrated tetrahydrofuran. 2.7 ml of a 3 M tetrahydrofuran solution of methylmagnesium chloride were dropped therein while cooling with ice followed by stirring the reaction solution for 3 hours while continuing to cool with ice. Subsequently, the reaction solution was added to 1 N hydrochloric acid solution followed by neutralizing with aqueous sodium bicarbonate and then extracting with ethyl acetate. The extract was washed with saturated saline and dried with magnesium sulfate followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.69 g of 2-[(8-fluoro-2-methylquinolin-3-yloxy)pyridin-2-yl]propan-2-ol.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:4].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[NH:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[C:48]([C:58]([F:61])([F:60])[F:59])[CH:47]=1)=[NH:45]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:15]2[O:17][N:45]=[C:44]([C:46]3[CH:51]=[CH:50][C:49]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[C:48]([C:58]([F:59])([F:60])[F:61])[CH:47]=3)[N:43]=2)=[CH:18][CH:19]=1)(=[O:9])=[O:10]
Reactant: N=C(NO)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Reactant: COC(=O)CCNS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)CCNS(=O)(=O)c1ccc(-c2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)no2)cc1
Reaction time: 16 h

Procedure:
4-(2-Methoxycarbonyl-ethylsulfamoyl)-benzoic acid (1 eq) is dissolved in DMF and EDC.HCl (1.3 eq) and HOBt (1.1 eq) are added. After 30 minutes at room temperature N-hydroxy-2-trifluoromethyl-biphenyl-4-carboxamidine (1 eq) is added and the reaction mixture is kept at 90° C. for 16 hours. After removal of the solvent the residue is dissolved in ethyl acetate and extracted with saturated NaHCO3 solution. Title compound is obtained after drying of the organic phase over Na2SO4 on silica gel using c-hexane/ethyl acetate/CH2Cl2 8/2/1 as mobile phase.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:5]([C:6](NC2C=CC=C3C=2N=CC=C3)=[O:7])=[C:4]([CH2:23][CH3:24])[CH:3]=1.S(=O)(=O)(O)[OH:26]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:23][CH3:24])[C:5]([C:6]([OH:7])=[O:26])=[C:19]([CH2:21][CH3:22])[CH:20]=1
Reactant: O=S(=O)(O)O
Reactant: CCc1cc(Br)cc(CC)c1C(=O)Nc1cccc2cccnc12
Product: CCc1cc(Br)cc(CC)c1C(=O)O
Temperature: 120 °C
Yield: 56 %

Procedure:
A mixture of 4-bromo-2,6-diethyl-N-quinolin-8-yl-benzamide (2.9 g, 7.6 mmol) in 40% sulphuric acid (15 ml) is heated at 120° C. for 16 h. After completion, the reaction mixture is extracted with ether (2×100 ml) and the combined organic layers are dried over sodium sulfate and concentrated to obtain 4-bromo-2,6-diethyl-benzoic acid (1.1 g, 4.28 mmol, 56%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)[CH:18]=3)[O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:42][O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:42][O:43][CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][O:45]4)=[O:27])[CH:18]=3)[O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
TEA (0.271 ml, 1.95 mmol) was added to solution of (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid (484 mg, 1.29 mmol) in DCM (10 ml). The mixture was cooled down to 0° C., and EDC (372 mg, 1.95 mmol) and HOBt (263 mg, 1.95 mmol) were added. The mixture was stirred at 0° C. for 3 h, then NH2OTHP (182 mg, 1.56 mmol) was added and the mixture was stirred at RT overnight. The solution was washed with aqueous 5% NaHCO3 solution and brine. The organic layer was then dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (499 mg) as a light yellow solid.