Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([Cl:11])[N:10]=[C:6]2[C:5]([C:12]([OH:14])=O)=[CH:4][C:3]=1Cl.[CH2:16]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([Cl:11])[N:10]=[C:6]2[C:5]([C:12]([NH:27][CH2:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Nc1c(Cl)cc(C(=O)O)c2nc(Cl)cn12
Reactant: CCCCN1CCC(CN)CC1
Product: CCCCN1CCC(CNC(=O)c2ccc(N)n3cc(Cl)nc23)CC1

Procedure:
The title compound was prepared according to the procedure described in the step 3 in EXAMPLE 5 using 5-amino-2-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 25, Step 3) and 1-(1-butyl-4-piperidinyl)methanamine (EXAMPLE 1, METHOD A, Step 5).
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:15][CH2:16][OH:17].N>C(O)(=O)C>[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][N:10]2[CH2:15][CH2:16][OH:17]
Reactant: OCCn1ccc2c(O)cccc21
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: OCCN1CCc2c(O)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
1.9 g of sodium cyanoborohydride were added to a solution of 8.85 g of 4-hydroxy-1-N-(β-hydroxyethyl)indole, obtained in the preceding stage, in 40 cm3 of acetic acid, the temperature being maintained below 30° C. After stirring for 30 minutes, the reaction mixture was poured onto 200 g of ice-cold water and the pH was neutralized to 7.5 by addition of 30% aqueous ammonia. The precipitate obtained was filtered off and dried. 7.75 g of 4-hydroxy-1-N-(β-hydroxyethyl)indoline were obtained, the melting point of which was 108° C. 13C. and proton nuclear magnetic resonance (N.M.R.) analysis of the product obtained was found to be in accordance with the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH:35]3[CH2:37][CH2:36]3)[N:7]=2)[CH:3]=1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH:35]3[CH2:37][CH2:36]3)[N:7]=2)[CH:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(C3CC3)nc12
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2cn(C3CC3)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(5-chloro-2-cyclopropyl-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (65 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (2 mL), cooled to 0° C., and treated with sodium cyanoborohydride (38.7 mg, 0.62 mmol) and formalin (0.45 mL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 16 mg (29%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.41 (m, 1H), 7.30-7.33 (m, 2H), 6.99-7.03 (m, 2H), 6.78 (m, 1H), 4.92 (q, J=6.4 Hz, 1H), 3.86-3.90 (m, 2H), 3.33-3.38 (m, 2H), 2.52-2.53 (m, 2H), 2.20 (s, 3H), 1.97-2.24(m, 6H), 1.41 (d, J=6.4 Hz, 3H), 1.25-1.28 (m, 2H), 1.13-1.17 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 161.3 (d, J=243.8 Hz), 145.4 135.2, 129.0, 128.9, 127.9, 122.3, 122.1, 117.0, 115.0, 114.9, 73.8, 52.1, 50.8, 46.4, 40.5, 34.7, 32.8, 22.8. Mass spec.: 442.44 (MH)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH3:10][O:11][C:12]1[CH:30]=[CH:29][C:15]([CH2:16][O:17][C:18](SC2N=C(C)C=C(C)N=2)=[O:19])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:30]=[CH:29][C:15]([CH2:16][O:17][C:18]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]2[C:7]([OH:9])=[O:8])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ccc(COC(=O)Sc2nc(C)cc(C)n2)cc1
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1

Procedure:
In the same manner as described in Reference Example 1-1 but using 10 g of trans-4-hydroxy-L-proline and 23.2 g of S-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine, trans-1-(p-methoxybenzyloxycarbonyl)-4-hydroxy-L-proline was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:11]([OH:13])=O.O[N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][C:34]([F:37])([F:36])[F:35])[NH2:26].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:9]=[C:10]([C:11]2[O:13][N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][C:34]([F:35])([F:36])[F:37])[N:24]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: Cc1cc(C(=O)O)ccc1N1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCCCC1

Procedure:
Oxalyl chloride (139 μL; 1.64 mmol; 3 eq.), Intermediate 33 (120 mg; 0.55 mmol; 1 eq.), Intermediate 2 (120 mg; 0.55 mmol, 1 eq.) and DIEA (2834; 1.64 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) afforded the title compound as a yellow oil.
Reaction SMILES: CO.Cl.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1.[F:14][C:15]([F:27])([F:26])[C:16](=O)[CH2:17][C:18]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=O.FC(F)(F)C(O)=O>C(O)(C)C.O>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:18]1[N:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=2)[N:13]=[C:16]([C:15]([F:14])([F:26])[F:27])[CH:17]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccco2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
Part A. In a flame-dried 1-L flask was combined anhydrous methyl alcohol (1.4 L), 4-methoxyphenylhydrazine hydrochloride (25 g, 140 mmol), 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (30 g, 140 mmol), and trifluoroacetic acid (1.1 mL, 14 mmol). The resulting red slurry was maintained at rt for 14 h. A 50% solution of isopropyl alcohol/water (500 mL) was then added, and the mixture was stirred vigorously for 5 min. The mixture was filtered; additional material precipitated from the filtrate upon standing, and the new mixture was filtered. After another 3 h, the resulting filtrate was filtered a third time, and the combined beige solid was oven dried under vacuum to afford 5-(2-furyl)-1-(4-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazole (42 g, 96%) as a light brown solid. 1H NMR (CDCl3) δ 7.42 (m, 1H), 7.35 (d, 2H), 6.98 (d, 2H), 6.89 (s, 1H), 6.33 (dd, 1H), 5.90 (d, 1H), 3.88 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][C:10]=2[NH2:11])=[CH:5][CH:4]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:24]=1[CH3:41].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:33][C:31]1[CH:30]=[C:29]([F:34])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:11][C:10]1[CH:12]=[C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:14]=[CH:15][C:9]=1[C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:24]([CH3:41])[C:25]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[N:26]2
Reactant: COc1ccc(-c2ccc(N3CCOCC3)cc2N)cn1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cn1
Temperature: 100 °C
Reaction time: 21 h

Procedure:
A mixture of 2-(6-methoxypyridin-3-yl)-5-morpholinoaniline (60.7 mg, 0.21 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (50.9 mg, 0.17 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (13.9 mg, 0.029 mmol), tris(dibenzylideneacetone)dipalladium (0) (6.5 mg, 7.10 μmol), and sodium tert-butoxide (43.3 mg, 0.45 mmol) in dry toluene (1.5 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 21 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (10-30% EtOAc in hexanes) to afford an impure orange residue. The light orange film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 5,7-difluoro-N-(2-(6-methoxypyridin-3-yl)-5-morpholinophenyl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (1H, ddd, J=4.8, 1.7, 1.0 Hz), 8.13 (1H, m), 7.99 (1H, td, J=7.7, 1.7 Hz), 7.78 (1H, dt, J=7.8, 1.0 Hz), 7.69 (2H, m), 7.55 (2H, m), 7.43 (1H, m), 7.06 (1H, d, J=8.4 Hz), 6.69 (1H, dd, J=8.4, 0.6 Hz), 6.66 (1H, m), 6.26 (1H, d, J=2.3 Hz), 3.80 (3H, s), 3.72 (4H, m), 3.05 (4H, m), 2.09 (3H, s). Mass Spectrum (pos.) m/e: 540.3 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1CSCCN1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(N2CCSCC2)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
In a 50 mL round-bottomed flask was charged 4-fluoro-2-methoxy-1-nitrobenzene (1.05 g, 6.14 mmol), thiomorpholine (1.164 ml, 12.27 mmol), and Hunig's Base (1.072 ml, 6.14 mmol) in acetonitrile (20.45 ml). The reaction was heated at 85° C. for three days. The mixture was concentrated and the residue was placed on a silica gel column. The product was eluted from the column with dichloromethane to give the title compound. MS (DCI(+)) m/e 255.1 (M+H)+.
Reaction SMILES: C([C:4]1[C:5]([C:24]([O-:26])=[O:25])=[C:6](C(C)C)[C:7]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([O-:11])=[O:10])(C)C.CO.[OH-].[K+]>O>[CH2:14]([S:13][C:7]1[CH:6]=[C:5]([C:24]([OH:26])=[O:25])[CH:4]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)c1cc(C(=O)[O-])c(SCc2ccccc2)c(C(C)C)c1C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)c(SCc2ccccc2)c1
Yield: 87 %

Procedure:
The diisopropyl-(benzylthio)-terephthalate obtained in Preparation 2 is refluxed with 500 ml. of methanol, 25 g. of potassium hydroxide and 50 ml. of water for 2 hours. The reaction mixture is then concentrated to a small volume, cooled, diluted with water and filtered through diatomaceous earth (Celite). The thus-obtained filtrate is acidified with 4N hydrochloric acid and the precipitate with forms is collected by filtraton and dried in an oven at 90°-100° C. to yield 45 g. (yield 87%) of (benzylthio)-terephthalic acid having a melting point of 299°-300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:6]=2[CH:19]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)oc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(=O)oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a mixture of tert-butyl (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetate (50 g) and dichloromethane (250 mL) was added TFA (67.4 mL), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then to the residue was added water. The resulting solid was collected by filtration and then washed with water to obtain (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid (38.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.C[O:20][C:21](=O)/[CH:22]=[C:23](\[NH:25][C:26](=O)[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=1)/[CH3:24]>C(Cl)Cl>[F:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[F:35])[O:28][CH2:27][C:26]1[N:5]([C:4]2[CH:6]=[CH:7][C:8]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[C:2]([F:1])[CH:3]=2)[C:21](=[O:20])[CH:22]=[C:23]([CH3:24])[N:25]=1
Reactant: COC(=O)/C=C(/C)NC(=O)COc1ccc(F)c(F)c1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(COc2ccc(F)c(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (0.39 g, 2.00 mmol) in DCM (15 mL) was added trimethylaluminium (3.5 mL, 7.0 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(2-(3,4-difluorophenoxy)acetamido)but-2-enoate (0.57 g, 2.00 mmol) in DCM (5 mL) was added slowly and the resulting mixture was stirred further at rt for 12 h. The mixture was then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale brown solid (0.50 g, 58%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][CH:15]2[O:30][C:18]3[CH:19]=[N:20][C:21]4[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([F:27])[C:26]=4[C:17]=3[CH2:16]2)[O:10][CH2:9]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C(O)=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[F:27][C:25]1[C:26]2[C:17]3[CH2:16][CH:15]([CH2:14][C@H:11]4[O:10][CH2:9][C@H:8]([NH:7][C:6]([C:40]5[CH:41]=[CH:42][C:36]6[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=6[CH:39]=5)=[O:5])[CH2:13][CH2:12]4)[O:30][C:18]=3[CH:19]=[N:20][C:21]=2[CH:22]=[CH:23][C:24]=1[O:28][CH3:29]
Reactant: COc1ccc2ncc3c(c2c1F)CC(C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1)O3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2c1F)CC(C[C@@H]1CC[C@@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CO1)O3

Procedure:
The titled compound is prepared as an off-white lyophilized powder following Scheme 3 and in analogy to Example 13 using (3R,6S)-[6-(9-fluoro-8-methoxy-1,2-dihydro-furo[2,3-c]quinolin-2-ylmethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting material.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13]2)[C:9]2[C:8](=[O:19])[N:7]([CH3:20])[CH:6]=[N:5][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)O1.C([O-])([O-])=O.[K+].[K+].CC(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[OH:18][CH2:17][C@H:14]1[CH2:15][CH2:16][N:12]([C:10]2[C:9]3[C:8](=[O:19])[N:7]([CH3:20])[CH:6]=[N:5][C:4]=3[CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[CH:33][CH:34]=3)[N:11]=2)[CH2:13]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
Reactant: Cn1cnc2cc(Cl)nc(N3CC[C@H](CO)C3)c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(N3CC[C@H](CO)C3)c2c1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-7-chloro-5-(3-(hydroxymethyl)pyrrolidin-1-yl)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (26 mg, 0.088 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (28 mg, 0.097 mmol), Pd(PPh3)4 (10.2 mg, 0.0088 mmol), K2CO3 (36 mg, 0.26 mmol), 2-propanol (3 mL) and H2O (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature and worked-up. The residue was purified on slilica gel flash column chromatography (eluent: 0-10% methanol in dichloromethane) to afford (S)-5-(3-(hydroxymethyl)pyrrolidin-1-yl)-3-methyl-7-(4-morpholinophenyl)pyrido[4,3-d]pyrimidin-4(3H)-one as a slightly yellow solid. 1H NMR (CDCl3) δ (ppm) 8.06 (d, 2H), 8.01 (s, 1H), 7.19 (s, 1H), 6.96 (d, 2H), 3.91-3.81 (m, 5H), 3.78-3.65 (m, 4H), 3.65-3.58 (m, 1H), 3.50 (s, 3H), 3.27-3.24 (m, 4H), 2.57-2.47 (m, 1H), 2.15-2.07 (m, 1H), 1.90 (s, br, 1H), 1.82-1.72 (m, 1H); HPLC-MS calculated C23H27N5O3 (M+H+): 422.22, found: 422.20.
Reaction SMILES: [H-].[Na+].C(OC([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH2:12][CH2:11]1)=O)(C)(C)C.CI.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>CN(C=O)C.C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH2:26]([N:16]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:36])[CH:21]=[CH:20]2)[CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)c2ccc3[nH]ccc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc2cc(N(Cc3ccccc3)C3CCNCC3)ccc21
Reaction time: 1 h
Yield: 71.7 %

Procedure:
NaH (60% in mineral oil, 30 mg, 0.74 mmol) was added to a solution of 4-[benzyl-(1H-indol-5-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.37 mmol) in DMF (1.0 mL). The reaction mixture was stirred for 1 hour and then methyliodide (0.06 mL, 0.93 mmol) was added. The resulting mixture was stirred for 2 hours and it was then quenched by addition of a saturated aqueous solution of NH4Cl. The organic layer was separated and the aqueous layer was extracted twice with EtOAc (20 mL); the combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered and evaporated under reduced pressure to give a yellow foam. This residue was dissolved in DCM (5 mL) and trifluoroacetic acid (0.29 mL, 3.7 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours; it was then evaporated under reduced pressure and the residue was purified by flash chromatography (0% to 20% of MeOH in DCM) to give 115 mg (97% yield) of benzyl-(1-methyl-1H-indol-5-yl)-piperidin-4-yl-amine trifluoroacetate, MS=320 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[CH:18]=[CH:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:24])[CH2:8][CH2:7]2)(=O)C.[OH-].[K+]>CO>[OH:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[CH:18]=[CH:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:24])[CH2:8][CH2:7]2
Reactant: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(CO)[C@H]1CC2

Procedure:
19-Acetoxyandrosta-4,16-dien-3-one (17) is treated with potassium hydroxide in methanol (i). Aqueous work-up is followed by extraction and purification to yield the alcohol (18).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:15])[CH:7]=1>C(Cl)Cl.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:15])[CH:7]=1
Reactant: COC(=O)C=Cc1cc(C)c(C=O)c(C)c1
Agent: [Pd]
Solvent: ClCCl
Product: COC(=O)CCc1cc(C)c(C=O)c(C)c1

Procedure:
A mixture of 3-(4-formyl-3,5-dimethylphenyl)-acrylic acid methyl ester (900 mg, 4.1 mmol) and 10% Pd/C (90 mg) in CH2Cl2 (20 mL) was hydrogenated at one atm overnight. The catalyst was filtered through Celite and washed with CH2Cl2. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (heptane/EtOAc=5:1) to give the title compound. MS: m/z 221 (M+1).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])C.Cl.C(Cl)Cl>CCO.[OH-].[Na+]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)=[O:20])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Yield: 101.8 %

Procedure:
1-(4-Fluoro-benzoyl)-piperidine-3-carboxylic acid ethyl ester (1.15 g, 4.42 mmol) was added in a mixture of EtOH/NaOH 3N:1/1 (8 ml) and the resulting heterogeneous solution was stirred at R.T for 1 h. Fuming HCl was added to the mixture until pH=1. The solution was poured with DCM. The organic layer was separated and the aqueous phase was extracted twice with DCM. The combined organic phase was washed twice with water. The solution was dried over Na2SO4, filtered and concentrated to afford 1.13 g (100%) of 1-(4-Fluoro-benzoyl)-piperidine-3-carboxylic acid as an orange oil which can be used without further purification.
Reaction SMILES: ClC(OCC)=O.[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=1[NH2:38]>C(Cl)(Cl)Cl>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([C:24]([NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[O:35][CH3:34])=[O:26])[CH2:22][CH2:23]1
Reactant: O=C(O)C1CCN(CC2COc3ccccc3O2)CC1
Reactant: COc1ccccc1N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)C1CCN(CC2COc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.4 %

Procedure:
Ethyl chloroformate (0.1 g) was added dropwise to a stirred solution of 1-(1,4-benzodioxan-2-ylmethyl)piperidine-4-carboxylic acid (0.28 g) and triethylamine (0.12 g) in chloroform (10 ml) at 0° C. After 30 minutes a solution of 2-methoxyaniline (0.12 g) in chloroform (5 ml) was added and the mixture stirred at ambient temperature for 16 hours. The reaction mixture was then washed sequentially with water, aqueous sodium hydroxide solution (1M), hydrochloric acid (1M) and water. The solution was dried over magnesium sulphate, the solvent was removed in vacuo, and the residue was eluted through a silica column using a 1:1 mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluant. The solvent was removed in vacuo to yield 1-(1,4-benzodioxan-2-ylmethyl)-N-(2-methoxyphenyl)piperidine-4-carboxamide as a solid (50 mg). This procedure was repeated on 9X scale with the following changes. The reaction was heated to 50° C. for 1 hour after being stirred at ambient temperature for 16 hours. The solvent was then removed in vacuo and the residue was eluted through a silica column as previously described. Further desired product (1.05 g) was obtained.