Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]=23)=[CH:4][C:3]=1[O:22][CH3:23].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31]>>[CH:18]1([C:10]2[N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[C:12]3=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[C:3]([O:22][CH3:23])[CH:4]=3)[N:9]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: Oc1ccccc1F
Reactant: COc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Br
Product: COc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Oc1ccccc1F

Procedure:
Prepared according to a procedure analogous to that described for synthesis of Example 171, except using 1-(4-bromo-3-methoxy-phenyl)-3-cyclobutyl-imidazo[1,5-a]pyrazin-8-ylamine and 2-fluoro-phenol. 1H NMR (400 MHz, CDCl3): δ=2.01-2.11 (m, 1H), 2.14-2.25 (m, 1H), 2.46-2.55 (m, 2H), 2.59-2.71 (m, 2H), 3.83 (t, J=8.6 Hz, 1H), 3.95 (s, 3H), 6.95-7.04 (m, 3H), 7.07-7.22 (m, 5H), 7.33 (d, J=2.0 Hz, 1H). MS (ES+): m/z 404.94 (100) [MH+].
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23][N:22]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.CO.Cl.[OH-].[Na+]>C(Cl)Cl.O1CCOCC1>[NH2:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23][N:22]4[C:32]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)c1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Intermediate Example Int-4 (0.96 g, 1.87 mmol) in DCM (12.0 mL) and methanol (7.6 mL) was added a solution of 4 M hydrochloric acid in dioxane (9.4 mL) and the mixture was stirred for 2 hours at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. The reaction was repeated using 2.5 g of the carbamate and the crude product from both reactions were combined. Purification was achieved by chromatography on silica (gradient elution: 95:5 DCM:ethanol to 8:2 DCM:ethanol) to give two fractions of the title compound (0.8 g, 88% purity & 1.6 g, 93% purity).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1.O1CCOCC1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]([CH:47]=[O:48])[S:45][CH:46]=2)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH:47]([C:44]1[S:45][CH:46]=[C:42]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH:43]=1)=[O:48]
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: O
Solvent: C1COCCO1
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Temperature: 150 °C
Yield: 60.7 %

Procedure:
To 5-bromo-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (170 mg, 0.37 mmol) in mixture of dioxane (4.5 mL) and water (1.5 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (265.2 mg, 1.11 mmol), potassium carbonate (309 mg, 2.22 mmol) and Pd(PPh3)4 (44.2 mg, 0.04 mmol) were added. The reaction mixture was heated by microwave at 150° C. for 20 minutes. Then all the solvent was evaporated. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The water layer was extracted with ethyl acetate (2×50 mL). The combined organic phase washed with brine (50 mL) and dried with Mg2SO4 and concentrated. The crude product was purified by Combiflash (dichloromethane/methanol, 1%-40% methanol, 25 min.) to give title compound (110 mg, 61%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:6]([N+:19]([O-])=O)=[CH:7][C:8]([N+:16]([O-])=O)=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H][H]>[Ni].CCO>[NH2:16][C:8]1[CH:7]=[C:6]2[C:5]([CH:4]=[CH:3][NH:19]2)=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(/C=C/N(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cc2cc[nH]c2cc1N
Yield: 29.4 %

Procedure:
A mixture of (E)-ethyl 5-(2-(dimethylamino)vinyl)-2,4-dinitrobenzoate (15 g, 0.050 mol) and Raney Nickel (5 g) in EtOH (500 mL) was hydrogenated at room temperature under 50 psi of hydrogen for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-5-carboxylate (3.0 g, 30%). 1H NMR (DMSO-d6) δ 10.68 (s, 1H), 7.99 (s, 1H), 7.01-7.06 (m, 1H), 6.62 (s, 1H), 6.27-6.28 (m, 1H), 6.16 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 1.32-1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:10]([CH:21]=[O:22])=[CH:9]2>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:10]([CH2:21][OH:22])=[CH:9]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2cccc(Cl)c2nc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium borohydride (0.159 g, 4.20 mmol) was added portion wise to a stirring solution of 8-chloro-2-(2-fluorophenyl)quinoline-3-carbaldehyde (0.800 g, 2.80 mmol) in 15 mL of THF. The reaction stirred at room temperature. After 1.5 h, the mixture was partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure: LC-MS (ESI) m/z 288.1 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16]/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25](=[O:35])[C:26]2[C:31]([OH:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=2)[C:10](=[O:36])[O:9][C@H:8]1[CH3:37])(=[O:5])[CH:2]([CH3:4])[CH3:3]>CCOC(C)=O.[Pd]>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25](=[O:35])[C:26]2[C:31]([OH:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=2)[C:10](=[O:36])[O:9][C@H:8]1[CH3:37])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCC/C=C/C[C@H]1C(=O)OC[C@H](NC(=O)c2nccc(OC)c2O)C(=O)O[C@@H](C)[C@@H]1OC(=O)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCC[C@H]1C(=O)OC[C@H](NC(=O)c2nccc(OC)c2O)C(=O)O[C@@H](C)[C@@H]1OC(=O)C(C)C
Yield: 100 %

Procedure:
(3S,6S,7R,8R)-8-((E)-hept-2-enyl)-3-(3-hydroxy-4-methoxypicolinamido)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (163 mg, 0.31 mmol) was dissolved in EtOAc (15 mL) and passed through an H-Cube® Continuous Flow hydrogenator equipped with a 10% Pd/C cartridge (full H2, 80° C., 1 mL/min flow rate). The resulting solution was concentrated in vacuo to give the title compound (162 mg, 99%) as a white solid: mp 131-134° C.; IR (neat) 3341, 1739, 1654, 1141 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.81 (s, 1H), 8.66 (d, J=8.1 Hz, 1H), 8.01 (d, J=5.2 Hz, 1H), 6.89 (d, J=5.2 Hz, 1H), 5.19 (m, 1H), 5.14-5.02 (m, 1H), 5.02-4.87 (m, 1H), 3.95 (s, 3H), 3.87-3.69 (m, 1H), 2.70-2.52 (m, 2H), 1.80-1.66 (m, 1H), 1.43-1.08 (m, 21H), 0.86 (t, J=6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.59, 172.71, 169.77, 169.00, 155.47, 148.87, 140.74, 129.98, 109.74, 75.20, 74.94, 65.12, 56.16, 50.07, 34.13, 31.70, 29.25, 28.98, 28.40, 27.09, 22.62, 18.98, 18.97, 17.82, 14.08; ESIMS m/z 523.4 ([M+H]+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]O.Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:15]2[C:14](=[CH:13][CH:12]=[C:11]([F:10])[CH:16]=2)[NH:17][CH:7]=1
Reactant: NNc1ccc(F)cc1
Reactant: OCCCCCCCl
Agent: Cl
Product: Fc1ccc2[nH]cc(CCCCCl)c2c1

Procedure:
from 6-chlorohexan-1-ol and 4-fluorophenylhydrazine hydrochloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5](N(OC)C)=[O:6].[CH3:14][Mg]Br>C1COCC1>[C:5]([C:4]1[CH:11]=[CH:12][N:13]=[C:2]([Cl:1])[CH:3]=1)(=[O:6])[CH3:14]
Reactant: CON(C)C(=O)c1ccnc(Cl)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccnc(Cl)c1
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a solution of 2-chloro-N-methoxy-N-methyl-isonicotinamide (20 g, 100 mmol) in THF (100 mL) is added a solution of methyl magnesium bromide (3M in THF, 73 mL, 220 mmol) at −40° C. After stirring the mixture for 2 hours at this temperature, the mixture is quenched with ice-cooled saturated ammonium chloride solution (300 mL). The organic phase is separated. The aqueous layer is extracted with ethyl acetate (2×150 mL). The combined organic layers are washed with brine and dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-acetyl-2-chloro-pyridine (14.4 g), which is used for the next reaction without further purification; ESI-MS (m/z): 156.0 (M++H).
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[N:15]1([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13][NH:12][CH2:17][CH2:16]1
Reactant: c1ccc(CN2CCN(c3nccc4ccccc34)CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc2c(N3CCNCC3)nccc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Ammonium formate (1.01 g, 16.0 mmol) and 10% Pd/C 42.5 mg, 0.4 mmol, 10 mol%) were added successively to a stirred solution of the product of Example 21 (1.23 g, 4.06 mmol) in methanol (4 ml). The mixture was stirred at room temperature for 6 h and was heated at 75° C. for 16 h. Methanol (40 ml) was added and the mixture filtered through Kieselguhr, and concentrated in vacuo to give the product as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Br)(=O)C([Br:49])=O.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C@@H:10]1[Br:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Br)C(=O)Br
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Br[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 95.9 %

Procedure:
2,3,4,6-Tetra-O-benzyl-D-glucopyranose (1.0 g, 1.9 mmol) was dissolved in anhydrous DCM (6 mL) and anhydrous DMF (0.4 mL) under argon. The resulting solution was stirred at 0° C. Oxalyl bromide (4 mL, 2M in DCM, 24 mmol) was added dropwise over a 5 min period . The reaction was stirred at RT. After a 40 min period, t.l.c. (petrol:ethyl acetate, 2:1) indicated the formation of a major product (Rf 0.7). The reaction was cooled to 0° C. and quenched with ice cold water (30 mL) added over a 5 min period. The reaction was partitioned between DCM (20 mL) and water. The aqueous layer was re-extracted with DCM (3×20 mL), the combined organic layers were washed with brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title product (1.10 g, 95%) as a crude yellow oil; δH (400 MHz, CDCl3), 3.57 (1H, dd, J1,2 3.5 Hz, J2,3 9.1 Hz, H-2), 3.68 (1H, dd, J5,6 2.1 Hz, J6,6′ 11.0 Hz, H-6), 3.79-3.84 (2H, m, H-4, H-6′), 4.07 (1H, at, J9.1 Hz, H-3), 4.07-4.11 (1H, m, H-5), 4.47-4.62 (3H, m, PhCH2), 4.74 (s, 2H, PhCH2), 4.84-4.89 (2H, m, PhCH2), 5.10 (1H, d, J11.1 Hz, PhCH2), 6.46 (1H, d, H-1), 7.15-7.41 (20H, m, Ar—H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([CH:31]=O)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc2ccccc12
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc2ccccc12

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 1-naphthaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 390.16 g/mol.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][NH:15][CH3:16]>>[Cl:1][C:2]1[N:11]=[C:10]([N:15]([CH3:16])[CH3:14])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: CNC
Product: COC(=O)c1cc(F)c(N(C)C)nc1Cl

Procedure:
Methyl 2,6-dichloro-5-fluoronicotinate was treated with dimethylamine in a sealed tube to obtain methyl 2-chloro-6-(dimethylamino)-5-fluoronicotinate, which was then reacted under a hydrogen atmosphere in the presence of palladium/carbon to obtain methyl 6-(dimethylamino)-5-fluoronicotinate.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Br:10])=[CH:8][N:7]=[CH:6][C:5]=1[C:11]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:21])[CH:14]=1)=[O:12])[CH:2]=[CH2:3].[CH3:22][Mg]Br>C1COCC1>[CH2:1]([C:4]1[C:9]([Br:10])=[CH:8][N:7]=[CH:6][C:5]=1[C:11]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:21])[CH:14]=1)([OH:12])[CH3:22])[CH:2]=[CH2:3]
Reactant: C=CCc1c(Br)cncc1C(=O)c1ccc(C#N)c(F)c1
Reactant: C[Mg]Br
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCc1c(Br)cncc1C(C)(O)c1ccc(C#N)c(F)c1

Procedure:
To a solution of 4-(4-allyl-5-bromo-pyridine-3-carbonyl)-2-fluoro-benzonitrile (as described above in Step C) (0.39 g, 1.13 mmol) in THF (20 mL) at 0° C. was added methylmagnesium bromide (1.13 mmol, 3M) and the reaction was monitored by TLC. Three more portions (1.13 mmol) of CH3MgBr were added until the reaction was complete. The reaction was quenched with saturated NH4Cl (20 mL), then partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound after purification by chromatography on silica eluting with hexane:ethyl acetate 7:3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])[S:11][C:10]=2[C:22]2[CH:23]=[C:24]([C:29]#[N:30])[CH:25]=[C:26]([F:28])[CH:27]=2)[CH:5]=[CH:6][C:7]=1F.BrC1C=C(C(OCC)=O)SC=1Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])[S:11][C:10]=2[C:22]2[CH:23]=[C:24]([C:29]#[N:30])[CH:25]=[C:26]([F:28])[CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(F)cc(-c2sc(C(=O)N3CNC(=O)C3)cc2-c2ccc(F)c(Cl)c2)c1
Agent: CCOC(=O)c1cc(Br)c(Br)s1
Product: N#Cc1cc(F)cc(-c2sc(C(=O)N3CNC(=O)C3)cc2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 10 starting with the compound from Example 8A. 8.2 mg (1% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:9])=[O:8])=[CH:3][CH:2]=1.[OH:19][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C(N(CC)CC)C>C1COCC1>[O:26]=[C:21]1[CH2:22][CH2:23][C:24](=[O:25])[N:20]1[O:19][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:1]2[CH:6]=[CH:5][C:4]([C:7]([Cl:9])=[O:8])=[CH:3][CH:2]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: O=C(Cl)c1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc(-c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A solution of 1.67 g (6.0 mmol) of 11 in 65 mL of dry THF was treated with 710 mg (6.17 mmol) of N-hydroxysuccinimide, followed by 0.835 mL (6.0 mmol) of triethylamine. The reaction was stirred at room temperature for 2 hours after which time it was filtered to remove triethylamine HCl. The filtrate was concentrated at reduced pressure to yield 2.0 g (93%) of 12 as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:10])C=O)[CH:2]=1.[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])CCC1C=CC=CC=1Cl)([CH3:14])([CH3:13])[CH3:12].ClC1C=CC=CC=1C=CC=O>>[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])[CH2:10][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Reactant: CC(C=O)c1cccnc1
Agent: O=CC=Cc1ccccc1Cl
Product: CC1CCN(C(=O)C(CCc2cccnc2)NC(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl{1-[(4-methylpiperidin-1-yl)carbonyl]-3-pyridin-3-ylpropyl}carbamate is prepared from pyridin-3-yl propionaldehyde (Kitbunnadaj, R. et al. J. Med. Chem, 2004, 47, 2414-2417) in the same manner that tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is prepared from 3-(2-chlorophenyl)propenal in Example 5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([SH:22])[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCc1nc(S)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Reactant: CCOC(=O)CCCCCBr
Product: CCCc1nc(SCCCCCC(=O)OCC)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2

Procedure:
The operation is carried out as in Stage 7 of Example 1 starting with the product obtained in Stage 6 of Example 1 and ethyl 6-bromo-hexanoate instead of ethyl 4-bromocyclohexaneacetate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:34][C:35]1[O:39][N:38]=[C:37]([CH:40]=O)[CH:36]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:40][C:37]5[CH:36]=[C:35]([CH3:34])[O:39][N:38]=5)[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: Cc1cc(C=O)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cc(CN2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)no1

Procedure:
4-(4-Methanesulfonyl-phenoxy)-1-[1-(5-methyl-isoxazol-3-ylmethyl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 5-methylisoxazole-3-carboxaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.92-1.95 (m, 2H), 2.17-2.33 (m, 4H), 2.40 (s, 2H), 2.95-2.97 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.57 (s, 2H), 4.74-4.80 (m, 1H), 6.24 (s, 1H), 7.62-7.64 (m, 2H), 8.04-8.07 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=469.
Reaction SMILES: [CH:1]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:40]([O:42]CC2C=CC=CC=2)=[O:41])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:39])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:30]=1)=[CH:15][CH2:14]2)[CH2:11][CH2:10]3)([CH3:3])[CH3:2].C([SiH](C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:40]([OH:42])=[O:41])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:39])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]1[CH:30]=[CH:31][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:34]=1)=[CH:15][CH2:14]2)[CH2:11][CH2:10]3)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)OCc6ccccc6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)O)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of (1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl 1-isopropyl-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (220 mg, 0.331 mmol), tert-butyldimethylsilane (77 mg, 0.662 mmol), TEA (0.074 mL, 0.529 mmol) and palladium (II) acetate (18.57 mg, 0.083 mmol) in DCM (2 mL) was heated up at 60° C. for 3 h, TLC indicated the starting material was consumed. The reaction mixture was filtered a pad of celite. The filtrates were concentrated under reduced pressure to provide the intermediate. To this intermediate in dioxane (2 mL) was added TBAF (346 mg, 0.993 mmol), the reaction mixture was stirred for 2 h at room temperature. LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water (5 mL), extracted with DCM (3×8 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a pale yellow solid (150 mg, 79%). LCMS: m/e 575.35 (M+H)+, 2.84 min (method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[C:16]=[O:17])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: NC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-chloro-3-(trifluoromethyl)benzamide (0.200 g), oxalyl chloride (0.012 mL) and EDC (15 mL) to afford 0.150 g of the desired product.