Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][C:17]=1[F:30].Cl>O1CCCC1.C1(C(F)(F)F)C=CC=CC=1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:17]([F:30])[CH:18]=1)#[N:29]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: FC(F)(F)c1ccccc1
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a suspension of sodium hydride (60% in oil, 25 g) in tetrahydrofuran (750 mL) was added dropwise a solution of ethyl 3-oxohexanoate (164 g) in tetrahydrofuran (250 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hr, and a solution of 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile in benzotrifluoride above mentioned was added at 0° C. The reaction mixture was further stirred at room temperature for 16 hr, and added to 1 M hydrochloric acid (1.0 L), and the obtained mixture was concentrated under reduced pressure. The obtained mixture was extracted with ethyl acetate, and the obtained extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless oil (145 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28].[NH3:29].[BH4-].[Na+].[NH4+].[OH-]>CCO.C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([NH2:29])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: N
Reactant: COc1cc(N2CCC(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)ccc1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCO
Solvent: ClCCCl
Product: COc1cc(N2CCC(C(N)Cn3nc(C(F)(F)F)cc3C)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
A mixture of 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanone (941 mg, 2.263 mmol), ammonia (5.7 mL of a 2.0 M solution in EtOH, 11.31 mmol) and titanium(IV) isopropoxide (1.34 mL, 4.53 mmol) was stirred at RT in a tightly stoppered flask for 16 h. At the conclusion of this period, the mixture was treated with anhydrous 1,2-DCE (2 mL), cooled in an ice bath and then treated with sodium borohydride (128 mg, 3.39 mmol) in portions. After 45 min, the mixture had changed to a thick foamy mixture. As a result, 1,2-DCE (3 mL) was added to facilitate stirring and the reaction was stirred for an additional 2 h. After this time, the mixture was poured into aqueous concentrated NH4OH (5 mL), diluted with CH2Cl2 (115 mL) and stirred vigorously for 30 min before being filtered through Celite. The filtrate was placed in a separatory funnel and the phases separated. The aqueous phase was extracted with CH2Cl2 (3 times). The combined extracts were washed with brine, dried (MgSO4) and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel using EtOAc and 5% MeOH/CH2Cl2 as eluents to provide 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanamine (490 mg, 1.175 mmol, 51.9% yield) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.18 (1 H, d, J=8.79 Hz), 6.50 (1 H, d, J=2.42 Hz), 6.41-6.47 (1 H, m), 6.30 (1 H, s), 4.22 (1 H, dd, J=13.84, 3.52 Hz), 3.91-3.99 (1 H, m), 3.87 (3 H, s), 3.69 (2 H, d, J=8.57 Hz), 3.22-3.28 (1 H, m), 2.65-2.75 (2 H, m), 2.33 (3 H, s), 1.89-1.98 (1 H, m), 1.84 (1 H, d, J=9.67 Hz), 1.53-1.63 (3 H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:36])([CH3:35])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[N:4][C:5]([NH:8]C2OC(N3CCN(C4C=CC=CN=4)CC3)=NN=2)=[N:6][CH:7]=1.[CH2:43](N)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:43]([NH:8][C:5]1[N:4]=[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:36])([CH3:35])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:41])[CH3:42])(=[O:39])=[O:38])[C:2]([Cl:1])=[CH:7][N:6]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)o2)ncc1Cl
Reactant: NCc1ccccc1
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(NCc2ccccc2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as described in Example 53) with benzylamine.
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C(=O)([O-])[O-].[Na+].[Na+].CCCCCC.CCOC(C)=O>CO>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=2[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: N#Cc1cccc(Cl)c1Cl
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2c(Cl)cccc2c1N
Yield: 12 %

Procedure:
The product from Example 56B (1.7 g, 10 mmol) was treated with 1 eq of methyl thioglycolate and 1 eq sodium carbonate in methanol as described in Example 41A to give after chromatography (4:1 hexane/EtOAc) the title compound in 12% yield. 1H NMR (300 MHz, CDCl3) d 3.81 (s, 3H), 5.90 (bs, 2H), 7.34 (t, J=8 Hz, 1H), 7.48 (dd, J=8.1 Hz, 1H), 7.56 (dd, J=8,1 Hz, 1H). MS (DCI/NH3) m/e 259 (M+NH4)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11](=[O:19])OC1C=CC=CC=1.Cl.[CH3:21][S:22]([N:25]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26]1)(=[O:24])=[O:23]>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[NH:10][C:11]([N:30]1[CH2:31][CH2:32][C:27]2([C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:25]([S:22]([CH3:21])(=[O:23])=[O:24])[CH2:26]2)[CH2:28][CH2:29]1)=[O:19]
Reactant: O=C(NC1Cc2ccccc2C1)Oc1ccccc1
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Product: CS(=O)(=O)N1CC2(CCN(C(=O)NC3Cc4ccccc4C3)CC2)c2ccccc21

Procedure:
Compounds of Examples 85 to 88 were obtained by following the same procedure as in Example 84, except that phenyl N-(2-indanyl)carbamate and 1-methanesulfonylspiro[indoline-3,4′-piperidine]hydrochloride used in Example 84 were replaced with the corresponding starting materials of each desired compound.
Reaction SMILES: O1CCC[CH2:2]1.CC(C)([O-])C.[K+].[Si:12]([O:19][C@@H:20]1[C@@:37]2([CH3:38])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:36]2[CH2:35][CH2:34][C@@:32]2([CH3:33])[C@H:28]3[CH2:29][CH2:30][CH2:31]2)[CH2:23][C@@H:22]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)=O.CO.CCCCCC.O>[Si:12]([O:19][C@@H:20]1[C@@:37]2([CH3:38])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:36]2[CH2:35][CH2:34][C@@:32]2([CH3:33])[C@H:28]3[CH2:29][CH2:30][C:31]2=[CH2:2])[CH2:23][C@@H:22]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC[C@H]3[C@@H]4CCC[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: O
Solvent: CO
Product: C=C1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of tetrahydrofuran (70 ml), methyltriphenylphosphonium bromide (50 g) and potassium t-butoxide (13.9 g) were stirred at 60° C. for 2 hours, while under suspension. To this suspension, was added 1α,3β-bis(tert-butyldimethylsilyloxy)androst-5-ene (18.7 g) and tetrahydrofuran (60 ml), followed by reaction for 2 hours under reflux. Under cooling with ice, the reaction mixture was slowly added to a cooled mixture of hexane (200 ml) and water (100 ml) to stop the reaction. The organic layer was washed with saturated brine twice, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent, giving crude crystals (27 g). The crude crystals were mixed with hexane (100 ml), stirred at room temperature while under suspension. After filtering off insoluble material from the suspension, the filtrate was evaporated under reduced pressure to remove the solvent, giving crude crystals, which were then dissolved in acetone (80 ml) by stirring at room temperature. The mixture was mixed with methanol (160 ml) and stirred at room temperature; the thus precipitated crystals were collected by filtration and dried to give the titled compound (13.2 g).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24]C)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].B(Br)(Br)Br.O>C(Cl)Cl>[CH:1]([O:4][C:5](=[O:30])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([OH:24])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(C#N)c(-c3ccc(NC(=O)OC(C)C)cc3)n(C3CCC3)c2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution [4-(3-cyano-1-cyclobutyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (950 mg, 2.35 mmol) in DCM (10 mL) is added BBr3 (556 uL, 5.9 mmol) over a period of 20 min. The reaction mixture is stirred further for 1 h at room temperature and then water (1 mL) is added. The solvents are removed under reduced pressure. The residue is dissolved in MeOH and then poured into cold water. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (650 mg, 71%).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH3:17].[CH2:18](I)C.O>CS(C)=O>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10](=[O:14])[N:11]2[CH3:18])=[CH:6][C:5]=1[CH3:17]
Reactant: CCI
Reactant: Cc1cc2c(cc1Br)NC(=O)CC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(cc1Br)N(C)C(=O)CC2(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 104.5 %

Procedure:
A mixture of powdered potassium hydroxide (3.35 g, 59.67 mmol) in DMSO (40 mL) was stirred at 0° C. for 10 min. 7-bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (Example 1e) (8.0 g, 29.83 mmol) was added cautiously, followed immediately by the addition of ethyl iodide (12 mL, 149.17 mmol). The reaction mixture was kept at 0° C. for 30 min then slowly warmed up to room temperature and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane washed with water and brine, dried (Mg2SO4), filtered and evaporated to give 8.8 g of 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one and used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 1.24 (t, J=7.2 Hz, 1 H), 1.25 (s, 6 H), 2.37 (s, 3 H), 2.45 (s, 2 H), 3.98 (q, 2 H), 7.13 (s, 1 H), 7.18 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].Cl[CH2:11][CH2:12][CH2:13][O:14][CH3:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCCCl
Reactant: Cc1ccc(Br)c(O)c1
Product: COCCCOc1cc(C)ccc1Br

Procedure:
Analogously to Method F, 10.0 g of 2-bromo-5-methylphenol and 11.6 g of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a slightly orange oil. Rf=0.31 (1:4 EtOAc-heptane); Rt=5.01.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH:10]1[CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:10]2[CH2:12][CH2:11]2)[CH:3]=1
Reactant: BrC1CC1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1cccc(OC2CC2)c1
Temperature: 180 °C
Yield: 83.1 %

Procedure:
A mixture of 3-bromophenol (4.80 mmol, 0.83 g), bromocyclopropane (27.71 mmol, 2.22 ml), K2CO3 (23.15 mmol, 3.2 g) in DMF (18 ml) was heated at 180° C. for 8 hours in a microwave oven. Water and diethyl ether were added and the organic phase was evaporated affording 0.85 g of the expected product.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:16][CH:17]=[CH:18][N:19]=2)=[N:6][CH:7]=[CH:8][N:9]=1.O.[O:34]1CCOC[CH2:35]1>CO>[CH3:35][O:34][C:4]1[C:5]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:16][CH:17]=[CH:18][N:19]=2)=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2nccnc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nccnc1OCCOc1nccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
NaH (50% in mineral oil; 0.010 g, 2.1 mmol) was added to a stirred solution of the product from Step 1 (0.38 g, 0.87 mmol) in dioxane (8 mL) and MeOH (2 mL) in a reaction tube. As the gas evolution had ceased, the tube was sealed and the mixture was stirred at 100° C. for 15 min. The reaction was poured into water and extracted with toluene, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent to give 0.178 g (47%) of the title product. Pos-EI-MS shows M+ and 11 ions supporting the stated structure. HRMS m/z calcd for C20H28N6O5 (M)+ 432.2121, found 432.2126.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][O:34]C)=[O:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36].B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][OH:34])=[O:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36]
Reactant: COCCNC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)NCCO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a soln of the product of Example 205 (50 mg, 0.1 mmol), in dichloromethane (2 mL) was added 1 M boron tribromide in dichloromethane (0.5 mL, 0.5 mmol). The mixture was stirred at 23° for 2 h, H2O was added, extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to give the crude material. Recrystallization from dichloromethane and hexane afforded the title product (30 mg, 62%). LC-MS: 484.2 (MH+, m/z), 1.59 (Rt, min).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][S:40]([NH:43][C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:48]4[CH:49]=[C:44]([NH:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH:45]=[CH:46][CH:47]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 76.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (90 mg, 0.15 mmol) was treated with (3-(methylsulfonamido)phenyl)boronic acid (216 mg, 0.73 mmol), sodium carbonate (77 mg, 0.73 mmols) and bis(triphenylphosphine)palladium(II) dichloride (22 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 25%, dichloromethane-ethyl acetate) to give 79 mg (73% yield) of the title compound. Purity 95%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15]I)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[CH3:25])[NH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Zn]>[NH2:21][C:20]1[CH:19]=[CH:18][C:24]([CH3:25])=[C:23]([CH2:15][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:22]=1
Reactant: Cc1ccc(N)cc1I
Reactant: COC(=O)C[C@H](CI)NC(=O)OC(C)(C)C
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Zn]
Product: COC(=O)C[C@H](Cc1cc(N)ccc1C)NC(=O)OC(C)(C)C
Yield: 65 %

Procedure:
Following the General Procedure of Description 15 (Part B), the zinc insertion product of (5c) was used in situ to cross couple with commercial 3-iodo-4-methyl-aniline (583 mg, 2.5 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (57 mg, 0.03 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (76 mg, 0.25 mmol, 10 mol-%) in anhydrous degassed DMF (6 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography with ethyl acetate (EtOAc)/hexane mixtures (EtOAc/hexane=7:3→1:1, v/v) furnished 1.04 g (65% yield) of the title compound (5d) as a yellow viscous oil. Rf˜0.28 (EtOAc/hexane=1:1, v/v). 1H NMR (400 MHz, CDCl3): δ 6.89 (d, J=8.4 Hz, 1H), 6.48-6.44 (m, 2H), 5.10-5.02 (br. m, 1H), 4.18-4.08 (m, 1H), 3.65 (s, 3H), 3.30 (br. s, 2H), 2.82-2.78 (br. dd, 1H), 2.70 (dd, J=10.2, 6.0 Hz, 1H), 2.51 (dd, J=16.0, 5.2 Hz, 1H), 2.45 (dd, J=16.0, 5.6 Hz, 1H), 2.19 (s, 3H), 1.38 (s, 9H) ppm. LC/MS: Rt=1.320 min. LC/MS: m/z=323.20 (M+H+)+, 345.15 (M+Na+)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[CH3:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[O:16][CH2:17][CH:18]=O>>[CH3:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[O:16][CH2:17][CH:18]1[NH:11][CH2:10][CH2:9][N:4]2[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]12
Reactant: CCc1nc(I)cn1CCN
Reactant: Cc1ccc(OCC=O)cc1C
Product: CCc1nc(I)c2n1CCNC2COc1ccc(C)c(C)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (6.000 mmol) and (3,4-dimethyl-phenoxy)-acetaldehyde (0.985 g; 6.000 mmol) afforded 8-(3,4-dimethyl-phenoxymethyl)-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.70 min.; [M+H]+=412.12 g/mol.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][NH:6][C:7]([C:9]1[N:13]2[N:14]=[C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:24][CH2:23]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1)=[O:8])C.[OH-].[Na+]>C(O)C>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([C:7]([NH:6][CH2:5][C:4]([OH:42])=[O:3])=[O:8])=[N:10][N:11]=4)[N:14]=3)[CH2:27][CH2:26]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)CNC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
1.29 g of N-[6-(3-[4-(diphenylmethoxy)piperidino]propylamino)[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]glycine ethyl ester was dissolved in 10 ml of ethanol; 4.5 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 30 minutes. The ethanol was distilled off under reduced pressure; the reaction mixture was adjusted to pH 4.5 using 1 N hydrochloric acid. The precipitated crystal was collected by filtration, washed with water and acetone, and dried, to yield 831 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([CH3:17])[OH:16])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:16][CH:15]([CH3:17])[C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)C1(c2cccc(Cl)c2)CCN(C)CC1
Product: CC(=O)OC(C)C1(c2cccc(Cl)c2)CCN(C)CC1

Procedure:
A mixture of 1.00 g of 4-(3′-chlorophenyl)-α,1-dimethyl-4-piperidinemethanol (Example 1) and 5 mL of acetic anhydride was heated under reflux for 90 minutes. Removal of the excess acetic anhydride and short-path distillation of the residue (170° C. bath temperature, 1 micron) gave 1.05 g of the title compound as an oil. 1H NMR (CDCl3): δ 7.1-7.4 (m, 4H); 4.9 (quartet, J=7 Hz,1H); 2.8 (m,2H); 2.2 (s,3H); 2.0 (s,3H); 1.9-2.4 (m,6H); and 0.9 (d,J=7 Hz,3H).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>S(=O)(=O)(O)O>[CH:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: C=Cc1ccccc1
Agent: O=S(=O)(O)O
Product: CC(c1ccccc1)c1ccccc1C1CCCCC1

Procedure:
In a reactor, 1 liter or cyclohexylbenzene and 200 ml of concentrated sulfuric acid were introduced and the resultant mixture was kept at 15° C. Then, 800 ml of a 1:1 mixture of cyclohexylbenzene and styrene was added dropwise to the resultant mixture over a period of two hours, while the temperature of the mixture was kept in the range of from 15° to 20° C. At the end of the dropwise addition of the mixture, 200 ml of concentrated sulfuric acid was added to continue the reaction further for 30 minutes. Then, the reaction mixture was washed repeatedly with water to remove residual sulfuric acid and then distilled to isolate 1-(cyclohexylphenyl)-1-phenylethane (a mixture of structural isomers). Then, 1 liter of 1-(cyclohexylphenyl)-1-phenylethane was introduced in the autoclave and, in the presence of a nickel catalyst, subjected to hydrogenation under the conditions of 100 kg/cm2G of initial hydrogen pressure and 140° to 170° C. temperature for two hours, to afford hydrogenated 1-(biphenylyl)-1-phenylethane (a mixture of structural isomers). The general attributes of this hydrogenation product were as shown in Table 4.