Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:16](=O)[CH2:15]2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C@H:14]2[CH2:15][CH2:16][N:17]([C@@H:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[CH2:18]2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CC2(NC(=O)OC(C)(C)C)CCC2)CC1=O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC[C@H](CC2(NC(=O)OC(C)(C)C)CCC2)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 83.8 %

Procedure:
In an atmosphere of nitrogen, 1 M borane-tetrahydrofuran complex solution (5.6 ml) was added dropwise to tetrahydrofuran solution (15 ml) of 4-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2pyrrolidone (isomer B1) (700 mg, 1.88 mmol) under ice-cooling, and the mixture was stirred at room temperature for 13 hours. The solvent was evaporated under a reduced pressure, and the resulting residue was mixed with 80% aqueous ethanol (15 ml) and triethylamine (3 ml) and heated under reflux for 4 hours. After cooling, the solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with chloroform (30 ml), washed with water (10 ml) and saturated sodium chloride aqueous solution (10 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was applied to a silica gel column chromatography and eluted with chloroform:methanol=20:1, thereby obtaining 565 mg (84%) of the title compound as colorless crystals.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Cl:11][C:12]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][NH:19][OH:20])=[O:15]>N1C=CC=CC=1>[Cl:11][C:12]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][N:19]([CH:8]=[O:10])[OH:20])=[O:15]
Reactant: O=C(NCCNO)c1cc(Cl)ccc1Cl
Reactant: O=CO
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)CCNC(=O)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 33 %

Procedure:
A mixture of acetic anhydride (2 mL) and formic acid (1 mL) was allowed to stand at 55° C. for 2.5 h. After cooling to 0° C., the resulting mixed anhydride (0.4 mL) was added to a solution of 2,5-dichloro-N-(2-hydroxyamino-ethyl)-benzamide (0.28 g, 1.1 mmol) in pyridine (10 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred for 2 h and the pyridine removed in vacuo. The residue was purified by preparative reverse-phase HPLC to provide the title compound (0.1 g, 33%) as a white solid. 1H NMR* (400 MHz, CD3OD): δ 8.35 (s, 0.5H); 7.95 (s, 0.5H); 7.45 (m, 3H); 3.78 (m, 1H); 3.73 (m, 1H); 3.62 (m, 2H). * 1:1 mixture of rotamers. ESMS: M+H=277.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[C:11]#[N:12])[CH3:2].N>[Ni].CO>[NH2:12][CH2:11][C:4]1[C:5](=[O:10])[NH:6][C:7]([CH3:9])=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(C)[nH]c(=O)c1C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCc1cc(C)[nH]c(=O)c1CN
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.6 %

Procedure:
To a suspension of Raney Nickel (6 g) in methanol (200 mL) was added 4-ethyl-1,2-dihydro-6-methyl-2-oxopyridine-3-carbonitrile (10 g, 61.7 mmol) and methanolic ammonia (750 mL). The reaction mixture was stirred at room temperature under hydrogen pressure (80 psi) for 48 hrs. The reaction mixture was filtered through Celite and washed with methanol (250 mL). The filtrate was concentrated under reduced pressure and the residue purified by filter column using silica gel (60-120 mesh), eluted with 10% MeOH in CHCl3, to afford 3-(amino methyl)-4-ethyl-6-methylpyridin-2(1H)-one (5.6 g, 54%) as an off white solid. 1H NMR (DMSO-D6, 400 MHz) (free amine): δ ppm 1.063-1.101 (t, 3H, J=7.6 Hz), 2.101 (s, 3H), 2.412-2.449 (m, 2H), 3.448 (s, 2H), 5.835 (s, 1H). MS (ES) [M+H]+ 167.06.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:54])[N:45]=[CH:46][C:39]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:54])[N:45]=[CH:46][C:39]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(F)cn1)(c1ccccc1)c1ccccc1
Reactant: Clc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl)C(=O)Nc1ccc(F)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (83 mg, 2.07 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-fluoropyridin-2-yl)-2-hydroxypropanamide (Intermediate BA2) (500 mg, 1.04 mmol) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BA3) (310 mg, 1.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was adjusted to pH 7 by addition of 1M citric acid and the reaction mixture diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 25 to 100% EtOAc in isohexane to afford the product (637 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 0.99 (9H, t), 3.69-3.72 (2H, m), 3.82 (2H, t), 4.16-4.24 (2H, m), 6.06 (1H, t), 7.31-7.47 (8H, m), 7.52-7.55 (2H, m), 7.63-7.66 (4H, m), 8.12 (1H, d), 8.26-8.29 (1H, m), 8.42 (1H, s), 8.58 (1H, s), 8.79 (1H, s).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)=[C:6]([N+:22]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[C:25]([O:29][C:30]([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:36]1[S:37][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:34]([C:46](=[O:47])[NH:22][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[N:8]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)[N:35]=1
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCC[C@H](NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: CCn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@H](NC(=O)C(F)(F)F)CC1
Yield: 66 %

Procedure:
Following the procedure for Example 517 starting with (S)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave (S)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (151 mg, 66%). 1H-NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.45-7.34 (m, 1H), 7.12-7.02 (m, 2H), 6.37 (d, J=8 Hz, 1H), 4.23-4.16 (m, 1H), 4.05 (q, J=7 Hz, 2H), 3.43-3.31 (m, 2H), 3.25-3.15 (m, 2H), 2.22-2.05 (m, 2H), 2.03-1.89 (m, 2H), 1.89-1.72 (m, 2H), 1.55 (s, 9H), 1.46 (t, J=7 Hz, 3H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[C:11]2=[N:12][CH:13]=[CH:14][C:15](O)=[C:10]2[S:9][CH:8]=1>ClCCCl>[Cl:3][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[C:7]([CH3:6])=[CH:8][S:9][C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1csc2c(O)ccnc12
Solvent: ClCCCl
Product: Cc1csc2c(Cl)ccnc12
Reaction time: 8 h
Yield: 55.8 %

Procedure:
Phosphorous oxychloride (2.2 mL, 24 mmol) in 1,2-dichloroethane (12 mL) was charged with 3-methylthieno[3,2-b]pyridin-7-ol (2.0 g, 12 mmol). The reaction stirred overnight at reflux under nitrogen. The mixture was the cooled and concentrated. Saturated NaHCO3 solution was carefully added to neutralize the residue. The biphasic mixture was extracted with dichloromethane, dried, and concentrated. Flash chromatography (15% EtOAc/hexanes) gave the title compound (1.23 g, 55%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:13][CH:14]=1.I[CH2:27][C:28]([NH2:30])=[O:29]>O>[F:8][C:9]1[CH:10]=[CH:11][C:12](=[N:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:13]([CH2:27][C:28]([NH2:30])=[O:29])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cn2)cc1
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(F)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.43 g, 0.018 mol) was mixed with N,N-Dimethylformamide (67.4 mL) and N-(5-fluoropyridin-2-yl)-4-methylbenzenesulfonamide 1 (4.0 g, 0.015 mol) was added. The reaction was stirred at room temperature for 10 minutes. Iodoacetamide (3.3 g, 0.018 mol) was added and the mixture was stirred at room temperature for 24 hours. The reaction was poured into water (100 mL) and extracted with ethyl acetate (4×75 mL). Organic layers were combined then dried with magnesium sulfate and the solvent removed. The crude product was chromatographed on silica using 5% methanol in dichloromethane to give 2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide 2 Rf 0.26, 5% methanol.dichloromethane; MS m/z 324 (M+H)
Reaction SMILES: CS(O[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)(=O)=O.F[C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][CH:6]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[N:34]2[C:33]2[CH:35]=[CH:36][C:30]([C:10]([CH3:15])([CH3:11])[CH3:9])=[CH:31][CH:32]=2)=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Nc1ccc(F)cc1
Product: CC(C)(C)c1ccc(N2C(c3ccc(Br)cc3)CCC2c2ccc(Br)cc2)cc1
Yield: 81 %

Procedure:
The product from Example 42B (5.2 g, 9.35 mmol) was subjected to the conditions described in Example 39D, substituting 4-tert-butylaniline (11.91 mL, 74.8 mmol) for 4-fluoroaniline to provide the title product (3.89 g, 81%) as a mixture of isomers.
Reaction SMILES: [CH2:1](OCC)C.[OH-].[K+].CN(N=O)C(N[N+]([O-])=O)=N.[CH2:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>O1CCCC1.C(O)(=O)C>[CH2:1]1[C:19]2([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:18]1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOCC
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a mixture of diethyl ether (25 mL) and 30% aqueous potassium hydroxide solution (5 mL) was added 1-methyl-3-nitro-1-nitrosoguanidine (containing 50% water, 2.17 g), and the mixture was stirred at room temperature for 10 min. To a solution (25 mL) of tert-butyl 4-methylidenepiperidine-1-carboxylate (1.00 g, 5.07 mmol) in tetrahydrofuran was added dropwise the above-mentioned ether layer, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added a ether layer prepared from diethyl ether (25 mL), 30% aqueous potassium hydroxide solution (5 mL), and 1-methyl-3-nitro-1-nitrosoguanidine (containing 50% water, 3.77 g), and the mixture was further stirred for 16 hr. To the reaction mixture was added acetic acid (1 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10) to give the title compound (261 mg, 24%) as a white powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[CH:11][C:10]2[C:13]3([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:25][CH2:24][C:19]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:18][CH:14]3[CH2:15][CH2:16][CH2:17][C:9]=2[CH:8]=1)(=O)=O.[CH:35](/B(O)O)=[CH:36]\[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][C@@:13]12[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][C@H:14]1[CH2:15][CH2:16][CH2:17][C:9]1[CH:8]=[C:7](/[CH:35]=[CH:36]/[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:12]=[CH:11][C:10]=12
Reactant: O=S(=O)(Oc1cc2c(cn1)C1(Cc3ccccn3)CCC3(CC1CCC2)OCCO3)C(F)(F)F
Reactant: OB(O)/C=C/c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C(=C/c1cc2c(cn1)[C@]1(Cc3ccccn3)CCC3(C[C@H]1CCC2)OCCO3)\c1ccccc1
Temperature: 90 °C
Yield: 74.1 %

Procedure:
A flask with stir bar and nitrogen line was charged with rac-(7aR,11aS)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolan]-3-yl trifluoromethanesulfonate (144, R2=Pyridin-2-ylmethyl) (9.14 g, 18.34 mmol) (assumed 100% for previous reaction), (E)-styrylboronic acid (3.39 g, 22.9 mmol), cesium carbonate (14.94 g, 45.9 mmol), 1,4-dioxane (130 mL), water (32.5 mL) and bis(triphenylphosphine)palladium(II) dichloride (0.644 g, 0.917 mmol). The mixture was warmed in an oil bath heated to about 90° C. for about 30 min. The mixture was cooled then concentrated under reduced pressure. The material was partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated then the organic solution was washed with brine (75 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure then the material was purified on silica gel (330 g) using 100% EtOAc. Product fractions were combined and concentrated under reduced pressure to yield (7aR,11aS)-11a-(pyridin-2-ylmethyl)-3-((E)-styryl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolane] (145, R2=Pyridin-2-ylmethyl) (6.15 g, 74%); LC/MS, method 3, Rt=2.50 min, MS m/z 453 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.14 (s, 1H), 7.59-7.52 (m, 3H), 7.38-7.35 (m, 2H), 7.33-7.05 (m, 4H), 6.97-6.94 (m, 1H), 6.23 (s, 1H), 4.04-3.90 (m, 4H), 3.49 (d, J=13.8 Hz, 1H), 3.39-3.29 (m, 1H), 3.25 (d, J=13.3 Hz, 1H), 2.97-2.89 (m, 1H), 2.28-2.20 (m, 1H), 2.11-1.96 (m, 4H), 1.92-1.86 (m, 1H), 1.84-1.70 (m, 2H), 1.69-1.48 (m, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:10]1([CH3:42])[CH3:41])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrN1C(C)(C)C(=O)N(Br)C1=O>CCCCCC.C1C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:26])[CH3:25])[C:10]1([CH3:41])[CH3:42])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 88.9 %

Procedure:
3β,24-Bis(tert-butyldimethylsilyloxy)-4,4-dimethylchol-5-ene (44 g) is dissolved in a warm mixture of hexane (2 l) and benzene (540 ml). 1,3-Dibromo-5,5-dimethylhydantoin (15.32 g) is added and the mixture is refluxed for 20 min and then cooled rapidly to room temperature, and the insoluble material is removed by filtration. The filtrate is concentrated under reduced pressure and o-xylene (2 l) and quinaldine (84 ml) is added. The mixture is refluxed for 1 hour. After aqueous work-up and trituration with methanol, 3β,24-bis(tert-butyldimethylsilyloxy)-4,4-dimethylchola-5,7-diene (39 g) is isolated. Melting point: 98-106° C. 1H-NMR (CDCl3, 400 MHz): δ=5.9 (1H, m); 5.54 (1H, m); 3.58 (2H, m); 3.35 (1H, m); 0.91 (18H, s); 0.05 (12H, m).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17](O)=[O:18])[N:14]=[N:13]2)=[C:8]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:18])[N:14]=[N:13]2)=[C:8]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: COCCN
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)O)nn2)c(OCCCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NCCOC)nn2)c(OCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]-2-(3-phenylpropoxy)phenyl}-1H-1,2,3-triazole-4-carboxylic acid (0.14 g) obtained in Example 133e) in DMF (4 ml) were successively added 2-methoxyethylamine (0.04 ml), triethylamine (0.06 ml), HOBt (0.07 g) and WSC (0.08 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the deposited precipitate was collected by filtration, washed with water, and recrystallized from ethanol-water to give the title compound as a white powder (0.14 g, 86%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[CH3:9][O:8][C:6]1[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=[C:2]([C:26]2[CH:25]=[N:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=2)[N:7]=1
Reactant: COc1ccc(CCNc2cc(Cl)nc(OC)n2)cc1
Reactant: COc1ccc(B(O)O)cn1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CCNc2cc(-c3ccc(OC)nc3)nc(OC)n2)cc1
Temperature: 85 °C
Yield: 100 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine (600 mg, 2.04 mmol), 2-methoxy-5-pyridyl-boronic acid (469 mg, 3.06 mmol, prepared according to the procedure described in J. Org. Chem., 2002, 67, 7541), and Cs2CO3 (1.66 g, 5.11 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL), at room temperature, is degassed with argon gas for 5 minutes and treated with tetrakis(triphenylphosphine)palladium (0) (118 mg, 0.1 mmol). The mixture is heated at 85° C. for 5 hours, diluted with water (50 mL), and extracted twice with EtOAc (50 mL). The combined extracts are dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with a mixture of EtOAc and heptane (1:1, v/v) affording [2-methoxy-6-(6-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [0.75 g, 100%, Example 35(o)] as an oil. LCMS: RT=2.74 minutes, MS: 367 (M+H). 1H NMR (300 MHz, CDCl3): □08.78 (1H, d, J=2.1 Hz), 8.21 (1H, dd, J=8.7, 2.4 Hz), 7.16 (2H, d, J=8.4 Hz), 6.88 (1H, dd, J=8.7, 2.4 Hz), 6.82 (2H, d, J=8.4 Hz), 6.3 (1H, s), 4.95 (1H, brs), 4.03 (3H, s), 4.02 (3H, s), 3.82 (3H, s), 3.72-3.63 (2H, m), 2.92 (2H, t, J=6.9 Hz). IC50=1.7 nM
Reaction SMILES: Br[C:2]1[C:11]([N:12]([CH3:14])[CH3:13])=[CH:10][C:9]2[C:8]([CH3:16])([CH3:15])[CH2:7][CH2:6][C:5]([CH3:18])([CH3:17])[C:4]=2[CH:3]=1.C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>C1COCC1>[CH3:13][N:12]([CH3:14])[C:11]1[C:2]([B:24]([OH:29])[OH:25])=[CH:3][C:4]2[C:5]([CH3:18])([CH3:17])[CH2:6][CH2:7][C:8]([CH3:16])([CH3:15])[C:9]=2[CH:10]=1
Reactant: CN(C)c1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)c1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a solution of 2-Bromo-3-dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (67.08 g, 0.216 mol) in 300 mL of anhydrous THF at −78° C. was added dropwise at −78° C. a 1.6 molar solution of n-butyl lithium (1.6 M, 203 mL, 1.5 eq.) over a period of 30 minutes. The reaction was stirred for 10 min. at −78° C. and 150 ml of tri(iso-propyl) borate (3 eq.) was added dropwise over 0.5 hr. The mixture was allowed to warm to room temperature overnight. The resulting thick mixture was diluted with THF, cooled to 0° C. and 1N hydrochloric acid was added. The reaction was stirred for 0.5 hr at room temperature. The resulting layers were separated and the aqueous phase was washed with EtOAc. The aqueous layer was neutralized to pH 7 to give a precipitate that was extracted with dichloromethane. The aqueous phase was saturated with sodium chloride and extraction was continued. The combined organic layers were dried over sodium sulfate, filtered and evaporated to yield an oil which slowly crystallized on standing. The solid was collected by filtration, washed with hexane and dried to afford 23.00 g of (3-dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (39%). 1H-NMR (300 MHz, DMSO-d6): 1.20 (s, 6 H), 1.23 (s, 6 H), 1.60 (s, 4 H), 2.62 (s, 6 H), 7.25 (s, 1 H), 7.64 (s, 1 H), 9.14 (s, 2 H).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:26])[CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[N:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:6]1.Br[CH2:28][CH2:29][CH2:30][CH3:31].O>CS(C)=O.C(OCC)(=O)C>[CH2:28]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][CH:5]([N:4]([CH3:26])[CH3:3])[CH2:6]3)=[CH:15][CH:14]=2)=[O:25])=[CH:19][N:20]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCBr
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)nc3)cc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)cn1
Reaction time: 0.17 h

Procedure:
A solution of 0.1 g of potassium hydroxide in 1ml of DMSO was stirred at room temperature for 10 minutes and then 0.1 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide was added. The reaction solution was stirred for 10 minutes and then 0.084 g of 1-bromobutane was added. The mixture was stirred at room temperature overnight. After addition of water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate.