Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](/[CH:9]=[C:10](\[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])/[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:25].ClCCl.[H][H]>CO>[NH2:1][C:2]1[C:3]([CH3:25])=[CH:4][C:5]([CH2:9][C@@H:10]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)/C(=C/c1cc(C)c(N)c(C)c1)C(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc(C)c(N)c(C)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A flame-dried 2 L Parr hydrogenation bottle was charged with (Z)-methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)acrylate (84.5 g, 239 mmoles), dichloromethane (300 mL), and methanol (300 mL). The bottle was swirled so that a light brown suspension was formed. The mixture was degassed using a flow of nitrogen for 30 min. To this was quickly added (−)-1,2-bis((2R,5R)-2,5-diethylphospholano)-benzene(cyclooctadiene) rhodium (I) tetrafluoroborate ([(2R,5R)-Et-DuPhosRh]BF4) (2.11 g, 3.20 mmoles). The bottle was immediately attached to a Parr Hydrogenator. After 5 cycles of hydrogen (60 psi) and vacuum, the bottle was pressurized to 65 psi and the suspension was agitated at room temperature for 16 h. The reaction had become homogeneous. The reaction mixture was concentrated, and the resulting residue purified by flash chromatography (silica gel, 1:9 ethyl acetate/dichloromethane) to give 82.9 g (98%). 1H-NMR (DMSO-d6) δ 2.04 (s, 6H), 2.65 (dd, J=13.4, 9.8 Hz, 1H), 2.82 (dd, J=13.7, 5.2Hz, 1H), 3.62 (s, 3H), 4.15-4.10 (m, 1H), 4.41 (s, 2H), 5.00 (s, 2H), 6.68 (s, 2H), 7.37-7.28 (m, 5H), 7.70 (d, J=7.9 Hz, 1H); 13C-NMR (DMSO-d6) δ 17.7, 35.9, 51.7, 56.1, 65.3, 120.4, 124.0, 127.5, 127.7, 128.2, 128.3, 136.9, 142.6, 155.9, 172.5.
Reaction SMILES: [CH3:1][C@:2]12[C@H:54]3[CH2:55][C@H:52]([C:53]3([CH3:57])[CH3:56])[CH2:51][C@H:3]1[O:4][B:5]([CH:7]([NH:12][C:13]([C@H:15]1[N:19]3[C:20](=[O:46])[C:21]([N:24]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=4)C(=O)OCC4C=CC=CC=4)=[CH:22][N:23]=[C:18]3[C@@:17]([N:48]=[N+]=[N-])([CH3:47])[CH2:16]1)=[O:14])[CH2:8][CH:9]([F:11])[F:10])[O:6]2>CO.[Pd]>[CH3:1][C@:2]12[C@H:54]3[CH2:55][C@H:52]([C:53]3([CH3:57])[CH3:56])[CH2:51][C@H:3]1[O:4][B:5]([CH:7]([NH:12][C:13]([C@H:15]1[N:19]3[C:20](=[O:46])[C:21]([NH:24][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:44])[F:45])[CH:37]=4)=[CH:22][N:23]=[C:18]3[C@@:17]([NH2:48])([CH3:47])[CH2:16]1)=[O:14])[CH2:8][CH:9]([F:10])[F:11])[O:6]2
Reactant: CC1(C)[C@@H]2C[C@H]3OB(C(CC(F)F)NC(=O)[C@@H]4C[C@@](C)(N=[N+]=[N-])c5ncc(N(Cc6cccc(C(F)(F)F)c6)C(=O)OCc6ccccc6)c(=O)n54)O[C@@]3(C)[C@H]1C2
Agent: [Pd]
Solvent: CO
Product: CC1(C)[C@@H]2C[C@H]3OB(C(CC(F)F)NC(=O)[C@@H]4C[C@@](C)(N)c5ncc(NCc6cccc(C(F)(F)F)c6)c(=O)n54)O[C@@]3(C)[C@H]1C2
Reaction time: 8 h

Procedure:
To a solution of 84a (141 mg, 0.177 mmol) in 5 mL MeOH, was added 10% Pd-C (50 mg). The mixture was evacuate and flushed with H2 (3×), then was stirred under an atmosphere of H2 for 8 h. The mixture was filtered and concentrated to give 113 mg (quantitative) of 84b. MS (ESI) 638.4 (M+H+), 660.3 (M+Na+), 636.3 (M−H+).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([NH:19][CH2:20][CH2:21][O:22][C:23]([F:26])([F:25])[F:24])=[C:10]([NH:12][C:13](=O)[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=1)(=[O:5])=[O:4])[CH3:2]>C(O)C.[OH-].[Na+]>[C:14]([C:13]1[N:19]([CH2:20][CH2:21][O:22][C:23]([F:26])([F:25])[F:24])[C:9]2[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:11][C:10]=2[N:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCS(=O)(=O)c1ccc(NCCOC(F)(F)F)c(NC(=O)C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CCOC(F)(F)F
Yield: 33.7 %

Procedure:
N-(5-(Ethylsulfonyl)-2-{[2-(trifluoromethoxy)ethyl]amino}phenyl)-2,2-dimethylpropanamide (187 mg, 0.47 mmol, step A) was dissolved in ethanol and 2N sodium hydroxide solution. The mixture was microwaved for 30 min at 140° C. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by PTLC (hexane:acetone=3:1 as eluent) to afford the title compound (60 mg, 34%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:29])([CH3:28])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[C:31]([O:35][C:36]([NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][CH:47]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:29])([CH3:28])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:52][C:49]2[CH:48]=[CH:47][C:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH2:39][NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])=[CH:51][CH:50]=2)[C:17]1=[O:27])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
To a solution of 819 mg (2.07 mmol) of 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]propanamide (Step A) in 7.0 mL of dry dimethylformamide under nitrogen at 0° C. was added 83 mg (2.1 mmol) of 60% sodium hydrideil dispersion. After stirring for 15 minutes, a solution of 810 mg (2.1 mmol) of 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step F) in 2.0 mL of dimethylformamide was added by cannula. The flask which originally contained the methanesulfonate ester was rinsed with 1.0 mL of dimethylformamide which was added to the reaction mixture. After stirring at 0° C. for 15 minutes, the reaction mixture was diluted with 400 mL of ethyl acetate and 50% saturated ammonium chloride. The mixture was transferred to a separatory funnel and the aqueous layer was separated. The organic layer was washed with 100 mL of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (55:45) to afford 1.2 g (84%) of the product as a white foam. 1H NMR (200 MHz, CDCl3): δ 1.38 (s, 9H), 1.48 (s, 3H), 1.52 (s, 3H), 1.78 (s, 1H), 2.35-2.70 (m, 3H), 4.18 (d, 6 Hz, 2H), 4.38-4.62 (m, 2H), 4.82 (d, 16 Hz, 1H), 5.05 (s, 2H), 5.25 (d, 16 Hz, 1H), 5.32 (s, 1H), 7.08 (d, 6 Hz, 1H), 7.12-7.43 (m, 18H). FAB-MS: calculated for C41 H46N4O6 690; found 691(M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH2:8][CH2:9][C:10](=[O:13])[NH:11][N:12]=2)[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O=[Mn]=O.O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cc(C2=NNC(=O)CC2)nc1-c1ccccc1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(=O)[nH]n2)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 41.2 %

Procedure:
A vigorously stirred mixture of 2.2 g of 4,5-dihydro-6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone, Example 1, Isomer A, MnO2 (Aldrich Chemical, 12 g) and dioxane (175 ml) is heated to 70° C. for 22 hours. The temperature is raised to 100° C. and maintained there for another 25 hours. Additional MnO2 (8 g) is added and refluxing continued for an additional 20 hours. The mixture is filtered, washed with hot dioxane, and finally with warm tetrahydrofuran. The combined filtrate and washings are concentrated to a small volume to yield 0.9 g of 6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone, as off-white crystals, mp 291°-292° C., dec.
Reaction SMILES: [ClH:1].Cl.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[O:15])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Cl.[N:27]([O-])=O.[Na+]>O>[ClH:1].[C:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][NH2:27])=[CH:21][CH:20]=2)=[O:15])=[CH:11][CH:12]=1)(=[O:5])[CH3:4]
Reactant: O=N[O-]
Reactant: CC(=O)Nc1ccc(CC(=O)NCCc2ccc(N)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(CC(=O)NCCc2ccc(NN)cc2)cc1
Temperature: 0 °C
Yield: 158.6 %

Procedure:
The compound of Section (b) (6.25 g) was suspended in a mixture of water (17 ml) and concentrated hydrochloric acid (8.5 ml). The mixture was cooled in an ice bath and a solution of sodium nitrite (1.39 g) in water (8.5 ml) was added dropwise. The reaction mixture was stirred in the ice bath for 10 min to give a yellow solution with a fine suspension. The suspension was removed by filtration and the filtrate was collected in a cool receiver. The fltrate was poured into a solution of tin (II) chloride (20.6 g) in concentrated hydrochloric acid (8.5 ml) to give a yellow gum, which was removed and dissolved in ethanol (100 ml). The ethanol solution was evaporated in vacuo and re-evaporation with toluene gave a yellow gum. This gum was triturated with ER (250 ml) to give the title compound (9.36 g) as a pale yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]2[C:12]([C:15](=[O:20])C(Cl)(Cl)Cl)=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])C.[NH3:21]>C(#N)C>[N:14]1[CH:13]=[C:12]2[N:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=13)[C:4](=[O:5])[NH:21][C:15]2=[O:20]
Reactant: N
Reactant: CCOC(=O)c1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Solvent: CC#N
Product: O=c1[nH]c(=O)c2cnc3cccc1n32
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.8 %

Procedure:
To a solution of 2.64 g (7.55 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 20 ml of acetonitrile was added 2.5 ml of 25% aqueous ammonia. The mixture was stirred for 5 hours at room temperature. The resulting crystals were collected by filtration and washed with acetonitrile to give 393 mg of the desired compound (27.8%, pale brown solid).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][C:11]#[N:12].[CH3:14][O:15][C:16]1[C:21]([C:22]2[N:26]3[N:27]=[C:28]([NH:31][C@@H:32]4[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]4)[CH:29]=[CH:30][C:25]3=[N:24][CH:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1>ClCCl>[CH3:14][O:15][C:16]1[C:21]([C:22]2[N:26]3[N:27]=[C:28]([NH:31][C@@H:32]4[CH2:37][CH2:36][CH2:35][N:34]([C:9](=[O:8])[CH2:10][C:11]#[N:12])[CH2:33]4)[CH:29]=[CH:30][C:25]3=[N:24][CH:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: COc1ncccc1-c1cnc2ccc(N[C@@H]3CCCNC3)nn12
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: ClCCl
Product: COc1ncccc1-c1cnc2ccc(N[C@@H]3CCCN(C(=O)CC#N)C3)nn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
3-[(2,5-Dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (prepared as described in BE875054(A1), 75 mg, 0.23 mmol) was added to a stirred solution of 3-(2-methoxy pyridin-3-yl)-N-[(3R)-piperidin-3-yl]imidazo[1,2-b]pyridazin-6-amine (Preparation 3b, 63 mg, 0.35 mmol) in dichloromethane (4 mL) and the mixture was stirred at ambient temperature for 18 hours. The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (100% ethyl acetate to 3:2 ethyl acetate/ethanol) to give the title compound (58 mg, 64%) as a solid.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/C.[CH:6]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])OCC.[N+]([O-])([O-])=O.[NH4+]>CCO.CCOC(C)=O>[CH2:14]([O:13][CH:6]([O:10][CH2:11][CH3:12])[CH:1]=[CH:2][CH3:3])[CH3:15]
Reactant: CCOC(OCC)OCC
Reactant: C/C=C/C=O
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC=CC(OCC)OCC
Reaction time: 22 h
Yield: 88.7 %

Procedure:
Crotonaldehyde (23.64 mL, 285.35 mmol), triethyl orthoformate (57.02 mL, 342.42 mmol) and ammonium nitrate (2.28 g, 28.54 mmol) were combined in 60 mL EtOH. After 22 h at ambient temperature, the reaction was diluted with EtOAc (60 mL) and washed with saturated sodium bicarbonate solution (40 mL). The aqueous layer was back extracted with EtOAc (20 mL). The combined organics were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 36.5 g (89%) of 1,1-diethoxybut-2-ene. 1H NMR (CDCl3, 400 MHz) 5.84 (m, 1H); 5.54 (m, 1H); 4.82 (d, J=5.7 Hz, 1H); 3.64 (m, 2H); 3.49 (m, 2H); 1.73 (m, 3H); 1.21 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[Cl:10].[CH3:11][CH2:12][N:13](CC)[CH2:14][CH3:15].N1CCCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:13]2[CH2:14][CH2:15][CH2:11][CH2:12]2)=[CH:4][C:3]=1[Cl:10]
Reactant: ClCc1ccc(Br)c(Cl)c1
Reactant: CCN(CC)CC
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: Clc1cc(CN2CCCC2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A solution of 1-bromo-2-chloro-4-(chloromethyl)-benzene (25.2 g, 105.03 mmol) and Et3N (16.1 ml, 115.53 mmol) in THF (150 ml) was stirred at r.t. Pyrrolidine (8.2 g, 115.53 mmol) was added dropwise. The r.m. was stirred overnight at r.t. and was then concentrated in vacuo. The residue was taken up into water and extracted with CH2Cl2 (3×100 ml). The combined organic layer was washed with saturated NaHCO3 and brine, and was then dried (MgSO4), filtered and the solvent was evaporated in vacuo. Yield: 25.8 g of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (90% yield, crude product; used in next reaction step, without further purification).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]/[C:45]([CH3:55])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:46]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]/[C:45]([CH3:55])([O:47][Si:48]([CH2:51][CH3:52])([CH2:53][CH3:54])[CH2:49][CH3:50])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=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
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C/CO[C@@H](C)C1=CC[C@H]2C3=CC=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
Yield: 104.1 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (E)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (116 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (85.9 mg, 99%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>>[CH3:10][Si:11]([CH3:13])([CH3:12])[C:14]#[C:15][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1ccc(Br)cc1
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1

Procedure:
By the method of example 53(A), 4-bromobenzaldehyde is coupled with (trimethylsilyl)acetylene to provide 4-(2-(trimethylsilyl)ethynyl)benzaldehyde as a pale yellow solid after sublimation in vacuo. This material (5.8 g) is desilylated by stirring with potassium carbonate (0.4 g) in methanol (20 ml) for two hours. The solution is evaporated, and the product dissolved in methylene chloride, washed with water, dried, and concentrated to provide 4-ethynylbenzaldehyde as a yellow solid (3.45 g, 90%). By the Wittig reaction of example 1(A), this is chain-extended to provide 1-ethynyl-4-(2-methoxyethenyl)benzene, obtained as a colorless oil after distillation in vacuo (3.10 g, 77%).
Reaction SMILES: [Br-].[Li+].Cl[C:4]1([O:17][C:12]1([CH:14]([CH3:16])[CH3:15])[CH3:13])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].O>C(=O)([O-])[O-].[Li+].[Li+]>[CH:14]([C:12](=[CH2:13])[C:4](=[O:17])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])([CH3:16])[CH3:15]
Reactant: CC(C)C1(C)OC1(Cl)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: O
Product: C=C(C(=O)C(=O)OC(C)(C)C)C(C)C
Reaction time: 48 h
Yield: 85.2 %

Procedure:
118 g of anhydrous lithium bromide were added under a nitrogen atmosphere at 5° C to a mixture of 117.5 g of tert.-butyl 2-chloro-2,3-epoxy-3-isopropyl-butanoate in 18.5 g of lithium carbonate and 1.15 liters of hexamethylphosphortriamide and after returning to room temperature, the mixture was stirred under a nitrogen atmosphere for 48 hours. 500 ml of distilled water were added thereto and the mixture was added to a decanting flask containing a 9:1 mixture of water and petroleum ether. After decanting, the aqueous phase was extracted with petroleum ether and the combined organic phases were washed with water, dried over magnesium sulfate, then the petroleum ether was evaporated under reduced pressure to obtain 84.6 g of tert.-butyl 3-isopropyl-2-oxo-3-butenoate in the form of a yellow liquid soluble in the usual organic solvents and insoluble in water.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]([OH:33])([CH3:31])[CH3:32])=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1C(C)(C)O
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1C(C)(C)O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 2-(6-chloro-2-methylpyridin-3-yl)propan-2-ol (89 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[N:12]=2)[N:3]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[C:29](O)=[O:30])=[CH:19][C:18]=1[CH3:32]>>[C:13]([C:11]1[N:12]=[C:8]([CH2:7][N:4]2[N:3]=[C:2]([NH:1][C:29]([C:24]3[N:25]=[C:26]([CH3:28])[O:27][C:23]=3[C:20]3[CH:21]=[CH:22][C:17]([I:16])=[C:18]([CH3:32])[CH:19]=3)=[O:30])[CH:6]=[N:5]2)[S:9][CH:10]=1)(=[O:15])[CH3:14]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(I)c(C)c2)o1
Reactant: CC(=O)c1csc(Cn2ncc(N)n2)n1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccc(I)c(C)c3)n2)n1

Procedure:
Following general procedure A, starting from 1-(2-((4-amino-2H-1,2,3-triazol-2-yl)methyl)thiazol-4-yl)ethanone and 5-(4-iodo-3-methylphenyl)-2-methyloxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.12 min; [M+H]+=549.20.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])[CH:15]=[CH:14]3)=[N:3][CH:2]=1.Br[CH2:34][CH2:35][OH:36]>CN(C=O)C>[OH:36][CH2:35][CH2:34][N:8]1[CH2:9][C:5]2[C:4]([O:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=3)=[O:21])[CH:15]=[CH:14]4)=[N:3][CH:2]=[N:1][C:6]=2[CH2:7]1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CNC4)ccc21
Reactant: OCCBr
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CN(CCO)C4)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (125.9 mg, 0.287 mmol) is dissolved in DMF (5 mL) and TEA (80 μL, 0.577 mmol) is added followed by 2-bromoethanol (80 μL, 1.133 mmol). The solution is stirred at rt overnight. Then the reaction is concentrated and absorbed onto silica gel and separated via FCC (0-10%, 10% NH4 in MeOH:DCM) to obtain 5-(6-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide. MS (ESI) m/z 484.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.38 (s, 1 H)8.56 (s, 1 H)8.27 (d, J=9.09 Hz, 1 H)8.09-8.14 (m, 2 H)7.97 (d, J=7.58 Hz, 1 H)7.65 (t, J=8.08 Hz, 1 H)7.48-7.52 (m, 2 H)7.15 (dd, J=8.84, 2.53 Hz, 1 H)6.80 (d, J=3.54 Hz, 1 H)4.57 (t, J=5.56 Hz, 1 H)3.98-4.03 (m, 4 H)3.58 (q, J=6.06 Hz, 2 H) 2.82 (t, J=6.06 Hz, 2 H).
Reaction SMILES: C([NH:3][CH:4]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)=O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>>[NH2:3][CH:4]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(CC(NC=O)c2cccnc2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ccc(CC(N)c2cccnc2)cc1
Temperature: 60 °C
Yield: 70.3 %

Procedure:
To 0.30 g of methyl 4-[2-formamido-2-(3-pyridyl)ethyl]benzoate in 10 ml of methanol-1,4 dioxane (1:1) in solution was added 5 ml of 4% sulfuric acid, and stirred under heating at 60 ° C for three hours, which was then poured into an aqueous saturated solution of sodium hydrogencarbonate to be extracted with ethyl acetate. The organic phase was washed in saturated aqueous sodium chloride solution, and dried over magnesium sulfate, to produce 0.19 g of methyl 4-[2-amino-2-(3-pyridyl)ethyl]benzoate after the evaporation of the solvent.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:21]4=[N:22][C:23](I)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:45]2[CH:50]=[CH:49][C:48]([C@@H:51]3[CH2:56][CH2:55][C@H:54]([OH:57])[CH2:53][CH2:52]3)=[CH:47][CH:46]=2)O1>>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:21]4=[N:22][C:23]([C:45]5[CH:50]=[CH:49][C:48]([C@@H:51]6[CH2:52][CH2:53][C@H:54]([OH:57])[CH2:55][CH2:56]6)=[CH:47][CH:46]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc([C@H]3CC[C@@H](O)CC3)cc2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(I)nc2n1COCC[Si](C)(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C

Procedure:
The title compound is prepared from 2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-5-iodo-3-((2-(tri-methylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine and (cis)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexanol following a procedure analogous to that described for Intermediate 7 Step 2. LC (method 5): tR=1.21 min; Mass spectrum (ESI+): m/z=716 [M+H]+.