Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[F:24]C1C=CC([Mg]Br)=CC=1>>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:24])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COC(=O)[C@H]1[C@@H](c2ccc([Si](C)(C)C)cc2)C[C@@H]2CC[C@H]1N2C
Product: COC(=O)[C@H]1[C@@H](c2ccc(F)cc2)C[C@@H]2CC[C@H]1N2C

Procedure:
This compound was synthesized using a similar reaction as 2β-Carbomethoxy-3β-(4′-trimethylsilylphenyl)tropane starting with anhydroecognine methyl ester and 4-fluorophenylmagnesium bromide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH:5]=[N:6][OH:7].OC1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[C:34]#[CH:35]>C(#N)C.C(OCC)(=O)C>[CH2:38]([O:37][C:33]([C:34]1[O:7][N:6]=[C:5]([C:4]2[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=2)[CH:35]=1)=[O:36])[CH3:39]
Reactant: C#CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1F
Agent: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])c(F)c2)no1
Yield: 70.1 %

Procedure:
To a solution of 3-fluoro-4-nitro-benzaldehyde oxime (6 g; 32.6 mmol) in acetonitrile (120 mL) was added hydroxy tosyloxy iodobenzene (16.58 g; 42.3 mmol) and ethyl propiolate (6.38 g; 65.2 mmol) under stirring. The resulting reaction mixture was stirred at 80° C. for 2-3 h. After the completion of the reaction, it was evaporated to dryness. The solid thus obtained was dissolved in ethyl acetate and washed with brine and dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by flash chromatography over silica gel with 20% ethyl acetate in light petroleum to give 6.4 g (74%) of the title compound. IR (KBr): 3134, 3060, 2975, 1717, 1610, 1593, 1522, 1458, 1446 cm−1; MS (m/z): 279 (M−−1); 1H NMR (DMSO-d6) δ: 1.31-136 (t, 3H, CH2CH3), 4.36-4.43 (q, 2H, CH2CH3), 8.04 (d, 1H, J=9.0, 6′-H), 8.09 (s, 1H, 4-H), 8.16 (d, 1H), 8.30 (t, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[N:19]=1.CN(C(ON1N=N[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.N1CCCCC1>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:41]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)=[O:17])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[N:19]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(-c3nc4ccncc4[nH]3)c2)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2ccc(Cl)c(-c3nc4ccncc4[nH]3)c2)CC1)N1CCCCC1
Temperature: 35 °C
Yield: 37.7 %

Procedure:
Method C—Step f A mixture of 1-[4-Cloro-3-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]-piperidine-4-carboxylic acid hydrochloride (0.09 g, 0.25 mmol), HATU (0.10 g, 0.26 mmol), triethylamine (TEA) (0.08 mL, 0.55 mmol), piperidine (0.03 g, 0.31 mmol) and dichloromethane (2 mL) was heated at 35° C. overnight. Reaction was cooled to room temperature, washed with ammonium chloride solution (3 mL) and the crude was purified by SCX (eluent: NH3 2N in MeOH) and flash chromatography (eluent: AcOEt:MeOH, 9:1), to obtain 0.04 g of the title compound (37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.CO.[F:14][CH2:15][C:16](=O)[CH3:17].N1CCCC1>CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:10])[CH2:9][C:16]([CH2:15][F:14])([CH3:17])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(Cl)cc1O
Reactant: CC(=O)CF
Solvent: COC(C)(C)C
Solvent: C1CCNC1
Solvent: CO
Product: CC1(CF)CC(=O)c2ccc(Cl)cc2O1
Reaction time: 72 h
Yield: 94.3 %

Procedure:
1-(4-Chloro-2-hydroxyphenyl)ethanone (10.2 g, 59.8 mmol), MeOH (100 mL), fluoroacetone (5.00 g, 65.8 mmol), and pyrrolidine (5.44 ml, 65.8 mmol) were stirred at ambient temperature. After 3 days, LCMS showed complete reaction. The reaction mixture was diluted with MTBE (250 mL), washed with water (100 mL), 2N HCl (2×50 mL), brine (50 mL), 2N NaOH (2×50 mL), and brine (2×50 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to provide the title compound (12.9 g, 56.4 mmol, 94% yield) as a brown oil. MS (DCI/NH3) m/z 246 (M+NH4)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[N:21]=[CH:20]2>>[OH:29][C:27]([CH3:30])([CH3:28])[CH2:26][N:22]1[C:23]2[C:19](=[CH:18][C:17]([CH2:16][NH:15][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: CC(C)(O)Cn1ncc2cc(CN)ccc21
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3CC(C)(C)O)c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and 1-(5-(aminomethyl)-1H-indazol-1-yl)-2-methylpropan-2-ol (step-2 of Example 22).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13](=[O:15])(=[O:14])[C:12]3[CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=[CH:19][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:23]=1)(=[O:3])[CH3:2].C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13](=[O:14])(=[O:15])[C:12]3[CH:16]=[C:17]([CH2:20][OH:21])[CH:18]=[CH:19][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:23]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2(=O)=O
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: CC(=O)c1ccc2c(c1)CCc1ccc(CO)cc1S2(=O)=O

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-acetyl-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[N:9][CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[C:8]2=[N:9][CH:10]=[C:11]([NH2:13])[CH:12]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc([N+](=O)[O-])cnc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCc2cc(N)cnc21
Yield: 65.1 %

Procedure:
A suspension of 0.43 g (2.08 mmol) of 1-acetyl-2,3-dihydro-5-nitro-1H-pyrrolo[2,3-b]pyridine (Tetrahedron Lett. 1987, 1589) and 0.044 g of 10% palladium-on-charcoal in 15 mL of ethanol is stirred vigorously for 6 hours at room temperature and under 5 atmospheres of hydrogen. After this time, the suspension is filtered through Celite and the filtrate is concentrated under reduced pressure to give 0.24 g of the expected product in the form of a solid.
Reaction SMILES: N#N.[C:3]([C:6]1[N:7]=[C:8]([CH2:11]OS(C)(=O)=O)[O:9][CH:10]=1)(=[O:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].[N+:23]([C:26]1[NH:30][N:29]=[CH:28][CH:27]=1)([O-:25])=[O:24].[Br-]>CC(C)=O>[N+:23]([C:26]1[CH:27]=[CH:28][N:29]([CH2:11][C:8]2[O:9][CH:10]=[C:6]([C:3](=[O:5])[CH3:4])[N:7]=2)[N:30]=1)([O-:25])=[O:24]
Reactant: CC(=O)c1coc(COS(C)(=O)=O)n1
Reactant: O=[N+]([O-])c1ccn[nH]1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: CC(=O)c1coc(Cn2ccc([N+](=O)[O-])n2)n1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 4-acetyl-oxazol-2-ylmethyl ester (70 mg, 0.32 mmol) in acetone (5.0 mL) was treated with K2CO3 (223 mg, 1.60 mmol) followed by 5-nitro-1H-pyrazole (37 mg, 0.32 mmol) and TBA bromide (21 mg, 0.06 mmol). The reaction mixture was stirred at rt until completion. The solvent was removed under reduced pressure and water (10 mL) followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow solid. TLC: rf (EA)=0.50. LC-MS-conditions 02: tR=0.74 min; [M+H]+=237.31.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.Cl.[NH2:14][CH2:15][CH2:16][SH:17]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[NH:14][CH2:15][CH2:16][S:17]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: NCCS
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(C2NCCS2)cc1OC
Temperature: 25 °C
Reaction time: 40 h
Yield: 65.6 %

Procedure:
To a solution of 3,4-dimethoxybenzaldehyde (2.19 g, 13.2 mmol) in ethanol (15 ml) was added dropwise a solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (5 ml) and the solution stirred at RT for 40 h. The bulk of the ethanol was removed by rotary evaporator and the residue was diluted with water (15 ml) and extracted with diethyl ether (3×20 ml) to remove excess aldehyde. The aqueous layer was basified with solid sodium carbonate (0.3 g) resulting in the formation of an oil. The mixture was extracted with ether (2×25 ml), washed with brine (1×50 ml), dried (MgSO4) and evaporated to give a clear oil that solidified on standing (0.77 g). The material was triturated with hexane (3×5 ml) to give 2-(3,4-dimethoxyphenyl)-1,3-thiazolane (8) as a friable white solid (0.65 g, 66%), mp 54-56°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:20])[N:8]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:9]3=[N:10]2)=[CH:5][CH:4]=1.Cl[CH2:22][CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27]>>[CH2:25]([N:24]([CH2:28][CH2:29][CH3:30])[CH2:23][CH2:22][N:13]1[C:9]2=[N:10][C:11]3[C:6]([C:7](=[O:20])[N:8]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]1=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:26][CH3:27]
Reactant: CCCN(CCC)CCCl
Reactant: COc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13
Product: CCCN(CCC)CCn1c2ccccc2n2c(=O)c3ccc(OC)cc3nc12

Procedure:
6-(2-di(n-Propyl)aminoethyl)-3-methoxybenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-methoxybenzimidazo[2,1-b]-quinazolin-12(6H)one and 2-chlorodi(n-propyl)aminoethane.
Reaction SMILES: [N:1]([CH:4]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH:13]([C:15]([O:17]C)=[O:16])[CH3:14])[C:5]1=[O:19])=[N+:2]=[N-:3]>[OH-].[Na+]>[N:1]([CH:4]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH:13]([C:15]([OH:17])=[O:16])[CH3:14])[C:5]1=[O:19])=[N+:2]=[N-:3]
Reactant: COC(=O)C(C)N1CCCCCCC(N=[N+]=[N-])C1=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)N1CCCCCCC(N=[N+]=[N-])C1=O

Procedure:
Add 170 mg of this azide to a suspension of 30 mg NaH in 3 ml THF followed by a solution of 400 mg methyl 2-iodoproprionate in 2 ml THF. Heat the reaction mixture under nitrogen at 55° for 18 hr. Cool the reaction and add a few drops of H2O followed by ether. Wash the mixture with 5% NaHSO3, water, and brine. Dry the organic phase and concentrate in vacuo. Chromatograph this crude product on silica gel eluting with ethyl acetatehexane and isolate 3-azido-1-(1-carbomethoxyethyl)- perhydroazonin-2-one. Hydrolyze this ester in 1M NaOH. Acidify the reaction and extract with methylene chloride to obtain 3-azido-1-(1-carboxyethyl)perhydroazonin-2-one. Separate the diastereomers by reverse phase chromatography using acetonitrile-water mixtures.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[CH3:9])(C)(C)C.[ClH:16]>O1CCOCC1>[ClH:16].[NH2:7][C@H:8]([CH3:9])[C:10]([N:11]([CH3:13])[CH3:12])=[O:14]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](N)C(=O)N(C)C

Procedure:
((R)-1-Dimethylcarbamoyl-ethyl)-carbamic acid tert-butyl ester (1.1 g, 5.1 mmol) was dissolved in 26 mL of cold 4M HCl in dioxane. After 1.5 h the reaction was evaporated to provide (R)-2-amino-N,N-dimethyl-propionamide hydrochloride which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH3:57])=[CH:51][CH:50]=2)=[CH:4][C:5]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[C:6]([OH:8])[CH:7]=1.CCN(CC)CC.[Br:65]Br.[NH4+].[Cl-]>CC(O)=O>[Br:65][C:7]1[C:2]([Cl:1])=[C:3]([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:56][CH3:57])=[CH:53][CH:54]=2)[CH:4]=[C:5]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)[C:6]=1[OH:8]
Reactant: BrBr
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(Br)c2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of phenol 27 (0.98 g, 1.24 mmol) in AcOH (12 mL) were added Et3N (0.37 mL, 1.86 mmol) and bromine (77 μL, 1.50 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min and at room temperature for 12 hours. The reaction mixture was cooled to 0° C. and aqueous saturated NH4Cl solution (30 mL) was added to the mixture. The mixture was extracted with EtOAc (100 mL). The organic layer was washed with H2O (50 mL×2), aqueous saturated NaHCO3 solution (100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude 2-bromo-3-chloro-4-(4-ethoxybenzyl)-6-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenol (28, 1.08 g) was carried on to the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].[Br:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14](Cl)=[N:15][CH:16]=1.[H-].[Na+].C(OCC)(=O)CO>O1CCOCC1>[Br:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14]([O:5][CH2:4][C:3]([O:7][CH2:8][CH3:9])=[O:6])=[N:15][CH:16]=1
Reactant: CCOC(=O)CO
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a suspension of sodium hydride (5.31 g, 133 mmol) in 1,4-dioxane (250 mL) was added drop wise ethyl glycolate (12.56 ml, 133 mmol) over a period of 30 minutes ensuring that the temperature was maintained below 30° C. The resulting thick suspension was stirred at room temperature for 15 minutes. In a separate 1 L round-bottomed flask was added 5-bromo-2-chloro-3-nitropyridine (21 g, 88 mmol) in 1,4-dioxane (150 mL) to give a brown solution. The sodium hydride/ethyl glycolate slurry was added drop wise over a period of 30 minutes. The resulting reaction mixture was heated to 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified via Biotage chromatography (silica 340 g column, gradient elution from 0% to 10% ethyl acetate in cyclohexane) to give a pale yellow solid (11.8 g, 43% yield). 1H NMR (500 MHz, CDCl3): 8.48 (1H, d), 8.42 (1H, d), 5.07 (2H, s), 4.25 (2H, q), 1.30 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[N:16]=[C:17]([CH3:19])[N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:22])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:22][C:13]1[N:12]2[N:16]=[C:17]([CH3:19])[N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: Cc1nc2cc(-c3ccc(Cl)cc3Cl)nc(O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: Cc1nc2cc(-c3ccc(Cl)cc3Cl)nc(Cl)n2n1

Procedure:
In analogy to Example 53A, 676 mg (49% of theory) of the product are obtained from 685 mg (2.31 mmol) of 7-(2,4-dichlorophenyl)-2-methyl[1,2,4]triazolo[1,5-c]pyrimidin-5-ol (Example 136A) by reaction in 6 ml of phosphoryl chloride and 1.59 g (6.96 mmol) of benzyltriethylammonium chloride.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH2:12][CH:13]=[CH:14][OH:15])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2[S:8][C:9]([CH2:12][CH2:13][CH2:14][OH:15])=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC=CCc1cnc(-c2ccccc2)s1
Agent: [Pd]
Solvent: CO
Product: OCCCc1cnc(-c2ccccc2)s1
Yield: 78.3 %

Procedure:
A solution of 960 mg of the product of Stage F in 10 ml of methanol was hydrogenated for 12 hours at one atmosphere, then for 9 hours under 1.4 atmospheres in the presence of 150 mg of palladium on charcoal. After filtration, evaporation to dryness under reduced pressure was carried out. The residue was chromatographed on silica (eluant: ethyl acetate-cyclohexane (4-6)) to obtain 759 mg of the desired product.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].Br[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[I-].[K+]>C(N(C(C)C)CC)(C)C>[F:1][CH:2]([F:5])[CH2:3][NH:4][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCBr
Reactant: NCC(F)F
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNCC(F)F
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 62.7 %

Procedure:
2,2-difluoroethylamine (0.50 g) was added to a suspension of ethyl 3-bromopropanoate (1.1 g), potassium iodide (0.10 g) in diisopropylethylamine (1.2 mL) and the mixture was stirred at 100° C. for 3.5 h. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the sub-title compound (0.69 g) as a pale yellow oil; 1H NMR (300 MHz, CDCl3); 5.81 (1H, tt), 4.13 (2H, q), 2.95 (2H, dt), 2.93 (2H, t), 2.48 (2H, t), 1.24 (3H, t).
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:11]([F:22])[CH:10]=2)[CH2:5][CH2:4]1.[Mg].Br[CH2:25][C@H:26]1[CH2:31][CH2:30][Si@H:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]1>[Cu]I.P(OCC)(OCC)(OCC)=O.C1COCC1>[CH2:32]([Si@H:29]1[CH2:30][CH2:31][C@H:26]([CH2:25][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)=[C:11]([F:22])[CH:10]=3)[CH2:5][CH2:4]2)[CH2:27][CH2:28]1)[CH2:33][CH3:34]
Reactant: CCC[Si@H]1CC[C@H](CBr)CC1
Reactant: Fc1ccc(-c2ccc([C@H]3CC[C@H](CBr)CC3)cc2F)cc1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)cc4)c(F)c3)CC2)CC1

Procedure:
38.3 g (0.1 mol) of 4-(trans-4-bromomethylcyclohexyl)-2,4'-difluorobiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 22.1 g (0.1 mol) of trans-1-bromomethyl-4-n-propyl-4-silacyclohexane. After a conventional after treatment, purification was conducted by means of chromatography to obtain 37.6 g (yield 81.3%) of 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-2,4'-difluorobiphenyl.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:27])[N:8]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:37][C:38]([Cl:45])([Cl:44])[CH2:39][O:40][C:41](Cl)=[O:42]>C1COCC1>[Cl:37][C:38]([Cl:45])([Cl:44])[CH2:39][O:40][C:41](=[O:42])[NH:27][C:7]1[N:8]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3cnn(CCN4CCOCC4)c3c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3cnn(CCN4CCOCC4)c3c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.1 %

Procedure:
A solution of Intermediate 24a (134 mg, 0.36 mmol) was formed in THF (10 mL). DIPEA (125 μL, 0.72 mmol) was added followed by the dropwise addition of a solution of 2,2,2-trichloroethylchloroformate (50 μ□L, 0.36 mmol) in THF (2 mL). The mixture was stirred at RT for 4 h, then partitioned between EtOAc/water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by FCC, using 0-10% MeOH in EtOAc, gave the title compound (200 mg, 99%) as a colourless film. LCMS (Method 4): Rt 2.59, m/z 543, 545 [MH+].
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(CN)cc3)ccc21

Procedure:
A solution of 8.2 g (26 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzonitrile (Example 1) in 150 ml of absolute ether was added dropwise to a suspension of 2.8 g (73 millimoles) of lithium aluminum hydride in 150 ml of absolute ether at room temperature in the course of 25 minutes. The mixture was stirred under reflux for 3.5 hours and then cooled, after which water was added carefully, sodium sulfate solution was added dropwise and the phases were separated. The aqueous phase was extracted twice with ether, and the combined ether phases were washed once with water, dried over Na2SO4 and evaporated down. 7.7 g (93%) of the title compound of melting point 84°-88° C. remained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:18][C:9]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)on1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of ethyl 5-(4-chlorophenyl)isoxazole-3-carboxylate (250 mg, 1.0 mmol) and N-chlorosuccinimide (267 mg, 2.0 mmol) in acetic acid (5 mL) was heated to reflux for 3 days. The reaction mixture was then allowed to cool to room temperature, poured over ice and the resulting pale yellow solid was collected, washed with portions of water, and dried to obtain ethyl 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylate (234 mg, 0.82 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]([Cl:24])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[CH3:16])[C:6]1=[O:17].B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([Cl:24])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[CH3:16])[C:6]1=[O:17]
Reactant: COc1cc(Cl)c(CC2CCN([C@@H]3CCCC[C@@H]3C)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CCCC[C@H]1N1CCC(Cc2c(Cl)cc(O)cc2Cl)C1=O
Temperature: 0 °C
Yield: 85.7 %

Procedure:
Dissolve 3-(2,6-dichloro-4-methoxybenzyl)-1-(cis-2-methylcyclohexyl) pyrrolidin-2-one (1.29 g, 3.47 mmol) in DCM (100 mL) and cool to 0° C. Stir the solution under N2 and add BBr3 (2.61 g, 10.42 mmol). Continue to stir the reaction mixture for 2 hours and add water (100 mL). Extract the aqueous layer with dichloromethane (3×200 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 40-100% of EtOAc-Hexane) to give 1.06 g (85%) of the title compound as a white solid: MS (APCI-pos mode) m/z (rel intensity) 356.1 (100), 358.1 (60).