Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][C:9]=2[N+:17]([O-])=O)=[CH:4][CH2:3]1.[NH4+].[Cl-]>[Fe].CCOC(C)=O.CCCCCC>[NH2:17][C:9]1[CH:10]=[C:11]([C:14](=[O:16])[CH3:15])[CH:12]=[CH:13][C:8]=1[C:5]1[CH2:6][CH2:7][C:2]([CH3:1])([CH3:20])[CH2:3][CH:4]=1
Reactant: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(N)c1
Yield: 77 %

Procedure:
The title compound was prepared by the procedure of Example 19, using 1-[4-(4,4-dimethyl-cyclohex-1-enyl)-3-nitro-phenyl]-ethanone (as prepared in the previous step, 382 mg, 1.40 mmol), iron powder (391 mg, 7.00 mmol), and NH4Cl (749 mg, 14.0 mmol). Silica gel chromatography (5-20% EtOAc/hexane) afforded the title compound (263 mg, 77%) as a faint yellow solid. Mass spectrum (ESI, m/z): Calcd. for C16H21NO, 244.2 (M+H), found 244.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[C:10]([C:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=3)[CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[C:32]1([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:7][CH:6]=3)[CH:13]=[CH:12][C:11]=2[NH:14][C:15]([C:17]2[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=[C:20]([C:22]#[N:23])[N:21]=2)=[O:16])[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(N)cc2)cc1C1=CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4′-amino-3-cyclohex-1-enyl-biphenyl-4-yl)-amide (as prepared in the Example 28, step (a), 28.1 mg, 0.0547 mmol) in 0.5 mL of DCM was added pyridine (113 μL, 0.16 mmol) followed by methanesulfonyl chloride (5.1 μL, 0.066 mmol). After stirring at RT for 16 h under Ar, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2-4% EtOAc/DCM) to afford 31 mg (95%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.79 (s, 1H), 8.42 (d, 1H, J=8.6 Hz), 7.79 (s, 1H), 7.58 (d, 2H, J=8.6 Hz), 7.48 (dd, 1H, J=8.6, 2.3 Hz), 7.37 (s, 1H), 7.29 (d, 2H, J=8.6 Hz), 6.64 (s, 1H), 5.97 (s, 2H), 5.91 (m, 1H), 3.68 (t, 2H, J=8.2 Hz), 3.05 (s, 3H), 2.24-2.38 (m, 4H), 1.75-1.93 (m, 4H), 0.99 (t, 2H, J=8.2 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C30H37N5O4SSi, 592.2 (M+H), found 591.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([NH:29]C(=O)OC(C)(C)C)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:37]2[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([NH2:29])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Yield: 99.7 %

Procedure:
A solution of tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}carbamate (2.65 g, 4.3 mmol) was stirred in dichloromethane (32 mL) and trifluoroacetic acid (8 mL) for 1.5 h. The reaction was concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with 3.8 M NaOH. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine and dried with MgSO4 to yield 2.21 g (99%) of pure 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.87 (d, J=13.56 Hz, 2 H) 2.15-2.39 (m, 2 H) 3.82-4.11 (m, 2 H) 5.10 (br. s., 2 H) 7.11-7.62 (m, 13 H) 8.40 (s, 1 H), [M+H]+ 515.8.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([CH2:18][C:19]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(O)=O)[CH3:2]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([CH2:18][C:19]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(CCCc1ccccc1)(CC(=O)N1CCOCC1)C(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCc1ccccc1)CC(=O)N1CCOCC1
Yield: 86.5 %

Procedure:
A Solution of 2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid monoethyl ester (809 mg, 2.14 mmol) in toluene (25 ml) was heated under reflux for 23 hours. The colorless solution was concentrated under reduced pressure, the residue was taken up in diethyl ether (50 ml), washed with saturated NaHCO3 and dried over MgSO4. The solvent was evaporated under reduced pressure to give 2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid ethyl ester as yellow oil (617 mg); 1H NMR (CDCl3) 7.3–7.1 (m, 5H), 4.2 (m, 2H), 3.8–3.4 (m, 8H), 3.0 (m ,1H), 2.75 (dd, J=15.9, 9.4 Hz, 1H), 2.65 (m, 2H), 2.35 (dd, J=15.9, 5.1 Hz, 1H), 1.8–1.55 (m, 4H), 1.29 (t, J=7.1 Hz, 3H). MS : 334 (MH30 ).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: C1COCCN1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (60 mg, 0.16 mmol) in DMF (1 mL) were added morpholine (17 mg, 0.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl) (38 mg, 0.20 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, ethyl acetate) yielding the Compound 48 as a solid (20 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCO.CN(C)C=O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:47]([O:50]CC)(=[O:49])[CH3:48]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:48][C:47]([OH:50])=[O:49]
Reactant: CCOC(C)=O
Reactant: OCCCCCCCCCCC(O)c1ccccc1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A 100 mL flask was charged with the previously made 1-(2-Hydroxy-phenyl)-undecane-1,11-diol (5.0 g, 18.9 mmol) and 50 mL of dimethyl formamide. To this was added pyridinium dichromate (32.9 g, 87.5 mmol). (The addition was mildly exothermic.) The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 50 mL of ethyl acetate and washed with 200 mL of water, 30 mL of 4% aqueous hydrochloric acid, 30 mL water, and finally with 30 mL of brine. The organic layer was then stirred with 10 g of silica gel for 15 minutes, dried with sodium sulfate, filtered, and solvent removed under reduced pressure. The off-white crude product was recrystallized from ethanol/water. The product (0.5 g, 10%) was isolated as an off-white solid, mp 85-87° C. Combustion analysis: Found: C, 69.01; H, 8.36%; C16H22O4 requires C, 69.54; H, 8.02% 1H NMR (d6-DMSO): δ 12.0, s, 1H(COOH); δ 7.9 dd, 1H (aryl H); δ 7.5, dt, 1H, (aryl H); δ 6.9, complex multiplet, 2H (aryl H's), 3.1, t, 2H (CH2 α to carbonyl); δ 2.2, t, 2H (CH2 α to COOH); δ 1.6, multiplet, 2H(CH2 β to carbonyl), δ 1.5, multiplet, 2H(CH2 β to COOH), δ 1.3, multiplet, 8H (rest of CH2's).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([O:23]C(=O)CCl)[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[Na+].[Cl-]>CO>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([OH:23])[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CC[C@H](CCCc2ccccc2)[C@H](OC(=O)CCl)C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CCCCOC(=O)N1CC[C@H](CCCc2ccccc2)[C@H](O)C1

Procedure:
A solution of 0.173 g (0.44 mmol) of 1-butyloxycarbonyl(cis)-3-(chloroacetoxy)-4-(3-phenylpropyl)piperidine and 0.30 g (2.2 mmol) of K2CO3 in 5 mL of methanol was stirred at rt for 24 h. To the reaction mixture was added 20 mL of sat'd NaCl solution and the mixture was extracted with ether. The combined organic fractions were dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 1:1) to give 1-butyloxycarbonyl (cis)-3-hydroxy-4-(3-phenylpropyl)piperidine. Removal of the BOC protecting group was achieved as described in Example 233, Step 6 to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:13][Si:14]([CH3:22])([CH3:21])[C:15]#[C:16][Si](C)(C)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](=[O:7])[C:16]#[C:15][Si:14]([CH3:22])([CH3:21])[CH3:13])([O-:3])=[O:2]
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[Si](C)(C)C#CC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 2-nitrobenzoyl chloride (13) (225 g; 1.2 moles) and 1,2-bis(trimethylsilyl)ethyne (205 g; 1.2 moles) in dichloromethane (3 L) was cooled to 0° C. Aluminum chloride (159.2 gram, 1.2 moles) was slowly added at 0° C. over 10 minutes while keeping the internal reaction temperature below 10° C. After the addition, the reaction mixture was stirred at 5-10° C. for 1 hour. With stirring, the black reaction mixture was poured into ice-water mixture (2 kg of ice and 1 kg of water). The resulting suspension was filtered and the filter cake was washed with dichloromethane (200 mL). The organic phase of the combined filtrate was separated. The aqueous phase was extracted 2-times with dichloromethane (2×2 L). The combined organic phase was washed with water (2 L), filtered through a Celite pad (200 g), dried over sodium sulfate (120 g), and concentrated at the temperature below 30° C. (bath temperature) to dryness to give 294 g (99% yield) of the desired product in 95% HPLC purity.
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[OH:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:15]
Reactant: COc1ccc2c(c1OC)CCCC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1CCCc2c1ccc(O)c2O
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution 5,6-dimethoxy-1-tetralone (100 g) in toluene (958 ml) was added aluminum chloride (200 g) in small portions. After the addition was complete the reaction was heated to 80° C. and mechanically stirred for 2 hours. The reaction was cooled and slowly poured into ice and concentrated HCl. The resulting solids were filtered and washed with cold dilute HCl. the resulting solids were taken up into monoglyme, dried (MgSO4), filtered, treated with charcoal, refiltered and concentrated. The residue was co-concentrated with acetonitrile to provide upon cooling 82.5 g of desired product as an off white solid, m.p. 191°-194° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:33]#[CH:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>ClCCl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:33]#[CH:34])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: C#Cc1cc(C(=O)Cl)cc(C#N)c1OC
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1cc(C(=O)N2CSc3ccccc32)cc(C#N)c1OC
Reaction time: 2.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (570 mg) and 37% formalin (0.38 mL) in the same manner as in Example 1 was dissolved in dichloromethane (10 mL), and triethylamine (1.2 mL) and 3-cyano-5-ethynyl-4-methoxybenzoyl chloride were added to the solution, and then the mixture was stirred at mom temperature for 2.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (283 mg) as a yellow oily substance.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[C:3]2=[CH:8][S:9][CH:10]=[C:2]12.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[N+:11]([C:5]1[C:4](=[O:7])[C:3]2[C:2](=[CH:10][S:9][CH:8]=2)[NH:1][CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc[nH]c2cscc12
Solvent: CC(=O)O
Product: O=c1c([N+](=O)[O-])c[nH]c2cscc12
Temperature: 70 °C
Reaction time: 0.05 h
Yield: 48.4 %

Procedure:
To a suspension of 4.00 g of thieno[3,4-b]pyridin-4(1H)-one 9 in 120 ml of acetic acid is added 3.00 g of nitric acid (d=1.38). The reaction mixture is stirred at 70° C. for 3 minutes and cooled to room temperature. The resulting crystals are collected by filtration, and then washed with water and methanol-ether, affording 2.51 g (48%) of Compound 10. An analytical sample is recrystallized from dimethylsulfoxide-methanol to give yellow crystals melting at 329°-332° C.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][C:18](=[CH2:21])[CH2:17][CH2:16]2)=[C:11]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.OO.[OH-].[Na+].S(S([O-])(=O)=O)([O-])(=O)=[O:44].[Na+].[Na+]>C1COCC1>[Si:23]([O:22][C:11]1[CH:10]=[C:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[CH:14]=[CH:13][C:12]=1[C@@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][OH:44])[CH2:19][CH2:20]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25]
Reactant: C=C1CCC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Reactant: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](CO)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: -78 °C

Procedure:
tert-Butyl[3-{[tert-butyl(dimethyl)silyl]oxy}-4-(4-methylenecyclohexyl)phenoxy]dimethyl silane (135 mg) was dissolved in anhydrous THF (5 ml) with stirring and cooled to −78° C. 9-Borabicyclo[3.3.1]nonane (3.13 ml, 0.5M in THF) was added to the stirred solution and the resulting reaction mixture allowed to warm to room temperature over 3 hr and then stirred for 3 days. Cooling to 0° C. was followed by addition of hydrogen peroxide (1 ml, 30% aqueous solution) and sodium hydroxide (1 ml, 2M aqueous solution). The reaction mixture was allowed to warm to room temperature with stirring over 1 hr, cooled to 0° C., and saturated aqueous sodium metabisulphate solution (30 ml) was added. The layers were separated and the aqueous layer extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous magnesium sulphate, and concentrated in vacuo. Purification via flash column chromatography (SiO2 eluting with petroleum ether:diethyl ether, 3:17 v/v) afforded the desired product as a yellow oil (73 mg, 52%). δH (CDCl3): 0.18 (6H, s), 0.22 (6H, s), 0.97 (9H, s), 1.00 (9H, s), 1.03-1.15 (0.5H, m), 1.22-1.33 (0.5H, m), 1.43-1.61 (4H, m), 1.77-1.94 (4H, m), 2.75-2.92 (1H, m), 3.47 (1H, d), 3.70 (1H, d), 6.26-6.29 (1H, m), 6.37-6.40 (1H, m), 6.93-6.97 (1H, m).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[N:28]=[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]=O)[N:20]2[N:19]=1.O>O1CCCC1>[CH3:17][C:18]1[N:28]=[C:21]2[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:20]2[N:19]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1nc2cccc(C=O)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cccc2nc(C)nn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a suspension of sodium hydride (0.570 g, 13.0 mmol) in tetrahydrofuran (50 mL) was added a solution of ethyl diethylphosphonoacetate (2.36 mL, 11.8 mmol) in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methyl[1,2,4]triazolo[1,5-a]pyridine-5-carbaldehyde (1.90 g, 11.8 mmol) in tetrahydrofuran (58 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (2.50 g, yield 92%).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.[Cl:10][C:11]1[CH:12]=[C:13]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][C:34]=3[O:36][CH2:37][CH2:38][NH:39][CH3:40])[N:29]=[CH:28][N:27]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][C:34]=3[O:36][CH2:37][CH2:38][N:39]([CH3:40])[C:4](=[O:6])[C@@H:3]3[CH2:7][CH2:8][CH2:9][N:2]3[CH3:1])[N:29]=[CH:28][N:27]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)[C@@H]1CCCN1C
Yield: 38 %

Procedure:
The procedure described in Example 1 was repeated using 1-methylproline and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 38% yield; NMR spectrum (DMSO-d6) 1.55-1.68 (m, 3H), 1.92-2.03 (m, 2H), 2.12 (s, 2H), 3.29 (s, 6H), 3.87-4.03 (m, 2H), 4.40-4.61 (m, 2H), 5.31 (s, 2H), 7.17 (d, 1H), 7.22 (d, 1H), 7.33 (d, 1H), 7.35-7.39 (m, 1H), 7.57-7.63 (m, 2H), 7.69-7.75 (m, 1H), 7.86-7.91 (m, 1H), 8.05 (d, 1H), 8.43 (s, 1H), 8.60 (d, 1H), 9.76 (s, 1H); Mass spectrum MH+ 547.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[C:8]([OH:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:15]([O-])([OH:17])=[O:16]>[N+](C)([O-])=O>[F:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([OH:14])=[C:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1
Reactant: CCCc1cc(F)c(C(=O)O)cc1O
Reactant: O=[N+]([O-])O
Solvent: C[N+](=O)[O-]
Product: CCCc1cc(F)c(C(=O)O)c([N+](=O)[O-])c1O
Temperature: 40 °C
Yield: 48 %

Procedure:
2-Fluoro-5-hydroxy-4-propylbenzoic acid (500 mg, 2.52 mmol) was dissolved in nitromethane (50 mL) through heating to 40° C. and nitric acid (90%, 120 μL, 2.52 mmol) was added. After 10 min at 40° C. followed by reaction at room temperature for 2 h the solvent was evaporated. The residue was dissolved in EtOAc (150 mL), washed with brine (10 mL), dried (MgSO4) and concentrated to dryness giving 640 mg of crude product. Subsequent purification by flash chromatography (SiO2, EtOAc-HOAc 50:1) afforded pure 6-fluoro-3-hydroxy-2-nitro-4-propylbenzoic acid (294 mg). Mp: 128.0°-129.0° C. 1H NMR (DMSO-d6); δ10.2 (br, 1H), 7.39 (d, J=10.4 Hz, 1H), 2.63 (t, J=7.6 Hz, 2H), 1.55 (m, J=7.5 HZ, 2H), 0.89 (t, J=7.4 Hz, 3H). 13C NMR (DMSO-d6): δ162.49, 151.66 (d, J=245 Hz), 143.69, 138.74 (d, J=5 Hz), 138.17 (d, J=8 Hz), 120.25 (d, J=23 Hz), 113.82 (d, J=21 Hz), 31.44, 21.92, 13.60. MS (EI, 70 eV): m/z (rel. int) 243 (M+, 88).
Reaction SMILES: [OH:1][C@H:2]([CH3:24])[CH2:3][NH:4][C:5]([CH3:23])([CH3:22])[CH2:6][C:7]([NH:9][C@@H:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[NH:12][C:11]1=[O:21])=[O:8].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42])(=O)=O>C(Cl)Cl>[CH2:41]([Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[O:1][C@H:2]([CH3:24])[CH2:3][NH:4][C:5]([CH3:23])([CH3:22])[CH2:6][C:7]([NH:9][C@@H:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[NH:12][C:11]1=[O:21])=[O:8])[CH3:42]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: C[C@@H](O)CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@H](C)CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a stirred solution of 660 mg (1.48 mmol) of the intermediate obtained in Step B in 3 mL of methylene chloride at room temperature was added 1.1 mL of N,N-diisopropylethylamine (0.81 g, 4.2 eq.) followed by 0.71 mL of triethylsilyl trifluoromethanesulfonate (0.83 g, 2.1 eq.). The resulting mixture was stirred at room temperature for 2 hours then partitioned between ethyl acetate and saturated aqueous sodium chloride (buffered to pH 9 with 2 drops of ammonium hydroxide). The organic layer was separated, washed with buffered brine, dried over magnesium sulfate, filtered and solvents evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica, eluting with ethyl acetate/0.1% ammonium hydroxide in methanol (85:15), to afford 480 mg (1.07 mmol, 72%) of product. 1H NMR (200 MHz,CD3OD): 0.63 (q,8 Hz,6H), 0.97 (t,8 Hz,9H), 1.14 (s,6H), 1.18 (d,6 Hz,3H), 2.05 (m,1H), 2.28 (d,2Hz,2H), 2.35-3.00 (m,5H), 4.01 (m,1H), 4.44 (dd;8,12 Hz;1H), 7.05 (d,8 Hz,1H), 7.10-7.35 (m,3H). FAB-MS: calculated for C24H41N3O3Si 447; found 448 (M+H, 100%).