Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:35]([O:36][CH3:37])=[CH:34][C:6]2[CH2:7][C:8](=[O:33])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:32])[CH2:16][CH2:17][CH2:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)(=[O:21])=[O:20])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Se](=O)=[O:39]>>[CH3:1][O:2][C:3]1[C:35]([O:36][CH3:37])=[CH:34][C:6]2[C:7](=[O:39])[C:8](=[O:33])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:32])[CH2:16][CH2:17][CH2:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)(=[O:21])=[O:20])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(S(=O)(=O)CCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Reactant: O=[Se]=O
Product: COc1ccc(S(=O)(=O)CCCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[3-(3,4-dimethoxy-phenylsulfonyl)-propyl]-methylamine and selenium dioxide analogously to Example 55.
Reaction SMILES: O1C=CC(C2C3C(=NC=C(N)C=3)NC=2)=C1.C([N:35]1[CH:39]=[C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46]([NH:49]C(=O)OC(C)(C)C)[CH:47]=3)[NH:42][CH:41]=2)[CH:37]=[N:36]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH:35]1[CH:39]=[C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46]([NH2:49])[CH:47]=3)[NH:42][CH:41]=2)[CH:37]=[N:36]1
Reactant: CC(C)(C)OC(=O)Nc1cnc2[nH]cc(-c3cnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3)c2c1
Agent: Nc1cnc2[nH]cc(-c3ccoc3)c2c1
Product: Nc1cnc2[nH]cc(-c3cn[nH]c3)c2c1
Yield: 10.9 %

Procedure:
Inhibitor 53 was synthesized following the method described for preparation of 48 using 51 (150 mg, 0.28 mmol). The reaction mixture was concentrated to dryness in vacuum and separated by means of LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 53 (6.07 mg, 11%). 1H NMR (400 MHz; CDCl3+3 drops of CD3OD) δ 7.26 (s, 1H), 7.66 (s, 2H), 8.54 (d, J=1.9 Hz, 1H), 8.68 (d, J=1.9 Hz, 1H); MS (ES) m/z 241 (MH++MeCN).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=1.[F:29][C:30]1[C:35](O)=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40]>C1COCC1>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[C:24]([O:26][C:35]1[C:34]([F:37])=[C:33]([F:38])[C:32]([F:39])=[C:31]([F:40])[C:30]=1[F:29])=[O:25]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cccc(C(F)(F)F)c1
Reaction time: 3.5 h
Yield: 90.1 %

Procedure:
N,N′-Dicyclohexylcarbodiimide (1.1 g, 5.3 mol) was added to a solution of α,α,α-trifluoro-m-toluic acid (1.0 g, 5.3 mmol) and pentafluorophenol (1.1 g, 5.8 mmol) in THF (10.0 mL). After stirring for 3.5 h, the solvent was removed under vacuum. The residue was dissolved in Et2O (20 mL), filtered, and washed with brine (2×10 mL), dried over Na2SO4, filtered, and evaporated to dryness to provide compound perfluorophenyl 3-(trifluoromethyl)benzoate as a yellow oil (1.7 g, 90%): 1H NMR (300 MHz, CD3OD) δ 8.51-8.39 (m, 2H), 8.09 (d, J=6.0 Hz, 1H), 7.88-7.79 (m, 1H); 19F NMR (282 MHz, CD3OD) δ −64.9 (3F), −155.6 (2F), −165.7 (1F), −168.9 (2F).
Reaction SMILES: C([O:3][C:4](=[O:21])[C@@H:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:9][CH:8]=1)C.[C:22]1([C:28]2[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][C:25]([O:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:19][CH3:20])[C:4]([OH:3])=[O:21])=[CH:12][CH:11]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCCO)cc1)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester and 4-phenylphenol via the standard Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to produce a white oily solid. 1H-NMR (200.15 MHz, CDCl3): δ 7.56–7.28 (m, 9H), 7.15 (d, 2H, J=8.4), 6.98 (d, 2H, J=8.8), 4.15 (t, 2H, J=6.2), 3.97 (dd, 1H, J=7.7, 4.4), 3.36 (s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.97 (dd, 1H, J=14.3, 7.7), 2.62 (t, 2H, J=7.0), 2.08 (qn, 2H, J=6.6).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:17]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.C(Cl)CCl>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:38]([C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:27][CH:28]=2)=[CH:37][CH:36]=1)=[O:39])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCOP(=O)(Cc1ccccc1N)OCC
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Nc3ccccc3CP(=O)(OCC)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 g of (2-amino-benzyl)-phosphonic acid diethyl ester, 2 g of 4′-octyloxy-biphenyl-4-carboxylic acid, 1.4 ml of EDC, 0.9 ml of DIEA and 100 mg of HOAt are dissolved in 30 ml of DMF and the mixture obtained is stirred at rt for 2 days. The mixture obtained is diluted with EtOAc and the solution obtained is washed with aqueous diluted HCl and aqueous NaHCO3 solution. The organic layer obtained is dried and solvent is evaporated. {2-[(4′-Octyloxy-biphenyl-4-carbonyl)-amino]-benzyl}-phosphonic acid diethylester is obtained in crystalline form and is recrystallized from iso-propanol/water.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[N:33]([CH2:36][CH3:37])=[C:34]=[O:35]>O1CCCC1>[CH2:36]([NH:33][C:34]([NH:24][CH2:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:18]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:25])[N:7]=4)[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)=[O:35])[CH3:37]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)NCc1ccc2c(c1)OCCc1sc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine 532 (0.050 g, 0.00014 mol) in tetrahydrofuran (1.0 mL) was added triethylamine (0.0588 mL, 0.000422 mol) then isocyanatoethane (0.110 mL, 0.00141 mol). The reaction was stirred at room temperature overnight, quenched with a small amount of methanol and concentrated in vacuo. The crude was precipitated from MeOH/H2O to give 525. MS (ESI+) 427.1
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH2:14][C:15]3=O)[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CO.C(O)(=O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH2:14][CH:15]3[NH:24][CH3:23])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc2c1CCC2=O
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCc2c(Oc3cc(Cl)ccc3C#N)cccc21
Yield: 78.7 %

Procedure:
4-Chloro-2-(1-oxoindan-4-yloxy)benzonitrile (0.12 g, 0.42 mmol), methylamine (33% in ethanol, 1.0 mL, 8.0 mmol) and sodium cyanoborohydride (100 mg, 0.86 mmol) were stirred at ambient temperature in a solution of glacial acetic acid (1.0 mL) in methanol (30 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (40 mg, 0.34 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-(1-methylaminoindan-4-yloxy)benzonitrile fumarate (111 mg, 63%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(C(C)C)CC)(C)C.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>C(#N)C>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: c1c[nH]cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1ccnc1
Yield: 95.4 %

Procedure:
To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (15.00 g; 71.8 mmol; 1 eq) and diisopropylethylamine (12.5 mL; 71.8 mmol; 1 eq) in anhydrous acetonitrile (650 mL), imidazole (4.88 g; 71.8 mmol; 1 eq) is added under argon. The reaction mixture is allowed to stir under reflux for 20 hours until 1-fluoro-2-nitro-4-(trifluoromethyl)benzene has completely reacted. The crude mixture is concentrated under vacuum and the resulting powder dissolved in ethyl acetate (250 mL). The organic phase is then washed with water (100 mL), brine (100 mL) and dried over sodium sulfate to provide an orange powder after concentration under vacuum. Further purification by flash chromatography on silica gel (ethyl acetate/cyclohexane 5:5) afforded the title compound (17.7 g; 68.5 mmol; 96%) as a brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[OH:29][C:30]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].[OH-].[Na+].Cl>C(Cl)Cl>[OH:29][C:30]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:33]
Reactant: COc1ccc(C(=O)Cl)c(O)c1
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2C(=O)NCCCC(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 1.00 g (4.50 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 ml of dry methylene chloride, add 4.50 g (38.50 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.58 g (5.70 mmol) of triethylamine and a solution of 0.71 g (38.5 mmol) of 2-hydroxy-4-methoxybenzoyl chloride dissolved in 10 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H2O). This yields 0.54 g (38%) of 4-[2-(2-hydroxy-4-methoxybenzoylamino)benzoylamino]butanoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH2:7][NH2:8].[O:30]=[C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[N:32]1[CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44].C(N(CC)CC)C>C(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH2:7][NH:8][S:43]([CH2:42][CH2:41][N:32]1[C:31](=[O:30])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:40])(=[O:44])=[O:45]
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CNS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of (2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl amine (0.060 g, 0.143 mmol) in methylene chloride (3 mL) was added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.043 g, 0.150 mmol) and triethylamine (0.060 mL, 0.43 mmol) and the solution was stirred 1 hr at ambient temperature. The reaction was diluted with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.073 g, 77%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=2[C:12]([OH:14])=O.[CH3:15][N:16]1[C:20]([C:21]2[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=2)[NH2:24])=[CH:19][N:18]=[C:17]1[CH3:28].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][N:16]1[C:20]([C:21]2[CH:22]=[C:23]([NH:24][C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[NH:3][C:2]([CH3:1])=[C:10]4[CH3:11])=[O:14])[CH:25]=[CH:26][CH:27]=2)=[CH:19][N:18]=[C:17]1[CH3:28]
Reactant: Cc1ncc(-c2cccc(N)c2)n1C
Reactant: Cc1[nH]c2c(C(=O)O)cccc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1[nH]c2c(C(=O)Nc3cccc(-c4cnc(C)n4C)c3)cccc2c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
To a suspension of 2,3-dimethylindole-7-carboxylic acid (95 mg) and 3-(1,2-dimethylimidazol-5-yl)aniline (94 mg) in dichloromethane (3 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) and 4-dimethylaminopyridine (30 mg). The mixture was stirred at ambient temperature for 18 hours and diluted with dichloromethane. The solution was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 3% methanol in dichloromethane to give N-[3-(1,2-dimethyl-1H-imidazol-5-yl)-phenyl]-2,3-dimethyl-lH-indole-7-carboxamide (73 mg, 40.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1/[CH:13]=[C:14]1\[CH2:15][N:16]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:18][CH:19]\1O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]([OH:43])(=[S:42])[CH3:41].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.O>C1(C)C=CC=CC=1>[C:40]([S:42][CH:19]1[CH2:18][CH2:17][N:16]([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:15]/[C:14]/1=[CH:13]\[C:9]1[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:12]=[CH:11][N:10]=1)(=[O:43])[CH3:41]
Reactant: CC(C)(C)OC(=O)n1ccnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1nccn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of (E)-3-{[1-(t-butoxycarbonyl)-1H-imidazol-2-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (2.45 g) in toluene (100 ml) were added successively thioacetic acid (0.60 ml) and N,N-dimethylformamide dineopentyl acetal (2.36 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane and dichloromethane (1:5:1) as the eluent to afford the title compound (0.72 g, yield: 26%) as a colourless amorphous solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[C:3]([O:10][CH3:11])[CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C=O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 51 %

Procedure:
To 400 mg (2.60 mmol) of 4-fluoro-3-methoxybenzaldehyde diluted in 10 ml of dimethylsulfoxide are respectively added 483 mg (2.60 mmol) of tert-butyl piperazine-1-carboxylate, then 394 mg (2.85 mmol) of potassium carbonate. The solution is heated to 90° C. for 40 h, then water is added and the product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue obtained is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 8:2) to yield 425 mg of tert-butyl 4-(4-formyl-2-methoxyphenyl)piperazine-1-carboxylate in the form of a colourless oil.
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)C.Cl.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:24]=1.C(N(CC)CC)C>C(#N)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:4]2[C:5](=[O:20])[C:6](=[O:19])[C:7]=2[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)=[C:25]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:24]=1
Reactant: Nc1ccc(Br)cc1-c1nnn[nH]1
Reactant: CCOc1c(Nc2cccc(C(F)(F)F)c2)c(=O)c1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1c(Nc2cccc(C(F)(F)F)c2)c(Nc2ccc(Br)cc2-c2nnn[nH]2)c1=O

Procedure:
0.29 g of 3-ethoxy-4-(3-trifluoromethylphenylamino)-3-cyclobuten-1,2-dione in 25 mL of acetonitrile was added 0.28 g of 4-bromo-2-(1H-tetrazol-5-yl)-phenylamine hydrochloride and 0.1 g of triethylamine. The reaction mixture was heated at reflux for 62 hours, the reaction mixture was concentrated to an oil, the oil was dissolved in ethyl alcohol (96%), to this solution was added hydrochloric acid (4M) and a solid precipitated. The product was isolated by filtration, washed with water and dried by pulling air though it on a glass filter. Yield 0.26 g (56%) mp. 150-165° C.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:50])([CH3:49])[O:6][C@H:7]([C@@H:22]([CH3:48])/[CH:23]=[C:24](/[CH3:47])\[CH2:25][C@H:26]([CH3:46])[C@@H:27]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C@H:28]([CH3:37])[C@@H:29]([OH:36])[C@@H:30]([CH3:35])/[CH:31]=[CH:32]\[CH:33]=[CH2:34])[C@@H:8]([CH3:21])[CH2:9][N:10]([CH3:20])[C:11](=[O:19])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:4])[CH3:3].ClC(Cl)(Cl)[C:53]([N:55]=C=O)=[O:54]>C(Cl)Cl>[NH2:55][C:53]([O:36][C@@H:29]([C@@H:30]([CH3:35])/[CH:31]=[CH:32]\[CH:33]=[CH2:34])[C@@H:28]([CH3:37])[C@H:27]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[C@@H:26]([CH3:46])[CH2:25]/[C:24](/[CH3:47])=[CH:23]\[C@H:22]([CH3:48])[C@@H:7]([O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:49])[CH3:50])[C@@H:8]([CH3:21])[CH2:9][N:10]([CH3:20])[C:11](=[O:19])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:54]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CN(C)C(=O)CC1CCCCC1
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CN(C)C(=O)CC1CCCCC1
Temperature: 23 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A solution of N-[(2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl]-N-methyl-cyclohexaneacetamide (70 mg, 0.096 mmol, 1 eq) in CH2Cl2 (2.0 mL) is treated with trichloroacetyl isocyanate (27.2 g, 0.145 mmol, 1.5 eq) at 23° C. (20 minutes). The solution is concentrated, and the residue dissolved in CH3OH (2.0 mL). To this solution is added K2CO3 (10 mg) and the mixture is stirred at 23° C. (2 hours). The reaction mixture is concentrated and the residue dissolved in Et2O (10 mL). The organic solution is filtered through Celite and concentrated. Chromatography (SiO2, 0–30% EtOAc-hexanes gradient elution) provided the desired compound (70 mg, 94%): HRMS ESI m/z 777.5984 (M+H+, C44H85O5N2Si2 requires 777.5997).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@H:23]4[C@H:19]([O:20][C:21]([CH3:25])([CH3:24])[O:22]4)[C@@H:18]([CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.ClCCCl.O=[C:42]1[CH2:45][CH:44]([CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:23]4[O:22][C:21]([CH3:24])([CH3:25])[O:20][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:28]([CH3:30])[CH3:29])[CH:42]4[CH2:45][CH:44]([CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CNC(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CCOC(=O)CCC1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCC1CC(N(C[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C(C)C)C1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-7-((3aS,4R,6R,6aR)-6-((isopropylamino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (9.50 g, 15.3 mmol) in 1,2-Dichloroethane (75 mL, 950 mmol) was treated with ethyl 3-(3-oxocyclobutyl)propanoate (3.92 g, 23.0 mmol) and Acetic acid (1.0 mL, 18 mmol;) dropwise followed by Sodium triacetoxyborohydride (4.58 g, 21.6 mmol) and the mixture was stirred at RT for 6 days. The reaction mixture was diluted with 150 mL CH2Cl2 and washed with 100 mL sat NaHCO3. The aqueous phase was washed with 100 mL CH2Cl2 and the combined organic phase was dried over Na2SO4, filtered and concentrated to yield a light brown viscous glass.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH2:10][CH:11]([OH:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[H-].[Na+]>C1COCC1>[C:12]([CH:11]1[O:16][C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:5]=2[O:9][CH2:10]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C1COc2c(nc(Cl)nc2N2CCOCC2)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.1 %

Procedure:
To a solution of 1-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-3,3-dimethyl-butan-2-ol (255 mg, 0.73 mmol) in THF (10 mL) was added sodium hydride (87 mg, 2.18 mmol, 60% dispersion in mineral oil) and the mixture was stirred at RT for 1.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution then extracted with ethyl acetate (×2). The combined organic layers were dried (Na2SO4) then passed through a pad of silica eluting with ethyl acetate. The relevant fractions were concentrated in vacuo giving 7-tert-Butyl-2-chloro-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as a white solid (250 mg, 100%). LCMS: RT=3.64 min, [M+H]+=314/316.