Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][C@H:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].N1C=CN=C1>C(Cl)Cl>[Si:5]([O:9][C@H:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CCOC(=O)C[C@@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.1 %

Procedure:
tert-Butylchlorodimethylsilane (547 g, 3.63 mol) was added to a stirred solution of (R)-ethyl 3-hydroxybutanoate (400 g, 3.03 mol) in DCM (800 mL) under nitrogen at 0° C. Imidazole (412 g, 6.05 mol) was added portion wise over 20 min to the reaction mixture during which time the mixture became a thick white slurry. Additional DCM (175 mL) was added and the mixture was allowed to warm to room temperature and stirred for 16 h. The white solid was removed by filtration, rinsed with DCM (500 mL), partitioned between water (1 L) and DCM (500 mL), and the aqueous layer was further extracted with additional DCM (500 mL). The filtrate was combined with the organic layers and washed with water (500 mL) and brine, dried over MgSO4 and filtered. The product was concentrated and dried under high vacuum to yield (R)-ethyl 3-(tert-butyldimethylsilyloxy)butanoate (777.5 g), containing unidentified impurities. The analytical data of the crude product complied with data reported in the literature. The material was used without additional purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[N:10]3[C:14]([CH2:15][NH:16][CH2:17][C:8]=2[CH:7]=1)=[N:13][N:12]=[C:11]3[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1>>[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[N:10]3[C:14]([CH2:15][N:16]([C:1](=[O:3])[CH3:2])[CH2:17][C:8]=2[CH:7]=1)=[N:13][N:12]=[C:11]3[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[CH:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1
Reactant: CC(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Yield: 37 %

Procedure:
The title compound was prepared from acetyl chloride and the amine of example 12, in 37% yield, using the procedure described in example 3.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.[CH3:31][C:32]1[CH:41]=[C:40]([OH:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.C[Si](Cl)(C)C.N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[OH:42][C:40]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[C:32](/[CH:31]=[CH:1]/[C:3]2[N:4]=[C:5]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[N:7][N:6]3[C:17]=2[C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:20][CH:19]=2)[CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: Cc1cc(O)c2ccccc2n1
Agent: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3cc(O)c4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a mixture of compound 5f (150 mg, 0.367 mmol) and 2-methylquinolin-4-ol (292 mg, 1.84 mmol) in 4 mL of DMF was added TMSCl (469 μL, 3.67 mmol) dropwise. The resulting mixture was stirred at 90° C. for 16 h. After cooling to rt, the mixture was treated with 60 mL of EtOAc and washed with water (3×20 mL) and brine (15 mL). The solvent was removed in vacuo and the residue was treated with DCM (5 mL). To this mixture was added imidazole (50.0 mg, 0.734 mmol), and the resulting mixture turned clear and was purified by flash column chromatography on silica gel (0:1-1:19 MeOH/DCM) to afford compound 64a as a yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 11.97 (br. s., 1H), 8.26 (d, J=7.8 Hz, 1H), 7.88-8.03 (m, 3H), 7.43-7.83 (m, 6H), 7.22 (t, J=7.5 Hz, 1H), 6.49 (s, 1H), 6.03 (d, J=5.6 Hz, 1H), 3.94 (br. s., 4H), 3.82 (br. s., 4H), 1.55 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C32H31N5O4, 550.2 (M+H). found 550.5.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([OH:32])[CH2:18][O:19][C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[NH:28][C:29](=[O:31])[CH3:30])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.CN(C=O)C.B(Br)(Br)[Br:41]>C(Cl)Cl>[Br:41][C:23]1[C:24]([O:26][CH3:27])=[CH:25][C:20]([O:19][CH2:18][C@@H:17]([OH:32])[CH2:16][N:13]2[CH2:12][CH2:11][CH:10]([N:6]3[C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][C:4]=4[NH:8][C:7]3=[O:9])[CH2:15][CH2:14]2)=[C:21]([NH:28][C:29](=[O:31])[CH3:30])[CH:22]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(NC(C)=O)c(OC[C@@H](O)CN2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(OC[C@@H](O)CN2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)c(NC(C)=O)cc1Br
Reaction time: 8 h
Yield: 45 %

Procedure:
To a stirred suspension of N-[2-({(2S)-3-[4-(5-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-methoxyphenyl]acetamide (Example 32 iii)) (0.17 g, 0.36 mmol) in CH2Cl2 (5 ml) with some drops of DMF a solution of boron tribromide (BBr3) in dichloromethane (CH2Cl2) (1M, 1.08 mmol, 1.08 ml) was added dropwise under nitrogen. The stirring was continued overnight art room temperature. Then the reaction mixture was quenched with methanol, diluted with water and extracted with dichloromethane (CH2Cl2) (2×10 ml) and ethyl acetate (2×10 ml). The combined organic extracts were dried with sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography of silica gel (CH2Cl2/MeOH, 9:1) to give a colourless solid (89 mg, 0.16 mmol, 45%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([O:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1)=[CH2:13])C>C1COCC1.O>[Br:1][CH2:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13]
Reactant: C=C(OCC)c1ncccc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: COc1cccnc1C(=O)CBr
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Add N-bromo-succinimide (306 mg, 1.7 mmol) to a stirred solution of 2-(1-ethoxy-vinyl)-3-methoxy-pyridine (305 mg, 1.7 mg) in THF (30 mL) and water (2 mL). Stir for 15 mins. at RT under N2. Adsorb on SiO2 and purify by flash chromatography on silica gel eluting with 0-40% EtOAc/hexanes to afford the title compound (211 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23](O)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][NH:33][CH2:32][CH2:31]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][CH:37]=[C:28]([F:27])[CH:29]=4)[CH2:34]3)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Reactant: Fc1ccc2c(c1)CCNC2
Agent: Cl
Product: COc1cc(-c2nc(C(=O)N3CCc4cc(F)ccc4C3)c3ccccc3n2)cc(OC)c1OC
Yield: 63.4 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 94 (63.4% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.88 and 3.07 (2t, 2H), 3.54 and 4.05 (2t, 2H), 3.76-3.78 (2s, 3H), 3.87 and 3.92 (2s, 6H), 4.50 and 5.00 (2s, 2H), 6.93-7.14 (m, 2H), 7.38-7.91 (m, 4H), 7.99-8.18 (m, 3H); MS (ESI) m/z 474 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:49])[C@@H:9]([CH3:48])[C:10]([NH:12][C@@H:13]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C:14]([N:16]1[CH2:20][C@@H:19]([NH:21][C:22]([O:24][CH2:25][CH:26]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:18][C@H:17]1[C:39]([OH:41])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:83]([NH2:90])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1>CN(C=O)C>[CH:28]1[C:27]2[CH:26]([CH2:25][O:24][C:22](=[O:23])[NH:21][C@H:19]3[CH2:18][C@@H:17]([C:39](=[O:41])[NH:90][CH2:83][C:84]4[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=4)[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:49])[CH3:48])[CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[CH2:20]3)[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)NCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To (2S,4S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid (Intermediate 27) in DMF at 0° C. was added DIPEA (116 μL, 0.66 mmol) and HATU (93 mg, 0.24 mmol). The mixture was stirred at 0° C. for 15 minutes and then benzylamine (26.1 mg, 0.24 mmol) in DMF (0.5 mL) was added dropwise, the cooling bath removed and the reaction stirred for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water, and brine and dried over anhydrous magnesium sulfate. Concentration gave ((3S,5S)-5-benzylcarbamoyl-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-pyrrolidin-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester as a foam which was used without purification.
Reaction SMILES: [C:1]([C:4]1[C:9]([OH:10])=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([OH:13])[C:5]=1[CH3:14])(=[O:3])[CH3:2].[CH3:15][O:16][CH:17]([O:21][CH3:22])[C:18](=O)[CH3:19].N1CCCC1>C1(C)C=CC=CC=1>[CH3:15][O:16][CH:17]([O:21][CH3:22])[C:18]1([CH3:19])[CH2:2][C:1](=[O:3])[C:4]2[C:9](=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([OH:13])[C:5]=2[CH3:14])[O:10]1
Reactant: COC(OC)C(C)=O
Reactant: CC(=O)c1c(C)c(O)c(C)c(C)c1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COC(OC)C1(C)CC(=O)c2c(C)c(O)c(C)c(C)c2O1
Yield: 70 %

Procedure:
15.0 g (77 mmoles) of acetyl-trimethylhydroquinone, 10.5 g (89 mmoles) of 1,1-dimethoxy-propan-2-one and 9.30 g (131 mmoles) of pyrrolidine were reacted in toluene solution by a method similar to that of Example 1 to give the above product. Boiling point: 165°-170° C./6.10-5 mbar (bulb tube); yield: 70%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([O:10][CH2:11][C:12]([NH2:15])([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].[C:24](Cl)(Cl)=[S:25]>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][C:12]([N:15]=[C:24]=[S:25])([CH3:14])[CH3:13])=[O:9])=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)OCC(C)(C)N)cc1
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(=O)OCC(C)(C)N=C=S)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
A biphasic mixture of 2-amino-2-methylpropyl 4-methoxybenzoate hydrochloride (0.24 g, 0.92 mmol), DCM (9.2 mL) and saturated aqueous Na2CO3 (18.5 mL) was cooled to 0° C. Thiophosgene (0.35 mL, 4.62 mmol) was added and the mixture was stirred for 15 min. The organic layer was separated, dried with Na2SO4, filtered and concentrated to give the title compound (0.24 g, 99%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.17-7.92 (m, 2 H), 7.06-6.81 (m, 2 H), 4.27 (s, 2 H), 3.89 (s, 3 H), 1.50 (s, 6 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:13])=[CH2:12])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1C=CN=C1.[N+](=C[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>C1(C)C=CC=CC=1>[C:1]([C:5]1[N:6]=[CH:7][C:8]([CH:11]2[CH2:13][CH:12]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(C)c1ccc(C(C)(C)C)nc1
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1ccc(C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
To a toluene (60 ml) solution of 2-tert-butyl-5-isopropenylpyridine (5.96 g, 34 mmol), Co(TPP) (0.69 g, 1.0 mmol) and 1-methyl-1H-imidazole (8.37 g, 102 mmol), ethyl diazoacetate (5.4 g, 48 mmol) was added and the mixture was stirred for 5 minutes at room temperature followed by additional stirring for 1 hour at 80° C. Then, evaporation of the solvent and purification by silica gel column chromatography, eluting with gradually from hexane to hexane/ethylacetate (30:1), gave the title compound (3.51 g, 39%, trans) as white solids.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:5]=O.[Cl-].[OH:15][NH3+:16].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][CH:2]([CH3:13])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:5]=[N:16][OH:15]
Reactant: CC(C)C=C(C=O)c1ccccc1
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)C=C(C=NO)c1ccccc1
Reaction time: 5 h
Yield: 58.3 %

Procedure:
To a solution of 4-methyl-2-phenyl-2-pentenal (5.0 g, 29 mmol) and hydroxylammonium chloride (2.5 g, 36 mmol) in a mixture of absolute ethanol (15 ml) and water (5 ml) was carefully added a solution of sodium carbonate (7.3 g, 69 mmol) in water (20 ml). After stirring for 5 h a precipitate was filtered off and dried in the air. The crude product was purified by column chromatography on silica gel (50 g, cyclohexane/ethyl acetate 3/1) to give 3.2 g of 4-methyl-2-phenyl-2-pentenal oxime as a solid. M.p. 107°-110° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][C@@H:5]([C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=3)[N:15]=[CH:14][CH:13]=2)=[O:10])[CH2:4]1.[O:24]=[C:25]1[NH:30][C:29]2[N:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[OH:8][C@H:7]1[C@@H:3]([CH2:2][NH:1][CH2:35][C:32]2[CH:33]=[CH:34][C:28]3[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=3[N:31]=2)[CH2:4][C@H:5]([C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=3)[N:15]=[CH:14][CH:13]=2)=[O:10])[CH2:6]1
Reactant: COc1ccc2nccc(NC(=O)[C@H]3C[C@H](CN)[C@H](O)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc(NC(=O)[C@H]3C[C@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@H](O)C3)c2n1
Reaction time: 24 h
Yield: 17.4 %

Procedure:
To a stirred solution of (±)-(1S,3R,4R)-3-(aminomethyl)-4-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]cyclopentanecarboxamide (0.48 g, 1.51 mmole) in dry CH2Cl2 (50 mL) and dry EtOH (20 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.29 g, 1.51 mmole). After 24 h, at RT was added NaBH4 (0.063 g, 1.66 mmole). After 4 h, the reaction solution was concentrated under vacuum to a solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.13 g, 17%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 8.68 (d, J=5.1 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 4.12 (s, 3H), 3.92 (m, 3H), 3.49 (s, 2H), 3.38 (m, 1H), 2.95 (m, 2H), 2.39 (m, 1H), 2.50 (m, 4H), 1.91 (m, 1H). LC-MS (ES) m/e 495 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[ClH:15]>O>[Cl:15][C:11]1[NH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:13][C:12]=1[CH3:14]
Reactant: COc1ccc(-c2nc(C)c[nH]2)cc1
Reactant: Cl
Solvent: O
Product: COc1ccc(-c2nc(C)c(Cl)[nH]2)cc1
Reaction time: 8 h
Yield: 17 %

Procedure:
A suspension of 2-(p-methoxyphenyl)-4-methylimidazole, (4.5 g, 0.024 mole) in concentrated HCl (96 ml)--H2O (34 ml) was stirred vigorously while a solution of KClO3 (1 g) in H2O (50 ml) was added dropwise over 11/4 hour. The precipitated hydrochloride salt was collected and suspended in H2O (200 ml), saturated Na2CO3 solution (50 ml). After an overnight period of stirring, the solid was collected, chromatographed on silica gel, the product eluted with 5% CH3OH--CHCl3 and crystallized from 50% CH3CN to yield 0.9 g (17%) of 38, m.p. 182°-186° C. A sample recrystallized from 50% CH3CN melted at 185°-187° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:5])=[O:4].[C:12](OC(=O)C)(=[O:14])C.O>C(O)=O>[CH:12]([NH:1][C@H:2]([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](Cc1cccs1)C(=O)O
Solvent: O=CO
Solvent: O
Product: O=CN[C@H](Cc1cccs1)C(=O)O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(2R)-2-Amino-3-(2-thienyl)propionic acid (5.00 g, 29.2 mmol) was dissolved in formic acid (50 ml). The solution was cooled to 0° C. Acetic acid anhydride (20 ml) was added dropwise. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was cooled to 0° C. Water (20 ml) was added dropwise. The solution was warmed to room temperature. The solvent was removed in vacuo. The resiude was suspended in ethyl acetate (20 ml). The precipitation was filtered off, collected, and dried in vacuo, to give 3.60 g of crude (2R)-2-(formylamino)-3-(2-thienyl)propionic acid, which was used for the following step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1.[Si:13]([O:20][CH2:21][CH2:22][C:23]#[CH:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:24]#[C:23][CH2:22][CH2:21][O:20][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=1
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)Cc1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(C#CCCO[Si](C)(C)C(C)(C)C)c1
Yield: 61.9 %

Procedure:
A mixture of (3-iodo-phenyl)-acetic acid methyl ester (948 mg, 3.4 mmol), 1-(t-butyldimethylsilyloxy)but-3-yne (644 mg, 3.5 mmol), copper(1)iodide (50 mg), and bis(triphenylphosphine)-palladium(II)chloride (50 mg) in Et3N (5 ml) was refluxed, under argon for 2 hr. The reaction was cooled, and the liquid was decanted off, diluted with diethyl ether, and washed with 1N HCl. The organic layer was dried and the solvent was evaporated. The residue was chromatographed on silica gel (hexane/methylene chloride 60/40) to give the title compound as an oil (700 mg, 62%). MS (ESI) 333.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1.Cl.O1CCOCC1.O>>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)OCCNC2=O
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)OCCNC3=O)ncc1Cl
Temperature: 100 °C
Yield: 73.2 %

Procedure:
A mixture of 8-amino-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.092 g, 0.0003 mol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (0.05 g, 0.00028 mol), 4 N HCl in dioxane/water (0.07 mL, 0.00028 mol) was heated at 100° C. for 4 hrs. The slurry was evaporated and the residue treated with ethyl acetate and a 10% sodium carbonate solution. The insoluble solid was collected, washed, dried to give 2-[5-chloro-2-(5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (0.09 g, 74%) as a yellow solid. MP: 293-5° C.; 1H-NMR (DMSO-d6) δ 11.62 (s, 1H), 9.74 (s, 1H), 8.72-6 (d, 1H), 8.70 (d, 1H) 8.29 (s, 1H) 8.11 (s, 1H), 7.77 (m, 2H), 7.51-3 (d, 2H), 7.33-5 (d, 1H), 7.15-9 (t, 1H), 4.27 (s, 1H); LC/MS (ESI+): 439 (M+H).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[Si:5]([Cl:9])(Cl)(Cl)[Cl:6].Cl>>[CH:2]([O:4][Si:5]([O:4][CH:2]([CH3:3])[CH3:1])([Cl:9])[Cl:6])([CH3:3])[CH3:1]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: CC(C)O
Agent: Cl
Product: CC(C)O[Si](Cl)(Cl)OC(C)C

Procedure:
This material is prepared after the manner of Chappelow et al. (J. Org. Chem. 1960, 25, 435-459.) 2-Propanol (887 g, 14.8 mol) was added slowly over a period of three hours under an atmosphere of Ar to SiCl4 (1475 g, 8.7 mol) at 0° C. The vented HCl gas from the reaction was neutralized by bubbling through a 25% (w/v) solution of KOH in water. The solution was allowed to react for 3 h whereupon, Ar was bubbled through the solution for 30 min. The solution was then distilled through a 30 cm Hemple column packed with 3 mm glass beads (Pot Temp: 180° C., Vapor Temp: 120° C.). The resulting fractions were analyzed by 1H NMR. Fraction A: 411 g (95% Mono: 5% Di); Fraction B: 184 g (22% Mono, 76% Di, 2% Tri); Fraction C: 511 g—27% yield, (95% Di, 5% Tri); and Fraction D: 393 g (50% Di, 50% Tri). Fractions B and D were pooled with other impure cuts from other runs and redistilled at a latter date. 1H NMR (CDCl3, 300 mHz) δ Mono: 4.53 (h, J=6.2 Hz, 1 H), 1.31 (d, J=6.2 Hz, 6 H). Di: 4.41 (h, J=6.2 Hz, 2 H), 1.26 (d, J=6.2 Hz, 12 H); Tri: 4.29 (h, J=6.2 Hz, 3 H), 1.21 (d, J=6.2 Hz, 12 H). 13C NMR (CDCl3, 75.5 mHz) δ Di: 69.27, 24.85.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([N:40]([CH3:44])[CH2:41][CH2:42][CH3:43])[CH:33]=2)[C:28]([OH:31])=[N:29][N:30]=1)C1C=CC=CC=1>CO.[Pd]>[OH:31][C:28]1[N:27]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([N:40]([CH3:44])[CH2:41][CH2:42][CH3:43])[CH:33]=2)[C:26]([C:10]2[CH:11]=[C:12]([CH:23]([CH3:24])[CH3:25])[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])=[N:30][N:29]=1
Reactant: CCCN(C)c1cc(-n2c(O)nnc2-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)ccc1OC
Agent: [Pd]
Solvent: CO
Product: CCCN(C)c1cc(-n2c(O)nnc2-c2cc(C(C)C)c(O)cc2O)ccc1OC
Reaction time: 16 h
Yield: 89.8 %

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-[4-methoxy-3-(methylpropylamino)phenyl]-4H-[1,2,4]triazol-3-ol (240 mg, 04 mmol) was dissolved in methanol (10 mL) then 10% palladium on charcoal (200 mg) was added and the reaction was stirred under an atmosphere of hydrogen for 16 hrs. Filtration was carried out through a silca gel plug and removal of the solvent under reduced pressure produced the desired compound as a white solid (150 mg, 94%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])C.[Br:17]CC(O)CO.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:17][CH2:16][C@@H:15]1[CH2:1][O:3][C@@H:4]([CH2:5][P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[O:14]1
Reactant: OCC(O)CBr
Reactant: CCOC(CP(=O)(OCC)OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(C[C@@H]1OC[C@@H](CBr)O1)OCC
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of diethylphosphonoacetaldehyde diethylacetal (15.00 g, 59.0 mmol) and 3-bromo-1,2-propanediol (11.00 g, 71.0 mmol, 1.2 eq.) in toluene (60 mL) was added pTSA (few cristals). The mixture was stirred at reflux for 72 hr and was cooled to room temperature. A saturated solution of sodium bicarbonate was added and the aqueous phase was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude material was pure by TLC and NMR and gave 17.93 g of the compound in a 96% yield.