Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>ClCCl>[C:27]([O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)N1c2ccccc2CC(=NO)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)ON=C1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 0.5 g (1.87 mmol) of 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide in 25 mL of dichloromethane and 0.72 g (9.16 mmol) of pyridine was treated with 0.57 g (5.61 mmol) of acetic anhydride. The resulting mixture was stirred at room temperature overnight and then diluted with 10 mL of dichloromethane. The organic phase was extracted with 20 mL of 1M aqueous HCl, a saturated solution of NaHCO3 and brine, then dried by sodium sulphate. The solvent was then removed by evaporation under reduced pressure and the crude product was crystallised from a mixture of dichloromethane and ethyl acetate to give the desired product as white crystals of m.p. 175.8°-176.9° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:11]([O:13]C)=[O:12])[CH2:5][CH3:6].C1COCC1.[OH-].[Li+]>O.CO>[CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=1)[C:11]([OH:13])=[O:12])[CH2:5][CH3:6]
Reactant: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reaction time: 2 h

Procedure:
To a solution of methyl 3-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-5-[(phenylmethyl)oxy]benzoate (6.85 g, 20 mmol) in 3:1 THF:methanol (100 mL) was added 1N lithium hydroxide solution in water (40 mL, 40 mmol), then a further 100 mL water was added portionwise at intervals while the resulting mixture was stirred for 2 hours. The organic solvents were removed by evaporation and the cloudy solution filtered. The pH of the filtrate was adjusted to 3 by the addition of 2 M hydrochloric acid. This was extracted with ethyl acetate (3×70 mL). The combined organic extracts were dried (MgSO4) and evaporated to afford the title compound as a colourless oil which solidified (6.36 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[CH:13]1([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([O:18][CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:20]=2)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: COc1ccc(CN)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(Cl)nc(C)c2[N+](=O)[O-])cc1OC1CCCC1
Temperature: -10 °C
Yield: 82.3 %

Procedure:
2,4-Dichloro-5-nitro-6-methylpyrimidine (2.0 g) was dissolved in tetrahydrofuran (14 ml), and added with a solution of 3-cyclopentyloxy-4-methoxybenzylamine (2.25 g) dissolved in tetrahydrofuran (7ml) with stirring and cooling on a salt-ice bath (−10° C.). Then, the mixture was added dropwise with triethylamine (1.4 ml), and stirred for 30 minutes on a salt-ice bath (−10° C.). The reaction mixture was further added with saturated brine, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was suspended and washed in a mixed solvent of ether and hexane (50:50) to obtain 3.11 g of the title compound.
Reaction SMILES: [Li+].[OH-].C[CH:4]([C@@H:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:10]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH2:9]1)[C:5]([O-:7])=[O:6]>O.C1COCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([C@H:14]([N:11]2[CH2:12][CH2:13][C@@H:8]([CH2:4][C:5]([OH:7])=[O:6])[CH2:9][C@H:10]2[C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:36][CH:35]=2)[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])=[CH:25][CH:24]=1)(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)CC[C@H](c1ccc(C(=O)c2ccccc2)cc1)N1CC[C@@H](C(C)C(=O)[O-])C[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC[C@H](c1ccc(C(=O)c2ccccc2)cc1)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of LiOH (10 mg, 0.42 mmol) in water (0.5 ml) was added to a stirred solution of the ester (Step 3, 42 mg, 0.074 mmol) in THF (1 ml) at RT. The reaction was stirred at RT O/N then quenched with 2N HCl (1 ml). The mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (×2). The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 2-8% MeOH/DCM) to give the acid (22 mg) as a colourless solid. 1H NMR (400 MHz, CD3OD): δ 0.60-0.70 (1H, m), 0.82-1.02 (7H, m), 1.14-1.24 (1H, m), 1.38-1.49 (2H, m), 1.72-1.75 (1H, m), 1.84-1.95 (4H, m), 2.18-2.20 (2H, m), 2.52 (1H, brt, J 11), 2.82 (1H, brd, J 11), 3.53 (1H, dd, J 9.8, 4.0), 3.87 (1H, brd, J 10), 7.45 (2H, d, J 8.2), 7.52 (2H, t, J 7.6), 7.64 (1H, J 7.4), 7.70-7.80 (8H, m); M/Z (ES+) 552 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:25][O:24][C:20]1[C:19]2[CH:15]([NH:14][C:11]3[O:12][CH2:13][C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)[CH:27]=[CH:26][C:9]=4[N:10]=3)[CH2:16][O:17][C:18]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CN1CCNCC1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CO2
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCN(C)CC4)cc3CO1)CO2
Yield: 79.3 %

Procedure:
Prepared from rac-2-chloro-N-[2-(4-methoxy-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 8) (370 mg, 0.95 mmol) and 1-methylpiperazine (2.12 ml, 19.08 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (340 mg, 79%), MS (ISP) m/e=452.3 [(M+H)+].
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][C:11]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([CH:24]1[CH2:26][CH2:25]1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.O>CS(C)=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:11]([CH:24]2[CH2:25][CH2:26]2)([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:32][CH:31]=1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(CCC#N)(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
16 mg (0.25 mmol) of potassium cyanide were added to 57 mg (0.12 mmol) of the compound from Example 116A in 1 ml of DMSO. The mixture was stirred at 80° C. for 16 h, water was added to the reaction solution, and the crude product was purified directly by preparative HPLC (mobile phase: acetonitrile/water gradient). 29 mg (60% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[S:17][C:16]([C:18](O)=O)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:35][C:36]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:37]=1[C:38]([NH2:40])=[O:39]>N1C=CC=CC=1.CN(C=O)C>[C:38]([C:37]1[C:36]2[N:35]=[C:18]([C:16]3[S:17][C:13]([CH:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:14][CH:15]=3)[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)(=[O:39])[NH2:40]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)s1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 34C (2.4 g) in pyridine (100 mL) and DMF (100 mL) was added CDI (1.6 g). The mixture was heated at 40° C. for 1 hour, treated with 2,3-diaminobenzamide dihydrochloride (1.8 g), stirred at ambient temperature overnight and concentrated. The concentrate was heated in acetic acid (50 mL) at 80° C. overnight and concentrated. The concentrate was flash chromatographed on silica gel with ethyl acetate.
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[OH:32][C:33]1[CH:62]=[CH:61][C:36]([CH2:37][NH:38][C:39]2[N:44]=[C:43]([O:45][CH2:46][C:47]([F:50])([F:49])[F:48])[N:42]=[C:41]([NH:51][C:52]3[CH:60]=[CH:59][C:55]([C:56](O)=[O:57])=[CH:54][CH:53]=3)[N:40]=2)=[CH:35][CH:34]=1.[NH2:63][CH2:64][CH:65]([OH:80])[CH2:66][N:67]1[CH2:72][CH2:71][N:70]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:69][CH2:68]1>CN(C=O)C.CCOC(C)=O>[OH:80][CH:65]([CH2:64][NH:63][C:56](=[O:57])[C:55]1[CH:59]=[CH:60][C:52]([NH:51][C:41]2[N:40]=[C:39]([NH:38][CH2:37][C:36]3[CH:61]=[CH:62][C:33]([OH:32])=[CH:34][CH:35]=3)[N:44]=[C:43]([O:45][CH2:46][C:47]([F:49])([F:50])[F:48])[N:42]=2)=[CH:53][CH:54]=1)[CH2:66][N:67]1[CH2:72][CH2:71][N:70]([C:73]([O:75][C:76]([CH3:77])([CH3:79])[CH3:78])=[O:74])[CH2:69][CH2:68]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)CN)CC1
Reactant: O=C(O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CC(O)CNC(=O)c2ccc(Nc3nc(NCc4ccc(O)cc4)nc(OCC(F)(F)F)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.7 %

Procedure:
N,N-diisopropylethylamine (0.30 g) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (0.44 g) were added into a solution of 4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (0.5 g) and tert-butyl 4-(3-amino-2-hydroxypropyl)piperazine-1-carboxylate (0.33 g) in DMF (2 mL). The mixture was stirred at room temperature for 16 hours. Then, 50 mL of EtOAc was added into the reaction mixture which was sequentially washed with water (2×20 mL) and brine (15 mL). The organic layer was dried over MgSO4 and concentrated under vacuum to give a residue which was purified by silica gel chromatography to provide tert-butyl 4-(2-hydroxy-3-(4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propyl)piperazine-1-carboxylate (0.20 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27](Cl)([CH3:29])[CH3:28])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:23])([F:25])[F:24])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27]([N:31]=[N+:32]=[N-:33])([CH3:29])[CH3:28])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(-n2c(C(C)(C)Cl)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCc1ccc(-n2c(C(C)(C)N=[N+]=[N-])nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 42 %

Procedure:
A mixture of 2-{4-[6-chloro-2-(1-chloro-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (step 1, 273 mg, 0.68 mmol), sodium azide (88 mg, 1.36 mmol), KI (112 mg, 0.68 mmol) in DMF (8 ml) was stirred under nitrogen at room temperature for 5.5 h. The reaction mixture was poured into water (5 ml) and the aqueous mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with water (5 ml) and brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (2/1) to afford 133 mg (42%) of the title compound as yellow oil.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:14][CH2:15][CH:16]([OH:19])[CH:17]=[CH2:18].O>CN(C=O)C>[Br:14][CH2:15][CH:16]([O:19][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:17]=[CH2:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(O)CBr
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(CBr)O[Si](C)(C)C(C)(C)C
Reaction time: 16 h

Procedure:
Imidazole (2.25 g) and tert-butyldimethylsilylchloride (4.75 g) were added to a solution of 1-bromo-3-buten-2-ol (4.5 g) in DMF (30 ml) at room temperature. The mixture was stirred at the same temperature for 16 hours, and water was added thereto, followed by extraction with hexane. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow, oily substance (7.0 g).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:17]([OH:19])=O)[CH3:2].C(Cl)(=O)C([Cl:23])=O.[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[ClH:23].[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[N:32]=[CH:33][C:34]([NH:37][C:17]([C:4]2[N:3]([CH2:1][CH3:2])[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:9][CH:10]=3)=[O:19])=[CH:35][CH:36]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: CCn1c(C(=O)O)cc2cc(OC(F)(F)F)ccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1c(C(=O)Nc2ccc(N(C)CCOC)nc2)cc2cc(OC(F)(F)F)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1-ethyl-5-trifluoromethoxy-1H-indole-2-carboxylic acid (65 mg, 0.24 mmol), CH2Cl2 (5 mL), and catalytic amount of DMF was stirred under Ar, and oxalyl chloride (2M in dichloromethane, 250 μL, 0.5 mmol) was dripped into the mixture over 5 min. The mixture was stirred at room temperature for 1.0 hr and then concentrated to dryness. Benzene was added and the solution was evaporated to dryness again. The residue was re-dissolved in 5 mL of CH2Cl2 and dripped, under Ar, into a solution of N-(2-methoxy-ethyl)-N-methyl-pyridine-2,5-diamine (43.0 mg, 0.24 mmol), and triethylamine (0.52 mg, 0.5 mmol) in 5 mL of CH2Cl2. The reaction was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in 50 mL of EtOAc and washed with 50 mL of saturated ammonium chloride, brine and dried with anhydrous sodium sulfate. The solvent was removed, and the crude product was purified by flash chromatography (hexanes:EtOAc) followed by conversion to HCl salt with 1N HCl in ether to afford the product, 1-ethyl-5-trifluoromethoxy-1H-indole-2-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide hydrochloride, as a pink solid (44 mg, 42% yield). LCMS for C21H23F3N4O3 calcd. (m/e) 436, observed 437 (M+H).
Reaction SMILES: [F:1][C:2]1[C:9](S(C(F)(F)F)(=O)=O)=[C:8]([O:17][CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:19][C:20]1[C:21](B(O)O)=[CH:22][C:23]2[C:24]([CH3:33])([CH3:32])[CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:17][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[C:9]=1[C:21]1[C:20]([CH3:19])=[CH:29][C:28]2[C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25][C:24]([CH3:33])([CH3:32])[C:23]=2[CH:22]=1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: COc1ccc(C=O)c(F)c1S(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C=O)c(F)c1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 61.2 %

Procedure:
A mixture of 2-fluoro-4-methoxy-3-trifluoromethanesulfonyl benzaldehyde (1.21 g, 4.01 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (1.08 g, 4.41 mmol) and potassium carbonate (2.22 g, 16.04 mmol) in 1,2-dimethoxyethane (30 mL) and water (2 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.2 mmol) was added and the mixture heated at reflux under argon for 16 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (Biotage, eluent: ethyl acetate/hexane, 0.5:8.5) to give 0.87 g of 4-methoxy-2-fluoro-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzaldehyde (62%). 1H NMR (500 MHz; CDCl3): δ1.26 (s, 6 H), 1.32 (s, 6 H), 1.69 (s, 4 H), 2.07 (s, 3 H), 3.85 (s, 3 H), 7.07 (d, J=8.8 Hz, 1 H), 7.07 (s, 1 H), 7.19 (s, 1 H), 7.90 (t, J=8.8 Hz, 1 H), 10.25 (s, 1 H).
Reaction SMILES: C(OCC[N:7]1[C:13]2[CH:14]=[CH:15][C:16](Cl)=[CH:17][C:12]=2[C:11]2(C3C=CC=CC=3F)OCC[N:10]2[CH2:9][C:8]1=O)(=O)C.[OH-:30].[Na+].O>CO>[N:7]1[C:13]2=[CH:14][CH2:15][CH2:16][C:17](=[O:30])[C:12]2=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: CC(=O)OCCN1C(=O)CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc21
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCC=C2N=CC=NC=C12
Reaction time: 3 h

Procedure:
A solution of 0.5g (0.0012 M) of 7-(2-acetoxyethyl)-10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d] [1,4]benzodiazepin-6(7H)-one in 5 ml of methanol was treated with 2 ml of 3N sodium hydroxide. After 3 hours, 50 ml of water was added and the solution was extracted with 40 ml of dichloromethane, which was then dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of methanol and water to give 10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo)3,2-d) [1,4]benzodiazepin-6(7H)-one as white prisms, m.p. and m.m.p. 141°-146°.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH:9]([OH:12])[CH:10]=[CH2:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:13]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:19]1)C[C:14]2=O>ClCCl.COC(OC)(C)C>[CH:10]([CH:9]1[O:12][C:13]([CH3:19])([CH3:14])[O:1][CH:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8]1)=[CH2:11]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: C=CC(O)CC(O)CC(=O)OC
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: C=CC1CC(CC(=O)OC)OC(C)(C)O1
Reaction time: 8 h

Procedure:
The crude β,δ-dihydroxy-6-heptenoic acid, methyl ester from the previous step was dissolved in a mixture of 30 ml of dichloromethane and 10 ml of 2,2-dimethoxypropane. Camphorsulfonic acid (0.05 g) was added, and the mixture was stirred overnight. Concentration of the reaction mixture and flashchromatography of the residue yielded 1.1 g of 6-ethenyl-2,2-dimethyl-1,3-dioxane-4- acetic acid, methyl ester which was employed in the subsequent step without further purification.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=[O:11].Cl>>[OH:11][C@@H:10]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[CH:9]=[C:8]([CH3:12])[CH3:7]
Reactant: COP([O-])OC
Reactant: CC(C)=CC=O
Agent: Cl
Product: COP(=O)(OC)[C@H](O)C=C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then 3-methyl-2-butenal (0.40 mmol) was added thereto. After reacting for 81 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-1-hydroxy-3-methyl-2-butenylphosphonate as a final product in a yield of 72%. The chemical reaction in this Example is shown in chemical formula 36. ##STR30##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[N:19]=[C:18]([NH:28][C:29]3([C:32]([O:34]CC)=[O:33])[CH2:31][CH2:30]3)[N:17]=2)=[CH:11][CH:10]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[N:19]=[C:18]([NH:28][C:29]3([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]3)[N:17]=2)=[CH:11][CH:10]=1)=[O:8]
Reactant: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)NCCCCN)cc3)nc(OCC(F)(F)F)n2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NCCCCNC(=O)c1ccc(Nc2nc(NC3(C(=O)O)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.5 %

Procedure:
Ethyl 1-(4-(4-(4-aminobutylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropanecarboxylate (80 mg) and potassium carbonate (64.8 mg) were dissolved in acetone (3 mL)/water (2 mL). After stirring at r.t. for 16 hours and then heated to 90° C. for 2 hours, the mixture was acidified with 1N HCl to pH=3. All the solvents were then removed under vacuum. The residue was purified by perp. HPLC to give 1-(4-(4-(4-aminobutylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropanecarboxylic acid (20 mg).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([OH:12])[CH2:9][CH2:10][CH3:11]>O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].C1(C)C=CC=CC=1>[CH2:6]([O:7][C:1]1([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:1][CH2:2][CH3:3]
Reactant: CCCCO
Reactant: O=C1CCCCC1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC1(OCCCC)CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 185.8 %

Procedure:
In a 300-ml three-necked flask, 98 g (1 mole) of cyclohexanone, 148 g (2 moles) of n-butanol, 50 g of molecular sieve 4A, 2 mg of cerium chloride hexahydrate and 40 g of toluene were charged. The resulting mixture was stirred at 25° C. under atmospheric pressure for 12 hours in a nitrogen atmosphere. After the removal of the molecular sieve 4A, the solvent (toluene) and unreacted starting materials were distilled off under reduced pressure. Distillation of the residue under reduced pressure gave 212.2 g of cyclohexanone dibutyl acetal (yield: 93.1%).