Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18].Cl.[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][C:38](=[O:40])[NH2:39])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.O>[ClH:7].[ClH:7].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([O:19][C:32]1[CH:31]=[CH:30][C:29]2[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=2)[C:33]=1[CH2:37][C:38](=[O:40])[NH2:39])=[O:18]
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1cccc(NC2=NCCN2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3cccc(NC4=NCCN4)c3)ccc2c1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
15 Milliliters of 20% hydrous pyridine was added to 634.1 mg of 3-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoic acid.hydrochloride, 676.7 mg of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 598 mg of DCC and 29.5 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours under cooling with water. Thereafter, the same procedure as in Example 1 was carried out to obtain 439.5 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[NH:10][N:9]=1.[CH3:20][O-].[Na+].CI>CO>[CH3:20][N:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[N:10]1
Reactant: Clc1ccccc1-c1n[nH]c(-c2ccccc2Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cn1nc(-c2ccccc2Cl)nc1-c1ccccc1Cl
Reaction time: 72 h
Yield: 25.4 %

Procedure:
The product of stage (b) (3.0 g) and sodium methoxide (0.57 g) were dissolved in methanol (75 ml) and treated with methyl iodide (1.3 g). After standing for 3 days the solution was evaporated to dryness, treated with water and extracted into dichloromethane. The extract was washed with water and dried. Evaporation yielded 0.8 g of a solid, mp 82°-85° C., which was recrystallised twice from petroleum ether (80°-100°).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1.CCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]3[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCCCOc1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCOc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-butoxyphenyl)pyridin-2-amine (690 mg) in THF (dry) (5 ml) was added to a suspension of NaH (60%, 569 mg) and 2-chloroethanesulfonyl chloride (0.893 mL) in THF (dry) (5 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration and washed with water and EtOAc, and then recrystallized from IPE-EtOH to give the title compound (502 mg) as a white solid.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:13][S:22]([CH3:21])(=[O:24])=[O:23])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCOCCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOCCOCCOS(C)(=O)=O
Reaction time: 1 h
Yield: 99.8 %

Procedure:
15 g of tetraethyleneglycol and 23.4 g of triethylamine were dissolved in 200 mL of dichloromethane, to which 22.1 g of methanesulfonylchloride was added dropwise at 0° C., and then the solution was stirred for 1 hour. The reaction solution was filtrated to remove insolubles, and then the filtrate was concentrated under reduced pressure. The residue was separated with ethyl acetate-water, and the organic layer was concentrated under reduced pressure after washing with water. The residue was purified with silica gel column chromatography to obtain 27 g of the objective compound.
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:19][N:18]([CH2:33][C:34]([OH:36])=[O:35])[C:17]1=[O:37])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:19][N:18]([CH2:33][C:34]([OH:36])=[O:35])[C:17]1=[O:37])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2cccc3ccccc23)CN(CC(=O)O)C1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1CC(c2cccc3ccccc23)SCC(NC(CCc2ccccc2)C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
216 mg of α-[6-(1-ethoxycarbonyl-3-phenylpropylamino)-2-(1-naphthyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetic acid prepared as described in Example 37, were mixed with 2 ml of a 1N aqueous solution of sodium hydroxide, and the mixture was stirred for 16 hours at room temperature. A small amount of insolubles was filtered off and the pH of the filtrate was adjusted to a value of 2.0 by adding 1N hydrochloric acid; the resulting powdery compound was collected by filtration and washed with a small amount of water, to yield 201 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccccc1)OCC
Agent: Cl
Product: NCC(CP(O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 4.0 g of ethyl 3-amino-2-phenylpropyl(diethoxymethyl)phosphinate in 40 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 2 h. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 20 ml of water under reduced pressure. The crude product is dissolved in 20 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-phenylpropylphosphonous acid m.p. 228°-235° C., 31P=+24.3 ppm (D2O).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:25][C:24]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:23]=2[O:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].ClCCl.C(N(C(C)C)CC)(C)C>O1CCOCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:27]2[CH:28]=[CH:29][C:23]3[O:22][CH2:21][CH2:20][N:19]([C:17]([O:16][C:13]([CH3:14])([CH3:12])[CH3:15])=[O:18])[CH2:25][C:24]=3[CH:26]=2)=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
A mixture of 2-amino-5-bromo-3-nitropyridine (0.70 g, 3.2 mmol), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (1.0 g, 3.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.15 mg, 0.2 mmol), diisopropylethylamine (1.8 g, 14 mmol) in 50% aqueous 1,4-dioxane (40 mL) was degassed with nitrogen for 5 minutes and then stirred at 90° C. for one hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 mL) then filtered over celite. The filtrate was washed twice with brine (50 mL), filtered and the filtrate dried over sodium sulfate, filtered again and concentrated. The residue was purified by silica gel chromatography (25% to 95% ethyl acetate in hexanes gradient) to give 1,1-dimethylethyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.58 g, 48% yield); MS (EI) for C19H22N4O5: 389 (MH+).
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C@@:25]2([CH3:26])[C@H:23]([O:24]2)[CH2:22][C@@H:21]([OH:27])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36]>CN(C)C=O.O>[C:14]([Si:1]([O:18][C@@H:19]1[CH2:20][C@H:21]([O:27][Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:22][C@@H:23]2[C@@:25]1([CH3:26])[O:24]2)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(C)(C)[Si](O[C@@H]1C[C@H](O)C[C@H]2O[C@]21C)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC[Si](CC)(CC)O[C@@H]1C[C@H]2O[C@@]2(C)[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Yield: 90 %

Procedure:
The compound of Example 13B (16.0 g, 42 mmol) was dissolved in 20 mL of dimethylformamide; 7.1 g of imidazole (100 mmol, 2.5 equivalents) was added, followed by 10.5 mL of chlorotriethylsilane. The resultant mixture was stirred overnight at ambient temperature, then was diluted with water and extracted with ethyl acetate. The organic phase was concentrated washed with brine and dried over Na2SO4. After concentrating in vacuo, the residue was purified by flash chromatography, eluting with a gradient from 50% to 100% dichloromethane in hexanes to provide the titled compound (14.0 g, 90%).
Reaction SMILES: [Si]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([F:20])[F:19])[N:14]([C:21]3[N:26]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:24]=[C:23]([N:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)[N:22]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:20][CH:18]([F:19])[C:15]1[N:14]([C:21]2[N:26]=[C:25]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:24]=[C:23]([N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[CH2:35][CH2:34]3)[N:22]=2)[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:8])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(O[Si](C)(C)C(C)(C)C)cccc43)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(O)cccc43)n2)CC1

Procedure:
Reaction of tert-butyl 4-[4-[4-(tert-butyldimethylsilyloxy)-2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate from the previous step with tetrabutylammonium fluoride in THF at 0° C. gave a quantitative yield of tert-butyl 4-[4-[2-(difluoromethyl)-4-hydroxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate: mp (MeOH) 228-230° C.; 1H NMR (CDCl3) δ 7.81 (d, J=8.4 Hz, 1H), 7.55 (t, JHF=53.6 Hz, 1H), 7.32 (t, J=8.2 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 3.88 (m, 8H), 3.79 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H); MS (APCI+) 534.1 [MH+]; Anal. Calcd. for C24H30F2N8O4: C, 54.1; H, 5.7; N, 21.0. Found: C, 54.15; H, 5.8; N, 21.3%.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([Si](C)(C)[O:24][C:25]1[CH:26]=[C:27]([C:31]2([OH:38])[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1)(C)(C)C>>[OH:38][C:31]1([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([OH:24])[CH:26]=2)[CH2:32][CH2:33][C:34](=[O:37])[CH2:35][CH2:36]1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C2(O)CCC(=O)CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CCC(O)(c2cccc(O)c2)CC1

Procedure:
The title compound was prepared as a white solid by TBAF de-protection of 4-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-hydroxy-cyclohexanone (as prepared in the previous step) using the procedure described in Step D of Example 40.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH:13]=O)[CH:7]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:15])[NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH2:13][NH:19][CH:16]2[CH2:18][CH2:17]2)[CH:7]=1
Reactant: COC(=O)NCc1ccc(Cl)c(C=O)c1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)NCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-carbamic acid methyl ester (3.22 g, 14.1 mmol) and cyclopropylamine (1.49 mL, 21.2 mmol) in MeOH (50 mL) was stirred at rt overnight. NaBH4 (1.07 g, 28.3 mmol) was added in portions, and the mixture was stirred at rt for 3 h. Aq. 1M NaOH (90 mL) was added, and the solvents were partially removed under reduced pressure. The aq. residue was extracted with EtOAc (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:1) yielded the title compound (3.24 g, 85%). LC-MS: tR=0.59 min; ES+: 310.31.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:31]=[CH:30][C:8]2[NH:9][C:10]([C:12]3[CH:13]=[C:14]([C:27](O)=[O:28])[CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[OH:26])[C:17]=3[OH:18])=[N:11][C:7]=2[CH:6]=1)(=[NH:4])[NH2:3].Cl.CN(C)CCCN=C=NCC.[NH2:44][CH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1>CN(C)C=O>[ClH:1].[C:2]([C:5]1[CH:31]=[CH:30][C:8]2[NH:9][C:10]([C:12]3[CH:13]=[C:14]([C:27]([NH:44][CH2:45][C:46]4[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=4)=[O:28])[CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[OH:26])[C:17]=3[OH:18])=[N:11][C:7]=2[CH:6]=1)(=[NH:4])[NH2:3]
Reactant: NCc1ccncc1
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)O)cc(-c4cc(F)ccc4O)c3O)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)NCc4ccncc4)cc(-c4cc(F)ccc4O)c3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-carboxylic acid hydrochloride (100 mg, 0.226 mmol), prepared as in Reference 23, O-(7-azabenzotrizol-1-yl)-1,2,3,3-tetramethyluroniumhexafluorophosphate monohydrate (37 mg, 0.242 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (46 mg, 0.237 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL). The mixture was stirred at room temperature for 1 hour and then 4-aminomethylpyridine (27 mg, 0.248 mmol) was added to the mixture. The mixture was stirred at ambient temperature for 18 hours and then concentrated to a gum under high vacuum. The residue was dissolved in 5% acetonitrile/95% 20 mM hydrochloric acid (10 mL) and product purified via preparative C18 reverse phase HPLC (5% to 35% acetonitrile gradient, 20 mM HCl aqueous to give 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-N-pyridin-4-ylmethyl-biphenyl-3-carboxamide hydrochloride (50 mg) as a tan powder. 1H-NMR (d6-DMSO) δ ppm: 9.45 (bs, 2H), 9.20 (bs, 2H) 9.11 (d, J=1.6 Hz, 1H), 8.86 (d, J=6.4 Hz, 2H), 8.22 (d, J=1.6 Hz, 1H), 8.04 (d, J=6.4 Hz, 2H), 8.00 (d, J=2.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.78 (dd, J=8.8, 1.6 Hz, 1H), 7.14-6.96 (m, 3H), 4.79 (d, J=5.6 Hz, 2H) MS LCMS Q+ 497.174 (calc.), 497.2 (obs.), Q− 495.158 (calc.), 454.9 (obs).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Si:26]([O:25][CH2:24][CH2:23][N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine HCl salt (0.040 g, 0.13 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (55 uL, 0.26 mmol), and cesium carbonate (120 mg, 0.38 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 50 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]([OH:20])=[CH:10][CH:9]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]([O:20][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]/[C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCCCc1ccc(O)c(CCC(=O)OC)n1
Product: COC(=O)CCCCc1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(CCC(=O)OC)n1
Yield: 44.7 %

Procedure:
Under the conditions of example 1 D, 490 mg of 5-[3-hydroxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-pentanoic acid methyl ester is reacted with 365 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 293 mg of 5-{2-(2-methoxycarbonylethyl)-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-pyridyl}-pentanoic acid methyl ester is obtained as oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]>[OH-].[Na+].O1CCOCC1>[C:6]([NH:4][CH2:3][CH2:1][OH:2])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: NCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NCCO)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
The procedure is generally as depicted in FIG. 16. Dissolve 6.1 g (10 mmol) of ethanolamine in 10 mL of 1N NaOH. Cool the solution with an ice bath and add to it a solution of 1.7 g (10 mmol) of benzyl chloroformate dissolved in 10 mL of 1,4-dioxane, dropwise, over a period of 30 minutes. When the addition is complete, remove the ice bath and stir for 30 minutes. Add 100 mL of ethyl acetate and wash with 3×50 mL of 1.0N HCl. Wash the ethyl acetate layer with 50 mL of brine. Dry the ethyl acetate layer over anhydrous sodium sulfate. Filter and concentrate the filtrate to a residue. Final purification is achieved by flash chromatography on silica gel with ethyl acetate/hexane as the eluent. N-Cbz-ethanolamine, compound 52, is isolated as an oil.
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][NH:7][C@@H:6]([CH2:9][OH:10])[CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[S:18](Cl)(Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH:1]([CH:4]1[CH2:8][N:7]2[S:18](=[O:20])(=[O:19])[O:10][CH2:9][C@H:6]2[CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)C1CN[C@@H](CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C1C[C@@H]2COS(=O)(=O)N2C1
Temperature: 25 °C
Yield: 9 %

Procedure:
A solution of ((2R)-4-isopropylpyrrolidin-2-yl)methanol (1.639 g, 11.44 mmol) and triethylamine (3.18 mL, 22.89 mmol) in DCM (100 mL) was cooled to −78° C. To this mixture was added sulfuryl chloride, 1.0 M solution in DCM (13.73 mL, 13.73 mmol) dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated onto a plug of silica gel and purified by ISCO, chromatograph through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% MeOH (with 2 M NH3) in DCM to give (3aR)-5-isopropyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (211.9 mg, 1.032 mmol, 9% yield) as light yellow oil. m/z (ESI, +ve) 206 (M+H).
Reaction SMILES: [NH2:1][CH:2]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[ClH:16].S(C1C=CC(C)=CC=1)(O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)(=O)=O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(O)C.O.CCOCC>[ClH:16].[ClH:16].[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][CH:2]([NH:1][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCCCC2)cc1
Reactant: CC(C)CCC(N)C(O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC(C)CCC(NCCCN1CCCCC1)C(O)c1ccccc1
Yield: 60 %

Procedure:
A mixture of (1RS,2SR)-2-amino-5-methyl-1-phenylhexan-1-ol (1.04 g, 5 mmol), 3-piperidinopropyl tosylate hydrochloride (2.00 g, 6 mmol) and sodium bicarbonate (1.05 g, 12.5 mmol) in ethanol (10 ml) was refluxed for 1 hour. After cooling, to the reaction mixture were added ether (100 ml), water (50 ml) and 2N-NaOH (5 ml) and the resulting mixture was well shaken. The ethereal layer was separated and washed three times with water, then once with brine, followed by drying and subsequent concentration under reduced pressure. The residue was dissolved in ethanol and to the solution was added 6N-HCl in EtOH (1.5 ml). Precipitated crystals were collected by filtration and then recrystallized from ethanol to obtain 0.73 g of the title compound as white crystals (yield: 36%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:22]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][CH:25]([CH2:24][NH:23][CH2:21][CH3:22])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of 1.00 g (3.53 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 10 ml of acetonitrile, 0.54 g (3.5 mmole) 1,8-diazobicyclo[5.4.0]undec-7-ene, and 0.48 g (3.7 mmole) of N-ethyl-3-pyrrolidinemethanamine is refluxed one hour, then stirred at room temperature overnight. The reaction mixture is then filtered and the precipitate washed with ethyl ether until dry to yield 1.22 g (88.4%) of the title compound, mp 256°-258° C.