Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=O.ON1C2N=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[NH:68]1[C:76]2[CH:75]=[CH:74][N:73]=[C:72]([NH:77][C:78]([CH:80]3[CH2:82][CH2:81]3)=[O:79])[C:71]=2[CH:70]=[CH:69]1.CCN(C(C)C)C(C)C>>[Cl:15][C:7]1[CH:8]=[C:9]([CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([N:68]1[C:76]2[CH:75]=[CH:74][N:73]=[C:72]([NH:77][C:78]([CH:80]3[CH2:81][CH2:82]3)=[O:79])[C:71]=2[CH:70]=[CH:69]1)=[O:6])[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(Nc1nccc2[nH]ccc12)C1CC1
Reactant: COC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: C[NH3+]
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A stirred solution of 2,6-dichloro-4-(methoxycarbonyl)benzoic acid (750 mg, 3 mmol, intermediate 32), 1-hydroxy-7-azabenzotriazole (614 mg, 4.5 mmol), dimethylaminopyridine (183 mg, 1.5 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1170 mg, 4.5 mmol) in N,N-dimethylacatamide was treated with N-(1H-pyrrolo[3,2-c]pyridin-4-yl)cyclopropane carboxamide (605 mg, 3 mmol, intermediate 28) and Hunig's base (1.33 ml, 7.5 mmol). The reaction mixture was stirred at room temperature for about 1 hour and was heated at 50° C. for about 5 hours. To the reaction mixture, ice cold water was added and the precipitated solid was filtered, washed with water and dried. The solid thus obtained was purified by silica gel (100-200 mesh) column chromatography using methanol and dichloromethane gradient elution to afford methyl 3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoate (600 mg, 47%) as an off-white solid.
Reaction SMILES: C1(N)CCCCC1.C1(N)CCCCC1.[N+:15]([CH2:18][C@:19]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:25][C@@H:24]2[C@H:20]1[CH2:21][CH2:22][CH2:23]2)([O-])=O.Cl>C(OCC)(=O)C>[NH2:15][CH2:18][C@:19]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:25][C@@H:24]2[C@H:20]1[CH2:21][CH2:22][CH2:23]2
Reactant: O=C(O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CCC[C@H]21
Agent: Cl
Solvent: NC1CCCCC1
Solvent: CCOC(C)=O
Product: NC[C@]1(CC(=O)O)C[C@H]2CCC[C@H]21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
The cyclohexylamine salt of the nitro acid from example 1 (100 g; 320 mmol) was added to a mixture of ethyl acetate (680 ml) and a 2M aqueous solution of hydrochloric acid (340 ml). The mixture was stirred vigorously for 10 minutes and the phases were separated. The organic layer was further washed with demineralised water (340 ml). The organic layer was separated and demineralised water (1360 ml) was added. To this two phase mixture 5% platinum on carbon as a 50% water wet catalyst (13.65 g) was added. The reaction mixture was then hydrogenated at 50° C. and a hydrogen pressure of 150 psi for 24 hours. The hydrogen was purged with nitrogen and the reaction mixture was heated to 70° C. The reaction mixture was filtered through Celite at 70° C. and the filter pad was washed with hot demineralised water (50 ml). The filtrate was allowed to settle, the phases were separated at 70° C. and the lower aqueous phase was removed and concentrated by distillation at atmospheric pressure to a sixth of its original volume. The white slurry was cooled to 50° C. and isopropanol (705 ml) was then added over a period of 1.7 hours. The white slurry was then cooled to between +5° C. and +10° C. over 90 minutes and stirred for 2.5 hours. The solid was collected by filtration and the damp filter cake washed with isopropanol (60 ml). The isolated solid was then dried in vacuo at 45° C. for 18 hours to give the title compound in high purity as a white crystalline solid (36.3 g) in 62% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33]([NH:35][C@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:28]([O:32][C:33]([NH:35][C@H:36]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:37]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:38])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: [O-][n+]1cc(Cl)c(CC(O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (5 g, 11.90 mmol), (R)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (4.73 g, 17.85 mmol), DMAP (1.599 g, 13.09 mmol), and EDC (4.56 g, 23.80 mmol) were dissolved in DMF (5 ml). The reaction was stirred at RT for 2 hours to achieve completion. The reaction mixture was diluted with water, and the precipitate was filtered, washed with water, dissolved in DCM and extracted with HCl 1N, Na2CO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was crystallized in EtOH to give 4-((S)-2-((R)-2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (3.2 g, 4.79 mmol, 40.3% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[O:10].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 195.3 %

Procedure:
To a stirred solution of methyl 3-bromo-4-[N′-(2-methylphenyl)ureido]phenylacetate (650 mg, 1.72 mmol) in THF (10 ml) was added 0.25 N NaOH (10 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 3-bromo-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.22 g, 100%) as colorless powder. 1H-NMR (DMSO-d6) δ2.26 (s, 3H), 3.32 (s, 2H), 6.93 (m, 2H), 7.10-7.17 (m, 4H), 7.76 (d, J=8.1 Hz, 2H), 8.52 (s, 1H); MS (ESI) m/z 385 (M++Na), 387 (M+2+Na).
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:10][NH:11][C:12]([NH2:14])=[S:13]>N1C=CC=CC=1>[CH3:10][NH:11][C:12]1[S:13][C:2]2[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=2[N:14]=1
Reactant: O=C1CCCC(=O)C1Br
Reactant: CNC(N)=S
Solvent: c1ccncc1
Product: CNc1nc2c(s1)C(=O)CCC2
Yield: 42.7 %

Procedure:
A solution of 2-bromo-cyclohexane-1,3-dione (8.0 g, 41.9 mmol) and methyl thiourea (3.77 g, 41.9 mmol) in pyridine (63 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum, extracted with CH2Cl2 /10% aq NaCl solution, dried, filtered, and concentrated under vacuum. Crystallization from EtOAc afforded the title compound as yellow crystals (3.26 g, 43%): mp 180-182° C. Anal. RP-HPLC: tR 8.4 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 7.90 (s, 1H, NH), 2.99 (s, 3H, CH3), 2.72 (t, 2H, J 6.1, CH2), 2.49 (t, 2H, J 6.1, CH2), 2.10 (qu, 2H, J 6.1, CH2). 13C-NMR (CDCl3): δ 191.0, 176.6, 168.0, 120.0, 37.5, 32.5, 27.7, 23.2. MS: (ESI+) m/z 183.07 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:26]3[CH2:30][O:29]C(C)(C)[O:27]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.O1CCOCC1.Cl.C(=O)([O-])O.[Na+]>CO>[F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:26]([OH:27])[CH2:30][OH:29])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCc1ccccc1C1COC(C)(C)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCc1ccccc1C(O)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a mixture of 273 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)benzyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, 3 ml of dioxane, and 3 ml of methanol was added 6 ml of 1 M hydrochloric acid under ice-cooling, followed by stirring at room temperature for 16 hours. The reaction mixture was ice-cooled and 0.6 g of sodium hydrogen carbonate was added thereto in small portions to make the mixture weakly basic. The precipitated solid was collected by filtration and washed with water to obtain 236 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[2-(1,2-dihydroxyethyl)benzyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:19][CH3:20])[C:3]=1[F:21].[NH2:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]3[C:24]=2[CH:25]=[N:26][C:27]([CH3:34])=[N:28]3)=[C:4]([O:19][CH3:20])[C:3]=1[F:21]
Reactant: COc1c(C(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(C(C)CC(O)(C=Nc2cc(F)cc3nc(C)ncc23)C(F)(F)F)ccc(Cl)c1F

Procedure:
In the same way as in Example 14, 100 mg (0.3 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 54 mg (0.3 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.1 ml of titanium tetraethoxide are reacted to give 4-(4-chloro-3-fluoro-2-methoxyphenyl)-1-[(7-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 150 mg of crude imine are cyclized in the same way as in Example 14 at −30° C. with 2.5 ml (2.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) and subsequent preparative thin-layer chromatography on amine phase (Merck) with ethyl acetate/methanol/triethylamine 25:3:1 yield 3.4 mg of product and 3 mg of the dihydroxy compound Ex. 16.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][C@H:19](/[C:23](/[CH3:31])=[CH:24]/[C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1)[CH2:20][CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[Si:11]([O:18][C@H:19](/[C:23](/[CH3:31])=[CH:24]/[C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1)[CH2:20][CH:21]=[O:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: C/C(=C\c1csc(C)n1)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: C/C(=C\c1csc(C)n1)[C@H](CC=O)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
A solution of dimethyl sulfoxide (2,04 ml, 28.8 mmol, 2.4 equiv) in 6.0 ml of dichloromethane is added dropwise within 5 min to a stirred solution of oxalyl chloride (1.14 ml, 13.2 mmol, 1.1 equiv) in 30 ml of dichloromethane cooled to −78° C. The mixture is stirred for 10 min at −70° C. A solution of (S,4E)-3-(tert-butyldimethylsilyloxy)-1-hydroxy-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene 16 (3.93 g, 12.0 mmol) in 5 ml of dichloromethane is added dropwise within 5 min. The mixture is stirred for 30 min at −70° C. The reaction is quenched by dropwise addition of triethyl amine (8.4 ml, 60.0 mmol). The mixture is warmed to r.t. within 45 min. Water (30 ml) is added and the mixture is stirred for 10 min. The organic layer is seperated and the aqueous layer is extracted with dichloromethane (3×100 ml). The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by flash column chromatography (pentane/diethyl ether 5:2) affords (S,4E)-3-(tert-butyadimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)-pent-4en-1-al 17 (3.21 g, 82%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:20]>CO>[C:1]([O:5][C:6]([NH:8][C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[NH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 74 %

Procedure:
15 g of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (0.052 mol) were suspended in 150 mL of gaseous ammonia in methanol and the mixture was stirred at room temperature in a close bottle at room temperature. The resulting solution was concentrated in vacuo until 10 g (74% yield) of the title compound precipitated which were collected by filtration.
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:60]([CH2:62][CH3:63])[CH3:61])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:11]([NH:13][C@@H:14]([CH2:42][C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=2)[C@@H:15]([C@H:17]2[CH2:21][C@H:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][N:18]2C(C2C=CC=CC=2)C2C=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:59])(=[O:3])[CH3:2].C(N[C@]1([C@@H](CC)C)CCN([C@@H](CCC2C=CC=CC=2)C(O)=O)C1=O)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@H](OC2C=CC=CC=2)CN1C(C1C=CC=CC=1)C1C=CC=CC=1)O.CN1CCOCC1>CN(C=O)C>[C:1]([NH:4][C@:5]1([C@@H:60]([CH2:62][CH3:63])[CH3:61])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:11]([NH:13][C@@H:14]([CH2:42][C:43]2[CH:44]=[C:45]([F:50])[CH:46]=[C:47]([F:49])[CH:48]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:21][C@H:20]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][NH:18]2)=[O:12])[C:6]1=[O:59])(=[O:3])[CH3:2]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccc3)CN2C(c2ccccc2)c2ccccc2)C1=O
Agent: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)O)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccc3)CN2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step 9 (C): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4S)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamide. To a solution of (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation A, 29 mg, 0.080 mmol) in DMF (2 mL) was added HATU (36.5 mg, 0.096 mmol). A solution of (1S,2S)-2-amino-1-((2R,4S)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol (Step 9 (B), 41.1 mg, 0.080 mmol) in DMF (2 mL) was then added, followed by N-methylmorpholine (37 μl, 0.336 mmol). The reaction mixture was stirred at rt for 3 h. pH 4 buffer was then added to quench. The mixture was extracted with ethyl acetate. The organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. The crude mixture was purified by reverse phase Prep HPLC to give the title compound (34 mg): 1H NMR (CDCl3, 300 MHz) δ 0.82 (3H, d, J=6 Hz), 0.98 (3H, m), 1.07-1.15 (1H, m), 1.51-1.61 (1H, m), 1.68-1.74 (1H, m), 1.85-2.08 (5H, m), 2.17-2.30 (1H, m), 2.41-2.57 (2H, m), 2.63-2.76 (2H, m), 2.80-2.95 (3H, m), 3.09 (1H, dd, J=3, 15 Hz), 3.47-3.54 (3H, m), 3.67-4.05 (6H, m), 5.08 (1H, m), 5.39 (1H, s), 5.99 (1H, s), 6.56-6.69 (4H, m), 6.86 (2H, d, J=9 Hz), 7.03 (1H, m), 7.14-7.34 (12H, m), 7.68 (2H, m), 7.63-7.66 (2H, m). HPLC retention time: 1.99 min (method C). MS (ESI) (M+H)+ 857.45.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[CH2:29][C:30](O)=[O:31]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:30](=[O:31])[CH2:29][C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:23]=3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(O)Cc1ncccn1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)Cc3ncccn3)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(pyrimidin-2-yl)acetic acid (Example 31a) (36% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.25 (m, 1H), 1.47-1.67 (m, 4H), 1.76 (m, 1H), 3.16 (t, 1H, J=12.6 Hz), 2.77-4.20 (m, 3H), 4.27-4.72 (m, 2H), 5.13 (m, 1H), 6.57 (d, 1H, J=8.2 Hz), 6.78 (br d, 1H, J=7.6 Hz), 7.35 (t, 1H, J=5.0 Hz), 7.40 (br t, 1H, J=8.2 Hz), 7.71 (br s, 1H), 7.91 (br s, 1H), 8.71 (m, 2H), 10.90 (br s, 1H). MS 431 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[Si:23]([O:30][C@H:31]([C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[C:49]([CH2:54][OH:55])[CH:48]=1)[CH2:32][NH:33][C:34]([CH3:46])([CH3:45])[CH2:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Si:23]([O:30][C@H:31]([C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[C:49]([CH2:54][OH:55])[CH:48]=1)[CH2:32][NH:33][C:34]([CH3:46])([CH3:45])[CH2:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([NH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:40])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: NCCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Cc1cccc(C(=O)NCCc2ccc(Cl)cc2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reaction time: 48 h

Procedure:
2-(4-Chlorophenyl)ethylamine (164 mg, 1.06 mmol) was added to a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (203 mg, 1.06 mmol), 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) (500 mg, 1.06 mmol), 1-hydroxybenzotriazole hydrate (160 mg, 1.06 mmol) and triethylamine (440 □l, 3.20 mmol) in dichloromethane (30 ml). The resulting solution was stirred for 48 hours under nitrogen. The solvent was removed in vacuo and the residue taken up in ethyl acetate (30 ml), washed with water (20 ml), sodium hydrogen carbonate (0.5 M, 2×20 ml), brine (2×20 ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title compound, the resulting material was taken up in methanol and evaporated, then taken up in diethylether and evaporated to yield a white foam (480 mg). 1H NMR (400 MHz, CD3OD) δ=7.64-7.60 (2H, m), 7.36-7.19 (7H, m), 7.05 (1H, dd), 6.72 (1H, d), 4.71-4.67 (1H, m), 4.60 (2H, dd), 3.57 (2H, t), 2.93-2.61 (6H, m), 1.09 (3H, s), 1.06 (3H, s), 0.78 (9H, s), −0.04 (3H, s), −0.22 (3H, s). LRMS (electrospray) m/z 611 [M+H]+, 633 [M+Na]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[NH:14][C:13]=2[C:12](=[O:20])[N:11]([CH3:21])[CH2:10]1.C([O-])([O-])=O.[K+].[K+].CS([CH:32]([CH2:36][CH:37]=[CH2:38])[CH2:33][CH:34]=[CH2:35])(=O)=O.CCOCC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[N:14]([CH:32]([CH2:36][CH:37]=[CH2:38])[CH2:33][CH:34]=[CH2:35])[C:13]=2[C:12](=[O:20])[N:11]([CH3:21])[CH2:10]1
Reactant: C=CCC(CC=C)S(C)(=O)=O
Reactant: CCc1nc2c([nH]1)C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCC(CC=C)n1c(CC)nc2c1C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17.9 %

Procedure:
Prepared by the method described in example 8 using the appropriate starting materials except for part “B” to give the desired product. Part “B” was replaced with the following procedure. A solution of 3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-1,2,3,7-tetrahydro-6H-purin-6-one (65 mg, 0.20 mmol) in anhydrous DMF (1.2 mL) was treated with finely ground K2CO3 (83 mg, 0.60 mmol). After stirring 5 min at rt, 4-methanesulfonyl-1,6-heptadiene (203 μL, 1.11 mmol) was added via syringe and the reaction mixture was heated at 90° C. for 4 h. The mixture was cooled to rt and transferred to a separatory funnel containing ether (50 mL). The organic layer was washed with water (4×15 mL), brine (15 mL), dried over MgSO4, filtered, and concentrated. Purification of the residue by prep plate (1000 μM silica gel plate, 25% ethyl acetate in hexanes) followed by further purification by reverse phase HPLC afforded the title compound (15 mg, 18% yield) as a colorless oil; HRMS (ESI) m/e 419.1435 [(M+H)+, calcd for C21H25N4OCl2 419.1405].
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[CH3:21])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][CH2:9][C@@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[CH3:21])[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(Br)ccc1[C@@H](CO)COCc1ccccc1
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
To 16E (8.0 g, 22.91 mmol), 4-methylmorpholine (3.02 mL, 27.5 mmol) in THF (100 mL) at −20° C. was added ethyl chloroformate (2.420 mL, 25.2 mmol). The mixture was stirred for 20 min. The cloudy reaction mixture was filtered. The filtrate was treated with sodium borohydride (1.213 g, 32.1 mmol) and MeOH (30 mL) slowly from −20° C. The mixture was stirred at −20° C. for 15 min. and then at rt for 1 h. The reaction was quenched with addition of sat. ammonium chloride. Organic solvent was removed under reduced pressure. The residue was partitioned between EtOAc/water. The organic layers were collected, washed with sat. sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-40% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give 16F (5.93 g, 17.69 mmol, 77% yield). MS (ESI) (m/z): 357, 359.4 (M+Na)+. 1H NMR (400 MHz, chloroform-d) δ ppm 7.27-7.40 (m, 7H) 7.01 (d, J=8.34 Hz, 1H) 4.56 (s, 2H) 3.92-4.04 (m, 1H) 3.67-3.89 (m, 3H) 3.35-3.49 (m, 1H) 2.34 (s, 3H).