Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC(=O)[C@@H](C)CC(N)CC1C=CC(C2C=CC=C(Cl)C=2)=CC=1)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[NH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CCN(C(C)C)C(C)C.[CH2:56]([O:58][C:59](=[O:81])[C@@H:60]([CH3:80])[CH2:61][CH:62]([N:77]=[C:78]=[O:79])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([Cl:76])[CH:71]=2)=[CH:66][CH:65]=1)[CH3:57]>CN(C=O)C>[CH2:56]([O:58][C:59](=[O:81])[C@@H:60]([CH3:80])[CH2:61][CH:62]([N:77]=[C:78]=[O:79])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([Cl:76])[CH:71]=2)=[CH:66][CH:65]=1)[CH3:57].[CH2:56]([O:58][C:59](=[O:81])[C@@H:60]([CH3:80])[CH2:61][CH:62]([NH:77][C:78]([NH:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:79])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([Cl:76])[CH:71]=2)=[CH:66][CH:65]=1)[CH3:57]
Reactant: CC(C)(C)OC(=O)CN
Agent: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)N=C=O
Agent: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(S)-5-(3′-Chloro-biphenyl-4-yl)-4-isocyanato-2-methyl-pentanoic acid ethyl ester is prepared from (S)-4-amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 31) and triphosgene analogous to the procedure described for Example 6-1. Next, to a solution of tert-butyl 2-aminoacetate (140 mg, 1.065 mmol) in DMF (5 mL) is added DIEA (344 mg, 2.66 mmol). The solution is stirred at room temperature for 5 minutes then (S)-5-(3′-chloro-biphenyl-4-yl)-4-isocyanato-2-methyl-pentanoic acid ethyl ester (330 mg, 0.887 mmol) is added. The mixture is stirred at room temperature for 2 hours then the solvent is removed under reduced pressure to give (S)-4-(3-tert-butoxycarbonylmethyl-ureido)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester which is used directly in the following reaction.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C1(C2CCC3C(=CC=C(OCCN)C=3)O2)C=CC=CC=1.[N:26]([CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[O:38][CH:37]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:36][C:35]2=[O:48])=[N+]=[N-]>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH2:26][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[O:38][CH:37]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:36][C:35]2=[O:48]
Reactant: [N-]=[N+]=NCCOc1ccc2c(c1)C(=O)CC(c1ccccc1)O2
Agent: CS(=O)(=O)O
Agent: NCCOc1ccc2c(c1)CCC(c1ccccc1)O2
Product: NCCOc1ccc2c(c1)C(=O)CC(c1ccccc1)O2

Procedure:
6-(2-Aminoethoxy)-2-phenylchroman-4-one methane sulfonate was prepared as described for 2-(2-phenylchroman-6-yloxy)ethylamine methane sulfonate in Example 4 (b) starting from 6-(2-azidoethoxy)-2-phenylchroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 7.91 (bs, 3H), 7.55-7.54 (m, 2H), 7.46-7.37 (m, 3H), 7.31 (d, 1H, J 3.1 Hz), 7.28 (dd, 1H, 8.8, 3.1 Hz), 7.12 (d, 1H, 8.8 Hz), 5.63 (dd, 1H, 13.0, 3.0 Hz), 4.17 (t, 2H, J 5.1 Hz), 3.25 (dd, 1H, J −16.9, 13.0 Hz), 3.23 (m, 2H), 2.86 (dd, 1H, J −16.9, 3.0 Hz), 2.29 (s, 3H).
Reaction SMILES: [AlH4-].[Li+].[CH3:3][CH:4]([N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1)[C:5](=O)[N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1>C1COCC1>[CH3:3][CH:4]([N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C(=O)N1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
To a mixture of 1.0 M of lithium tetrahydroaluminate in THF (11.3 mL. 11.3 mmol) in THF (40 mL) was added drop-wise, a solution of 4-[1-(1-methyl-2-oxo-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (2.57 g, 5.64 mmol) in THF (20 mL). The mixture was refluxed for 30 min. The mixture was cooled at 0° C., quenched with 0.44 mL of water, followed by 0.44 mL of 15% NaOH, then 1.32 mL of water. The mixture was stirred at RT for 30 min, filtered through Celite. The filtrate was dried over sodium sulfate, concentrated to dryness under reduced pressure. The resultant residue was purified on silica gel, eluting with 0 to 10% methanol (containing 10% 2M NH3/EtOH) in dichloromethane, to give the desired product (690 mg, 27.7%). LCMS calculated for C22H36N7OSi (M+H)+: m/z=442.3; Found: 442.3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][N:10]=[C:9]([CH3:12])[CH:8]=1.[I-].[K+].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]2[O:23][CH2:24][CH2:25][N:26]=2)[CH:19]=[C:18]([Cl:27])[C:17]=1[OH:28].[OH-].[K+]>C(#N)C>[Cl:15][C:16]1[CH:21]=[C:20]([C:22]2[O:23][CH2:24][CH2:25][N:26]=2)[CH:19]=[C:18]([Cl:27])[C:17]=1[O:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][N:10]=[C:9]([CH3:12])[CH:8]=1
Reactant: Cc1cc(CCCCCCl)sn1
Reactant: Oc1c(Cl)cc(C2=NCCO2)cc1Cl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)sn1
Yield: 76.9 %

Procedure:
A suspension of 6.5 g 5-(5-chloropentyl)-3-methylisothiazole, 5.3 g potassium iodide, 9.1 g 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol and 3.9 g potassium hydroxide in 300 ml acetonitrile was heated at reflux for 40 hours. Filtration, concentration and flash filtration (silica gel; 1:1 hexane/ethyl acetate) gave 9.8 g of oily product which when crystallized from hexane at Dry Ice temperature gave 5.3 g 2-}3,5-dichloro-4-[(5-(3-methyl-5-isothiazolyl)pentyl)oxy]phenyl}-4,5-dihydro-oxazole as a colorless solid, m.p. 38°-39.5° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][OH:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[O:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CO)no1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(C=O)no1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
1.35 g of (5-t-butyl-isoxazol-3-yl)methanol was dissolved in 50 ml of 1,4-dioxane, and 6.42 g of manganese dioxide was then added. The mixture was stirred and heated under reflux for 10 hours. The reaction mixture was cooled to room temperature and then filtered through Celite®. The filtrate was concentrated under reduced pressure to obtain 1.29 g of 5-t-butyl-isoxazole-3-carbaldehyde.
Reaction SMILES: [OH:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.[I-].[Na+]>CCOC(C)=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:11][CH:12]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)[C@H](C)O
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)OCc1ccc(OC)cc1
Temperature: 150 °C
Yield: 61.9 %

Procedure:
A mixture of (S)-methyl 2-hydroxypropanoate (1.5 g, 14.41 mmol), 1-(chloromethyl)-4-methoxybenzene (3.38 g, 21.61 mmol), DIPEA (4.03 ml, 23.05 mmol) and sodium iodide (0.150 g, 1.001 mmol) was heated to 150° C. for 2 h. Reaction mixture then was cooled to room temperature diluted with EtOAc (100 mL) and washed with saturated NaHCO3 solution (2×50 mL) and brine. Combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The crude mixture was purified by flash chromatography on silica gel using an ISCO system (eluted with 9:1 Hexanes and EtOAc) to give (S)-methyl 2-((4-methoxybenzyl)oxy)propanoate (2 g) as a gummy liquid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=O)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:31])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(O)C>[CH2:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][C:11]([CH3:31])=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1oc2c(C)c(C)c(NC(=O)c3ccccc3)c(C)c2c1-c1ccc(C(C)C)cc1
Solvent: CCO
Product: Cc1oc2c(C)c(C)c(NCc3ccccc3)c(C)c2c1-c1ccc(C(C)C)cc1
Yield: 55 %

Procedure:
By using N-[3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 55%. Melting point: 94-95° C. (Ethanol).
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O-2].[Zn+2:39].[Zn].[C:41](=[S:43])=[S:42]>>[CH2:20]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:41](=[S:42])[S-:43])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[Zn+2:39].[CH2:20]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:41](=[S:42])[S-:43])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: S=C=S
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Agent: [O-2]
Agent: [Zn+2]
Agent: [Zn]
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=S)[S-]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a 250 mL round bottomed flask was placed 60 g of dioctadecylamine (a fatty amine derived from a natural oil) and 2.40 g of zinc oxide. Carbon disulfide, 9.0 g, was then added dropwise, and the mixture was stirred for 30 minutes. The flask was then stirred and heated for 2 hours at 70° C., and then stirred for an addition 2 hours at 90° C. A vacuum was then applied to remove water of reaction and the temperature was increased to 130° C., and the reaction was maintained in this state for 3 hours. The pale yellow material was then filtered through Celite at 120° C., to give, upon standing at ambient temperature a waxy solid with a Zn content of 4.2%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH:41][NH2:42])=O)[CH:34]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:39]([C:35]3[CH:34]=[C:33]([O:32][CH3:31])[CH:38]=[CH:37][N:36]=3)=[N:41][N:42]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: COc1ccnc(C(=O)NN)c1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1ccnc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (0.25 g, 0.859 mmol) in anhydrous Dichloromethane (DCM) (2.147 ml) was added triethyloxonium tetrafluoroborate (0.179 g, 0.945 mmol) and the mixture was stirred overnight at room temperature under argon. The white suspension turned to a solution and 4-(methyloxy)-2-pyridinecarbohydrazide (0.158 g, 0.945 mmol, commercially available from e.g. Matrix Scientific, Anichem or 3B Scientific) was added at once. It was a suspension at first but straight after it changed to a yellow solution. After ½ hour a precipitate formed again. LCMS showed that the major product was the intermediate and very little unreacted starting amide was present.
Reaction SMILES: [Li][CH3:2].Cl[Si](C)(C)C.[CH3:8][O:9][C:10](=[O:18])[CH:11]=[C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[NH4+].[Cl-]>C(OCC)C.[Cu]I.ClCCl>[CH3:8][O:9][C:10](=[O:18])[CH2:11][C:12]1([CH3:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: [Li]C
Reactant: COC(=O)C=C1CCCCC1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CC1(C)CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
Step B To a suspension of CuI (7.61 g, 40 mmol) in anhydrous ethyl ether (20 mL) at 0° C. was added an ethyl ether solution (1.6 M) of MeLi (50 mL, 80 mmol) The reaction mixture was stirred at 0° C. for 10 min. The solvent was evaporated under reduced pressure, then dichloromethane (20 mL) was added under nitrogen at 0° C. The mixture was stirred for 5 min. The solvent was evaporated again. To the residue was added dichlormethane (20 mL), and the temperature of the mixture was lowered to −78° C. To the mixture was added chlorotrimethylsilane (4.3 g, 40 mmol) and a dichloromethane solution (20 mL) of cyclohexylidene-acetic acid methyl ester (3.1 g, 20 mmol). The reaction mixture was allowed to slowly warmed to 0° C. and stirred for 1 h. Aqueous saturated NH4Cl solution was added to quench the reaction. The mixture was extracted with ethyl ether twice. The organic layers were combined, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:5) to give (1-methyl-cyclohexyl)-acetic acid methyl ester as a colorless oil (3.3 g, 97%).
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:8][CH:7]2[N:9](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:3]1[CH2:4][O:5][CH2:6]2.[Li+].[OH-].SCC(O)=O>CN(C=O)C>[F:1][C:2]1([F:22])[CH2:8][CH:7]2[NH:9][CH:3]1[CH2:4][O:5][CH2:6]2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1C2COCC1C(F)(F)C2
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC1(F)CC2COCC1N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound 108d (90 mg) and LiOH (36 mg) in DMF (5 mL) was added mercaptoacetic acid (36 mg) slowly, the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo to give 6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octane 108a as an oil, which was used in next step without purification. MS: calc'd (MH+) 150, measured (MH+) 150.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][O:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12](B(O)O)=[CH:11][N:10]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[CH3:7][O:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:11][N:10]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Brc1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2nccs2)c(OC)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
2-bromo-1,3-thiazole (commercially available from Aldrich, 0.165 ml, 1.829 mmol) was dissolved in degassed 1,2-Dimethoxyethane (DME) (5 ml). Pd(Ph3)4 (106 mg, 0.091 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (commercially available from Aldrich, 707 mg, 3.84 mmol) and 5 mL of degassed 1M aqueous solution of NaHCO3 were added to the reaction mixture under N2 atmosphere. After 2 h 30 min stirring at 90° C., the reaction mixture was diluted with water and extracted with DCM. The collected organic phases were evaporated. The residue was purified by flash chromatography eluting with cyclohexane/EtOAc 5:1. 294 mg of the title compound were isolated as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23]([C:25]([OH:27])=O)=[CH:24][C:19]3=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:44][NH:45][O:46][CH3:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23]([C:25](=[O:27])[N:45]([O:46][CH3:47])[CH3:44])=[CH:24][C:19]3=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(C(=O)O)cnn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)c1cnn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Yield: 91.9 %

Procedure:
A solution of the compound of example 8, step 11 (1.002 g, 1.75 mmol), N,O-dimethylhydroxylamine hydrochloride (0.213 g, 2.19 mmol), EDIA (0.76 ml, 4.38 mmol) and TBTU (0.702 g, 2.19 mmol) in 15 ml of anhydrous DCM was stirred at room temperature for 4 h. DCM (15 ml) was then added and the solution was washed with 0.5 N hydrochloric acid (30 ml), a saturated solution of sodium hydrogencarbonate (15 ml) and brine (15 ml), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 50:50, then 40:60, then 35:65) to give 0.99 g of the title compound as a yellow oil.
Reaction SMILES: [Cl-].[CH3:2][C@@H:3]1[O:11][C:10](=[O:12])[C@@H:9]([NH3+:13])[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C@H:4]1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH:29][C:30]1[C:31]([C:38](O)=[O:39])=[N:32][CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:29][C:30]1[C:31]([C:38]([NH:13][C@H:9]2[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[C@@H:4]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:3]([CH3:2])[O:11][C:10]2=[O:12])=[O:39])=[N:32][CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: Cc1ccc(C[C@H]2CCC[C@H]([NH3+])C(=O)O[C@@H](C)[C@@H]2Oc2ccccc2)cc1
Reactant: COc1ccnc(C(=O)O)c1O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(C(=O)N[C@H]2CCC[C@H](Cc3ccc(C)cc3)[C@@H](Oc3ccccc3)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.7 %

Procedure:
A 25 mL screw top vial was charged with (3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8-phenoxyoxonan-3-aminium chloride (259 mg, 0.642 mmol), 3-hydroxy-4-methoxypicolinic acid (122 mg, 0.721 mmol), anhydrous CH2Cl2 (6.5 mL), and N,N-diisopropylethylamine (340 μL, 1.95 mmol). To the mixture was added PyBOP (376 mg, 0.723 mmol) and the reaction was stirred at room temperature for 1.5 h and then directly purified by column chromatography on SiO2 (2→30% acetone/hexanes) to provide the title compound as a white solid (162 mg, 49%): mp 62-66° C.; 1H NMR (400 MHz, CDCl3) δ 12.09 (s, 1H), 8.48 (d, J=8.2 Hz, 1H), 7.98 (d, J=5.1 Hz, 1H), 7.37-7.28 (m, 2H), 7.12-6.93 (m, 7H), 6.86 (d, J=5.2 Hz, 1H), 5.14 (dq, J=9.2, 6.4 Hz, 1H), 4.62 (dt, J=10.9, 7.4 Hz, 1H), 4.35 (t, J=8.9 Hz, 1H), 3.93 (s, 3H), 2.99 (dd, J=13.3, 3.2 Hz, 1H), 2.42-2.26 (m, 5H), 2.16-2.04 (m, 1H), 1.79-1.52 (m, 3H), 1.41-1.23 (m, 4H), 1.08-0.98 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 172.06, 168.59, 159.58, 155.27, 148.66, 140.47, 136.92, 135.38, 130.28, 129.63, 128.98, 128.59, 121.16, 115.48, 109.43, 81.02, 74.89, 55.99, 51.43, 45.59, 36.34, 33.47, 26.57, 20.95, 18.78, 18.33; ESIMS: m/z 519 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[S:28]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][S:28]4(=[O:35])=[O:34])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 70.9 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (452 mg) described in Preparation Example 112 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (359 mg) was obtained.
Reaction SMILES: [CH2:1](OP(O)(O)=O)[C@H:2]1O[C@H:5](OP(OP(O)(O)=O)(O)=O)[C@H:4](O)[C@@H:3]1O.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[NH2:54][C@H:55]([C:62]([OH:64])=[O:63])[CH2:56][C:57]1N=[CH:60][NH:59][CH:58]=1>>[NH2:54][C@H:55]([C:62]([OH:64])=[O:63])[CH2:56][C:57]1[C:5]2[C:60](=[CH:1][CH:2]=[CH:3][CH:4]=2)[NH:59][CH:58]=1
Reactant: O=P(O)(O)OC[C@H]1O[C@H](OP(=O)(O)OP(=O)(O)O)[C@H](O)[C@@H]1O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
5-Phosphoribosyl-α-1-pyrophosphate (hereinafter, “PRPP”) and adenosine-5′-triphosphate (hereinafter, “ATP”) are the initial substrates in histidine biosynthesis. PRPP can sometimes induce the histidine biosynthesis to follow divergent pathways, resulting in the biosynthesis of pyrimidine nucleotides, purine nucleotides, pyridine nucleotides, and tryptophan (Escherichia coli and Salmonella, Second Edition, Editor in Chief: F. C. Neidhardt, ASM Press, Washington D.C., 1996).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[N:7][C:6]([N:13]=[C:14]=S)=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH2:24][CH2:25][C@@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[N:7][C:6]([NH:13][C:14]1[O:34][C@:26]3([CH2:25][N:24]=1)[CH:31]1[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]1)[CH2:27]3)=[CH:5]2
Reactant: S=C=Nc1cc2cc(Cl)c(Cl)cc2cn1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Clc1cc2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)cc2cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To 6,7-dichloro-3-isothiocyanatoisoquinoline (0.13 g, 0.510 mmol) in DMF (10 mL) was added cesium carbonate (0.42 g, 1.27 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.118 g, 0.515 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with DMF (10 mL) and N,N′-diisopropylcarbodiimide (0.238 mL, 1.529 mmol). The reaction was heated to 90° C. for 18 hours. The reaction was cooled to room temperature and concentrated to yield the crude product, which was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(6,7-dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.12 g, 0.312 mmol, 61.2% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.03 (s, 1H), 8.87 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.24 (s, 1H), 3.88-4.06 (m, 1H), 3.60-3.74 (m, 1H), 3.42 (d, J=14.65 Hz, 1H), 2.82-3.15 (m, 5H), 2.23-2.34 (m, 1H), 2.18 (s, 1H), 1.72-1.87 (m, 1H), 1.48-1.70 (m, 2H). MS (LC/MS) R.T.=1.63; [M+H]+=377.1.