Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH:15]([CH3:17])[CH3:16])[C:5]2=[O:18].CC(O)=O.[Cl:23][C:24]1[C:29]([CH:30]=O)=[C:28]([O:32][CH3:33])[N:27]=[CH:26][CH:25]=1>CO>[Cl:23][C:24]1[CH:25]=[CH:26][N:27]=[C:28]([O:32][CH3:33])[C:29]=1[C:30]1[NH:11][C:10]2=[CH:9][C:8]3[C:7](=[O:14])[N:6]([CH:15]([CH3:17])[CH3:16])[C:5](=[O:18])[C:4]=3[CH:3]=[C:2]2[N:1]=1
Reactant: CC(C)N1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O
Reactant: COc1nccc(Cl)c1C=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C(C)C)C3=O
Temperature: -50 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a suspension of 5-amino-2-isopropyl-6-nitroisoindoline-1,3-dione (0.37 g) in 250 mL of MeOH was added 5 mL of AcOH. The resulting solution was degassed with argon and then charged with 10% Pd/C (0.12 g, 50% wet) and hydrogenated at 40 psi of hydrogen for 16 h. Another 2 mL of AcOH was added to the mixture and then solids were filtered off. The filtrate was cooled to −50° C. and a solution of 4-chloro-2-methoxynicotinaldehyde (0.31 g, 1.78 mmol) in 200 mL of MeOH was added dropwise under inert atmosphere. The resulting solution was allowed to warm up to rt and stirred for 16 h. Solvent was evaporated and the oily residue was purified by column chromatography (7.5% MeOH in dichloromethane) to give title compound as a solid (0.23 g, 29.3%). 1H NMR (500 MHz, CDCl3) δ58.18 (s, 1H), 8.12 (d, 1H), 8.03 (s, 1H), 7.90 (d, 1H), 6.92 (d, 1H), 6.75 (d, 1H), 5.39 (s, 2H), 4.56 (p, 1H), 3.72 (s, 3H), 3.61 (s, 3H), 1.50 (d, 6H). ESI MS: m/z 371.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH:10]2[N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:11]2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:13]1[C:12]2([CH2:17][CH2:18][NH:19][CH:10]([CH2:9][NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH2:11]2)[CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1CNc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(NCC2CC3(CCCC3)CCN2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
(±)tert-butyl 7-(((5-chloropyridin-2-yl)amino)methyl)-8-azaspiro[4.5]decane-8-carboxylate (intermediate 74, 1 g, 2.63 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0° C., then trifluoroacetic acid (30 ml) was added. After 1 hour at 0° C. and 2 hours at room temperature the solution was evaporated, the residue re-dissolved in dichloromethane was washed with saturated NaHCO3 aqueous solution. The organic layers were dried (Na2SO4) and concentrated under vacuum to obtain Obtained 600 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:31](=[O:37])[C:32]([O:34]CC)=[O:33])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:31](=[O:37])[C:32]([OH:34])=[O:33])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Yield: 46.7 %

Procedure:
{1-Benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetate (0.737 g, 1.42 mmol), potassium hydroxide (0.260 g, 4.63 mmol) in THF (9 mL) and water (9 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from acetonitrile and drying at 88° C. furnished the title compound as a white solid (0.326 g, 47%), mp: 206-207° C. Mass spectrum (+APCI, [M+H]+) m/z 492; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.3 (br s, 1H), 8.75 (s, 1H), 8.5 (s, 1H), 8.25 (s, 2H), 8.1 (s, 1H), 7.75 (s, 2H), 7.25-7.35 (m, 5H), and 5.6 ppm(s, 2H). Elemental Analysis for C25H15F6NO3: Calculated: C, 61.11; H, 3.08; N, 2.85. Found: C, 60.91; H, 2.87; N, 2.83.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:12][CH2:13][CH2:14]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[CH2:1]([O:8][C:9]([N:11]([CH2:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:12][CH2:13][CH2:14][Br:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: NC(=O)CCN(CCCO)C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: NC(=O)CCN(CCCBr)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of acrylamide (2 g) in ethanol (30 mL) was added 3-amino-1-propanol (3.23 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added tetrahydrofuran (30 mL) and N-(benzyloxycarbonyloxy)succinimide (14 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=40/1-20/1-5/1) to give 3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl)amino]propionamide (3.51 g). To a solution of the obtained 3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl)amino]propionamide (0.5 g) and carbon tetrabromide (0.65 g) in dichloromethane (5 mL) was added triphenylphosphine (1.03 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/4-dichloromethane/methanol=10/1) to give the title compound (0.41 g).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[C:20]([NH:37][C@H:38]([C:42]([O:44][CH:45]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C:46](O)=[O:47])=[O:43])[CH:39]([CH3:41])[CH3:40])([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:46](=[O:47])[CH:45]([O:44][C:42](=[O:43])[C@H:38]([CH:39]([CH3:40])[CH3:41])[NH:37][C:20]([O:22][CH2:23][CH:24]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: CCCCCCCCCCCCCCCCC(OC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)O
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCC(OC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (404 mg, 1.5 mmole), 2-(N-FMOC-L-valyloxy)stearic acid (1.24 g, 2 mmole), DMAP (24 mg, 0.2 mmole) and HOBT (264 mg, 1,95 mmole) was coevaporated two times with DMF and reduced to about 30 ml. DCC (372 mg, 1.8 mmole) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (50 ml) was added and the organic phase washed twice with 5% acetic acid, with 5% sodium hydrogen carbonate and with water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1.C(O)(=O)C.[N:20](OC(C)(C)C)=O>C1COCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[N:20][N:9]([C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)ON=O
Reactant: Cc1cc(Nc2cnccn2)c(N)cn1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc2c(cn1)nnn2-c1cnccn1
Yield: 23.2 %

Procedure:
To a solution of 6-methyl-N4-(pyrazin-2-yl)pyridine-3,4-diamine (520 mg, 2.58 mmol) in THF (30 mL) was added acetic acid (0.44 mL, 7.75 mmol) and tert-butyl nitrite (0.51 mL, 3.88 mmol). The reaction was heated to reflux. After 30 min the reaction was cooled and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (0-7% [2M NH3 in MeOH]CH2Cl2) to give the desired product (127 mg, 25%). MS (ESI) mass calcd. C11H9N5, 212.08. m/z found, 213.1 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4ccccc4)CC3)n1-2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ccccc3)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenyl-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.065 g, 0.16 mmol) and triethylamine (0.046 ml, 0.33 mmol) in dichloromethane (5 ml) was added methanesulphonyl chloride (0.013 ml, 0.17 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.043 g, 60%) as white solid. MS m/e: 457 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([SH:21])=[S:20])[CH2:15][CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].[CH3:24]O>[Cl-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:14][CH2:15][N:16]([C:19]([S:21][CH3:24])=[S:20])[CH2:17][CH2:18]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(N2CCN(C(=S)S)CC2)cc(OC)c1OC
Reactant: CO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(N2CCN(C(=S)SC)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
In a nitrogen atmosphere, 1.5 g (4.6 mmol.) of 4-(3,4,5-trimethoxyphenyl)-1-piperazinecarbodithioic acid was suspended inmethanol. After addition of 0.2 g of granular sodium hydroxide, the suspension was stirred at room temperature for one hour. The reaction mixture was chilled in a mixture of ice and sodium chloride. To the reaction mixture was dropwise added a solution of 0.29 ml of methyl iodidein 3.7 ml of methanol. After the addition was complete, the mixture was stirred at room temperature for 1 hour. Precipitated crystals were collected by filtration to give 0.8 g of the desired compound as a gray-brown powder, m.p. 135°-137° C. (decomp.), yield 50.8%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(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>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([O:10][CH3:9])[CH:16]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1ccccc1Br
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccccc2Br)c1
Reaction time: 12 h
Yield: 69.7 %

Procedure:
20.0 g (85.52 mmol) of 1,2-dibromobenzene, 11.70 g (76.97 mmol) of 3-methoxyphenylboronic acid, 0.99 g (0.86 mmol) of Pd(PPh3)4, and 18.13 g (171.04 mmol) of sodium carbonate were put, suspended in 300 ml of toluene and 100 ml of ethanol, and refluxed and agitated for 12 hours. After the reaction was finished, extraction was performed by dichloromethane, filtering was performed by silica gel, and the column was used at a ratio of hexane:MC=4:1 (v/v) to obtain 14.12 g of 2-bromo-3′-methoxybiphenyl that was the target compound (yield 63%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[S:11][CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[S:11][CH:12]=1
Reactant: COC(=O)CCCCc1csc(-c2ccccc2OC)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CCCCc1csc(-c2ccccc2O)n1

Procedure:
Dissolve 5-[2-(2-methoxy-phenyl)-thiazol-4-yl]-pentanoic acid methyl ester (3.3 g, 10.8 mmol) in CH2Cl2 (30 mL) under nitrogen at room temperature. Add boron tribromide (1M in CH2Cl2, 27 mL) and stir at room temperature until the reaction is complete. Quench the mixture with methanol, add ice/water and extract with CH2Cl2. Dry the combined extracts over Na2SO4 and concentrate. Chromatograph the resulting residue over silica gel (EtOAc/CH2Cl2) to allow for isolation of 5-[2-(2-hydroxy-phenyl)-thiazol-4-yl]-pentanoic acid methyl ester (2.2 g, 70%). MS (ES): (M+1)+ 292.1 m/z.
Reaction SMILES: [Cl-:1].[CH3:2][N:3]([CH3:29])[C:4]1[CH:28]=[CH:27][C:7]([CH:8]=[N:9][N+:10]2[CH:14]=[CH:13][N:12]([N:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:11]=2[CH3:26])=[CH:6][CH:5]=1.[CH3:30][N:31]([CH3:40])[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.N1CCCCC1>C(O)C>[Cl-:1].[CH3:25][N:23]([CH3:24])[C:20]1[CH:21]=[CH:22][C:17]([CH:16]=[N:15][N+:12]2[CH:13]=[CH:14][N:10]([N:9]=[CH:8][C:7]3[CH:6]=[CH:5][C:4]([N:3]([CH3:2])[CH3:29])=[CH:28][CH:27]=3)[C:11]=2[CH:26]=[CH:36][C:35]2[CH:38]=[CH:39][C:32]([N:31]([CH3:40])[CH3:30])=[CH:33][CH:34]=2)=[CH:18][CH:19]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)c1ccc(C=Cc2n(N=Cc3ccc(N(C)C)cc3)cc[n+]2N=Cc2ccc(N(C)C)cc2)cc1
Reaction time: 20 h

Procedure:
0.82 g of 1,3-bis[[p-(dimethylamino)-benzylidene]amino]-2-methylimidazolium chloride is suspended in 30 ml of ethanol, whereupon the suspension is treated with 0.3 g of 4-dimethylaminobenzaldehyde and 0.17 g of piperidine and heated to boiling under reflux. A deep red solution results. After 20 hours it is left to cool. The precipitated product is removed by filtration and re-precipitated from methylene chloride/ether. After recrystallization from toluene there is obtained 1,3-bis[[p-(dimethyl-amino)benzylidene]amino]-2-[p-(dimethylamino)styryl]imidazolium chloride as a red solid of melting point 238°-240°.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[CH2:26](OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[C@@H:27]1[O:29][CH2:28]1>>[O:29]1[CH2:28][C@@H:27]1[CH2:26][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:22]=[CH:23][C:4]([O:3][C:2]([F:1])([F:24])[F:25])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Product: FC(F)(F)Oc1ccc(OC2CCN(c3ccc(OC[C@H]4CO4)cc3)CC2)cc1

Procedure:
A target compound was manufactured as in Example 1, using 4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol and (R)-glycidylnosylate as starting raw materials.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[CH2:11][C:12](=[O:14])[NH:13][C:9]2=[N:8][C:7](=[O:15])[C:6]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([O:31]C)=[O:30])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O>[CH2:1]([C:5]1[N:10]2[CH2:11][C:12](=[O:14])[NH:13][C:9]2=[N:8][C:7](=[O:15])[C:6]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([OH:31])=[O:30])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c(=O)nc2n1CC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1c(Cc2ccc(-c3ccccc3C(=O)O)cc2)c(=O)nc2n1CC(=O)N2
Yield: 51.7 %

Procedure:
A solution of 0.17 g of 5-butyl-6-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]imidazo[1,2-a]pyrimidin-2,7-dione in 2 ml of MeOH is added with 32 mg of NaOH dissolved in 0.05 ml of H2O. After 24 h under reflux, the solvent is evaporated under reduced pressure and the residue is taken up in H2O and acidified to pH 5, to separate a solid which is filtered off and washed thoroughly with H2O. The purification is carried out by FC (eluent CH2Cl2 --MeOH--AcOH 89:10:1), to obtain 85 mg of a white solid (51% yield; m.p.=220°-222° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:10][S:11]([C:14]1[CH:27]=[CH:26][C:17]([CH2:18][CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:8][C:7]1[C:2]2[N:1]=[C:23]([CH3:24])[C:19]([CH2:18][C:17]3[CH:16]=[CH:15][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:27][CH:26]=3)=[C:20]([CH3:21])[C:3]=2[C:4]([OH:9])=[CH:5][CH:6]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 160 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (0.36 g), 3-(4-methanesulfonylbenzyl)pentane-2,4-dione (0.5 g) and p-toluenesulfonic acid monohydrate (0.05 g) was heated at 160° C. for 2.5 hours. The mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (50:1 to 2:1 by volume) to afford title compound (7:10 mixture of keto-enol tautomers) as a beige solid, 0.32 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.C(N(CC)CC)C.[CH:31]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:9])=[O:10])=[C:4]([CH2:22][NH:23][S:37]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)(=[O:39])=[O:38])[CH:3]=1
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reactant: O=S(=O)(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CNS(=O)(=O)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
To a stirred solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (0.6 g, 1.8 mmol) and triethylamine (0.7 mL, 5 mmol) in 100 mL of DCM was added cyclohexanesulfonyl chloride (0.3 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 16 hours. After majority of the solvent was removed under vacuum, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated, the crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a yellow powder (112 mg, yield 13%). MS calcd for (C20H26BN3O6S2): 479.1. MS found (ESI negative): (M−H)−=478.0. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.03 (s, 1H), 9.17 (bs, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.33 (t, J=6.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.10 (dd, J=8, 2 Hz, 1H), 6.81 (d, J=2 Hz, 1H), 6.40 (dd, J=8.8, 2.4 Hz, 1H), 4.86 (s, 2H), 4.44 (d, J=6.4 Hz, 2H), 2.93 (m, 1H), 2.02 (m, 2H), 1.80 (m, 2H), 1.64 (m, 1H), 1.33 (m, 5H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[C:39]([CH2:40][N:41]2[CH2:61][CH2:60][C:44]3([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]4[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=4)=[O:51])[CH2:45]3)[CH2:43][CH2:42]2)=[CH:38][CH:37]=[CH:36][C:27]=1[CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33](O)=[O:34].CCN(C(C)C)C(C)C.[CH3:71][O:72][CH:73]([O:83][CH3:84])[CH2:74][NH:75][CH:76]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]1>CN(C=O)C>[CH:76]1([N:75]([CH2:74][CH:73]([O:83][CH3:84])[O:72][CH3:71])[C:33](=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:27]2[CH:36]=[CH:37][CH:38]=[C:39]([CH2:40][N:41]3[CH2:42][CH2:43][C:44]4([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]5[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=5)=[O:51])[CH2:45]4)[CH2:60][CH2:61]3)[C:26]=2[F:25])[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]1
Reactant: COC(CNC1CCCCCC1)OC
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4F)CC3)C2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(CN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1F)C1CCCCCC1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of HATU (0.143 g) in DMF (0.5 mL) was added to a solution of 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid [Example 7, step d] (0.133 g), Hunig's base (0.22 mL) and N-(2,2-dimethoxyethyl)cycloheptanamine [WO 2008075025] (0.050 g) in DMF (0.5 mL). The resulting dark solution was stirred overnight at RT. The solvent was evaporated and the residue partitioned between ethyl acetate (25 mL) and 20% aqueous brine (25 mL). The organic layer was separated and washed with 20% aqueous brine (2×25 mL). The organic solution was evaporated and the residue purified by silica gel chromatography, elution gradient 65:30:5 to 47.5:47.5:5 isohexane:ethyl acetate:triethylamine. The fractions containing the product were combined and evaporated to give the subtitled compound as an oil. Yield 0.165 g.
Reaction SMILES: [NH2:1][OH:2].[N:3]1([C:9]#[N:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO.CCOCC>[OH:2][NH:1][C:9]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=[NH:10]
Reactant: N#CN1CCOCC1
Reactant: NO
Solvent: CO
Solvent: CCOCC
Product: N=C(NO)N1CCOCC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 139.3 %

Procedure:
A mixture of hydroxylamine (4.0 mL, 65 mmol) and morpholine-4-carbonitrile (5.00 g, 44.6 mmol) was heated at 80° C. for 24 h. After cooling to room temperature, the reaction mixture was diluted with MeOH and Et2O, then allowed to stand at room temperature for 2 days. The resultant precipitate was collected by filtration to give 9.02 g of the desired product as a white solid.