Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])[CH3:19]>>[CH2:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)[CH3:19]
Reactant: CCc1cccc(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: CCc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 3-ethylaniline (18 μl, 0.144 mmol) similar to Example 92 and isolated as a yellow oil (12 mg, 36%). 1H NMR (CDCl3): 8.84–8.82 (m, 1H), 8.57–8.54 (m, 1H), 7.89–7.84 (m, 1H), 7.72 (s, 1H), 7.44–7.40 (m, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.14–7.11 (m, 3H), 7.01 (s, 1H), 2.69 (q, J=7.8 Hz, 2H), 1.27 (t, J=7.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17].C(=O)(O)[O-].[Na+]>COCCOCCOC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=[S:17]
Reactant: COc1cc2[nH]ccc(=O)c2cc1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Product: COc1cc2[nH]ccc(=S)c2cc1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
After suspending the 6,7-dimethoxy-1H-quinolin-4-one (10.3 g, 50.0 mmol) described in WO9717329, phosphorus pentasulfide (26.7 g, 60.0 mmol) and sodium bicarbonate (26.7 g, 318 mmol) in diglyme (diethyleneglycol dimethyl ether) (100 ml), the suspension was heated and stirred at 80° C. for 2 hours. The reaction solution was returned to room temperature and poured into ice water (1000 ml), and the precipitated crystals were filtered out, washed with water and blow-dried to obtain the title compound (8.19 g, 37.0 mmol, 74%) as yellow crystals.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[NH2:12][C@@:13]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C@H:14]1[CH2:28]O>ClCCl>[CH2:21]([O:20][CH2:19][C@@H:16]1[O:17][CH2:18][C@@:13]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[C@H:14]([CH2:28][S:11][C:10]([NH2:9])=[N:12]2)[CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2ccccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Solvent: ClCCl
Product: NC1=N[C@@]2(c3ccccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzoyl isothiocyanate (893 μl) was added dropwise to a solution of [(2R,4R,5S)-5-amino-2-benzyloxymethyl-5-(2-fluorophenyl)tetrahydropyran-4-yl]methanol (2.08 g) in dichloromethane (30 ml). The reaction solution was stirred at room temperature for three hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. Several drops of concentrated hydrochloric acid were added to a solution of the resulting intermediate in methanol (40 ml), and the mixture was heated under reflux for five hours. The reaction solution was returned to room temperature, and then the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (40 ml) and DBU (2 ml) was added, followed by heating under reflux for five hours. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (1.61 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[C-:10]#[N:11].[Na+].CS(C)=O>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][C:10]#[N:11])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(CC#N)OCC
Reaction time: 5 h

Procedure:
A mixture of 8 g of bromo-acetaldehyde diethyl-acetal, 3 g of sodium-cyanide and 20 ml of dimethyl-sulfoxide is admixed at a temperature of 80° C. for 5 hours. The reaction mixture is poured on 80 ml of water, then twice extracted with 50 ml of chloroform. The chloroform extract is washed twice with 30 ml of water, dried on magnesium sulfate, then distilled in vacuo.
Reaction SMILES: CC1(C)OCC2(CCC(CCN[C@H](C3C=CC=CC=3)CC)(O)CC2)C[O:3]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CC1(C)OC[C:43]2([CH2:63][CH2:62][C:46]3([O:51][C:50](=[O:52])[N:49]([C@H:53]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[CH2:54][CH3:55])[CH2:48][CH2:47]3)[CH2:45][CH2:44]2)CO1>>[C:56]1([C@@H:53]([N:49]2[CH2:48][CH2:47][C:46]3([CH2:45][CH2:44][C:43](=[O:3])[CH2:63][CH2:62]3)[O:51][C:50]2=[O:52])[CH2:54][CH3:55])[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: CC[C@@H](c1ccccc1)N1CCC2(CCC3(CC2)COC(C)(C)OC3)OC1=O
Reactant: CC[C@H](NCCC1(O)CCC2(CC1)COC(C)(C)OC2)c1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC[C@@H](c1ccccc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 3,3-dimethyl-9-{2-[(S)-1-phenyl-propylamino]-ethyl}-2,4-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 12,12-dimethyl-3-[(S)-1-phenyl-propyl]-1,11,13-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained thereafter is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 56% of theory; LC (method 8): tR=1.20 min; Mass spectrum (ESI+): m/z=302 [M+H]+.
Reaction SMILES: [CH:1]1([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1.O>N1C=CC=CC=1>[C:21]([O:19][C:16]1[CH:15]=[CH:14][C:13]([CH:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:18][CH:17]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Oc1ccc(C2CCCCCCCCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Oc1ccc(C2CCCCCCCCCCC2)cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
8 g (30.8 mmol) of p-cyclododecylphenol and 5.9 g (33.2 mmol) of nicotinic acid chloride hydrochloride was mixed with 140 ml of dry pyridine and kept at 30° C. for 15 hours. Subsequently, 42 ml of water was added slowly drop by drop, and the mixture cooled to 0° C. The crystallized precipitate was sucked off, freed from pyridine by washing with water and dried.
Reaction SMILES: BrC[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.C1N2CN3CN(C2)CN1C3.[C:25](O)(=[O:27])C.Cl>O>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:3][CH:4]=2)[C:9]=1[CH:25]=[O:27]
Reactant: COc1ccc2cc(CBr)ccc2c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: COc1ccc2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromomethyl-6-methoxynaphthalene (12.68 g), hexamine (14 g), glacial acetic acid (21 ml) and water (21 ml) were heated under reflux with stirring for 30 minutes. Concentrated hydrochloric acid (16.6 ml) was then added and the mixture stirred and refluxed for a further 15 minutes. The reaction was cooled to room temperature and extracted with toluene (2×25 ml). The combined toluene extracts were washed with water (2×10 ml), saturated sodium bicarbonate solution (2×10 ml) and water (1×8 ml) and the toluene solution dried over MgSO4. The drying agent was filtered off and the solvent was removed by distillation under vacuum. This afforded 8.6 g of crude product which was recrystallised twice from isopropanol (2×50 ml) to give 6.07 g of 97.8% purity 2-methoxynaphthaldehyde as a light beige solid. The material had a melting point of 79.2° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1.[CH3:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:11][CH2:12][CH2:13][CH2:14]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][N:25]([S:38]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([CH3:31])[CH:33]=4)(=[O:40])=[O:39])[CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B6*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19]CC(F)(F)C(F)(F)F)=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=2)[C:3]1=[O:42].CC1(C)N(CCCCCCCCCSCC[C:62]([F:74])([F:73])[C:63]([F:72])([F:71])[C:64]([F:70])([F:69])[C:65]([F:68])([F:67])[F:66])C(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O>>[CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][C:62]([F:74])([F:73])[C:63]([F:71])([F:72])[C:64]([F:69])([F:70])[C:65]([F:68])([F:67])[F:66])=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:39])([F:41])[F:40])[CH:30]=2)[C:3]1=[O:42]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 85 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 14 replacing the compound of Example 1. A pale yellow oil is obtained with a yield of 85% (145 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:23](Br)[CH2:24][CH2:25][CH3:26].[H-].[Na+]>CN(C=O)C>[CH2:23]([N:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[C:11]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12])[CH2:24][CH2:25][CH3:26]
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3ccccc32)cc1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(C(=O)C1CCCc2ccccc21)c1ccc(C(C)C)cc1
Reaction time: 0.5 h

Procedure:
N-(4-Isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and butyl bromide (0.22 mL) were dissolved in DMF (3 mL), and sodium hydride (0.08 g) was added under ice-cooling. The mixture was stirred at the same temperature for 30 min and then at room temperature for 3 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N-butyl-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[C:3]=1[C:17](=[O:19])[NH2:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>CCO.N1CCCCC1>[C:17]([C:3]1[C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:25][C:24]1[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=1)(=[O:19])[NH2:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1c(Nc2ccc(C(=O)O)cc2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc(C(=O)O)cc2)n[nH]c1N=Cc1ccc(O)cc1

Procedure:
4-((5-amino-4-carbamoyl-1H-pyrazol-3-yl)amino)benzoic acid was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 4-((4-carbamoyl-5-((4-hydroxybenzylidene)amino)-1H-pyrazol-3-yl)amino)benzoic acid as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16](O)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][OH:17])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(CC(=O)O)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCO)CC1
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
A solution of borane dimethyl sulphide complex in tetrahydrofuran (11.7 mL, 23.32 mmol, 3.0 eq) is added dropwise within 10 minutes at −5° C. to a stirred solution of (4-tert-butoxycarbonylamino-cyclohexyl)-acetic acid (2.0 g, 7.77 mmol, 1.0 eq) in tetrahydrofuran (50 mL). The reaction mixture is stirred at −5° C. for 20 minutes then at room temperature for 3 hours. Methanol (10 mL) is cautiously added to the reaction mixture that is then evaporated and repeatedly treated with methanol and concentrated to dryness to afford [trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester as a white solid (1.89 g, 99.5% yield).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ccccc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-phenyl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: S([O-])(O)=O.[Na+].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:15]=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C.[C-:30]#[N:31].[K+]>O>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:15]([OH:16])[C:30]#[N:31])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(O)C#N
Reaction time: 8 h

Procedure:
A solution of sodium hydrogensulfite (0.92 g) in water (5 ml) is added to a suspension of (2S)-2-(tert-butoxycarbonyl)amino-3-phenylpropanal (2.00 g, Reference compound No. 2-1) in water (20 ml) under ice cooling, then the temperature is raised to room temperature, and the mixture is stirred overnight. Ethyl acetate (100 ml) is added to the mixture, and the whole is stirred for one hour. Then, a solution of potassium cyanide (0.58 g) in water (5 ml) is added thereto, and the whole is further stirred for four hours. The reaction mixture is extracted with ethyl acetate, and the extract is washed with saturated brine. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled reference compound (1.18 g).
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14](=[O:24])[O:13][CH2:12][C@H:11]([NH:25]C(OC(C)(C)C)=O)[C:10](=[O:33])[O:9][C@H:8]1[CH3:34])(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[OH:36][C:37]1[C:38]([C:45]([OH:47])=O)=[N:39][CH:40]=[CH:41][C:42]=1[O:43][CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CCOC(C)=O>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:14](=[O:24])[O:13][CH2:12][C@H:11]([NH:25][C:45](=[O:47])[C:38]2[C:37]([OH:36])=[C:42]([O:43][CH3:44])[CH:41]=[CH:40][N:39]=2)[C:10](=[O:33])[O:9][C@H:8]1[CH3:34])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CC(=O)OC(C)(C)C)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Temperature: 22 °C
Reaction time: 6 h
Yield: 43.1 %

Procedure:
To a solution of (3S,6S,7R,8R)-8-(2-tert-butoxy-2-oxoethyl)-3-(tert-butoxycarbonylamino)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (130 mg, 0.267 mmol) in EtOAc (3 mL) was added 1M HCl in EtOAc and the solution was stirred at room temperature (about 22° C.) for 6 h. The solvent was evaporated and the residue was dissolved in CH2Cl2 (1.5 mL). To this solution was added 3-hydroxy-4-methoxypicolinic acid (58 mg, 0.345 mmol), HATU (139 mg, 0.367 mmol) and N-methylmorpholine (120 mL, 1.09 mmol), sequentially. The reaction was allowed to stir at ambient temperature for 12 h and then loaded directly onto a SiO2 column and purified by flash chromatography (hexanes/EtOAc gradient) to give the title compound (62 mg, 43%) as a white solid: mp 192-194° C.; 1H NMR (400 MHz, CDCl3) δ 11.79 (d, J=0.5 Hz, 1H), 8.63 (d, J=8.3 Hz, 1H), 8.01 (d, J=5.2 Hz, 1H), 6.89 (d, J=5.1 Hz, 1H), 5.45 (s, 1H), 5.21 (dd, J=15.5, 8.3 Hz, 1H), 5.12-5.01 (m, 1H), 5.01-4.87 (m, 1H), 3.95 (s, 3H), 3.80 (d, J=25.0 Hz, 1H), 2.98 (ddd, J=11.8, 9.9, 3.2 Hz, 1H), 2.86-2.74 (m, 1H), 2.62 (dt, J=14.0, 7.0 Hz, 1H), 2.35-2.23 (m, 1H), 1.41 (s, 9H), 1.30 (dd, J=6.2, 2.4 Hz, 3H), 1.22 (dd, J=7.0, 1.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 175.50, 172.00, 170.26, 169.90, 169.01, 155.45, 148.86, 140.73, 129.97, 109.74, 81.74, 74.79, 74.07, 65.03, 56.13, 49.80, 45.81, 34.93, 34.02, 27.97, 18.96, 18.84, 17.79; ESIMS m/z 539 ([M+H]+).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:25])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][C:6]([CH3:27])=[N:5]1)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+:36](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl-].[NH4+].C(N(CC)CC)C>CN(C)C=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([NH2:36])=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][C:6]([CH3:27])=[N:5]1)([CH3:2])[CH3:3]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(CC(=O)O)cc2OCC3)n(C(C)C)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CC(N)=O)cc2OCC3)n(C(C)C)n1
Reaction time: 0.67 h

Procedure:
A mixture of 58 mg (0.158 mmol) of 2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetic acid, 76 mg (0.20 mmol) of N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate, (HATU, 16 mg, 0.30 mmol) of ammonium chloride and 28 uL (0.200 mmol) of Triethylamine in N,N-3.0 ml of Dimethylformamide was stirred for 40 min. The mixture was concentrated in vacuum and triturated with 10 ml of water. The solid was collected and purified by RP HPLC (acetonitrile gradient) to give 300. Yield 8.1 mg. M/z 367.2, calc. 366.18. 1H NMR (500 MHz, DMSO) δ 8.30 (d, J=8.2, 1H), 7.86 (s, 1H), 7.44 (s, 1H), 7.04 (d, J=8.3, 1H), 6.96 (s, 1H), 6.88 (s, 1H), 5.80 (dt, J=13.1, 6.5, 1H), 4.49 (q, J=6.2, 4H), 3.38 (s, 2H), 2.25 (s, 3H), 1.45 (d, J=6.6, 6H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[Li]CCCC.[CH3:25][N:26]([CH3:44])[S:27]([N:30]1[C:34]([CH:35]=[O:36])=[CH:33][N:32]=[C:31]1[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=[O:29])=[O:28]>C1COCC1>[CH3:25][N:26]([CH3:44])[S:27]([N:30]1[C:34]([CH:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[S:8][CH2:7][CH2:6][CH:5]3[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[OH:36])=[CH:33][N:32]=[C:31]1[Si:37]([C:40]([CH3:42])([CH3:41])[CH3:43])([CH3:39])[CH3:38])(=[O:28])=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OC1CCSc2ccc(Br)cc21
Reactant: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c(C(O)c2ccc3c(c2)C(O[Si](C)(C)C(C)(C)C)CCS3)cnc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of (6-bromo-thiochroman-4-yl-oxy)-tert-butyl-dimethyl-silane (Intermediate-K3) (2.74 g, 7.64 mmol) in TH F (30 mL) was treated with nBuLi (3.1 mL of a 2.5 M soln) at −78° C. for 30 m. A solution of 2-(tert-butyl-dimethyl-silanyl)-5-formyl-imidazole-1-sulfonic acid dimethylamide (see the General Method above, Intermediate K1) (2.42 g, 7.63 mmol) in THF (10 mL) was added via cannula. After 15 m, the reaction mixture was allowed to warm to rt for 16 h. The mixture was quenched with water, washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by chromatography on silica gel with 20% EtOAc:hexane to afford 2-(tert-butyl-dimethyl-silanyl)-5-{[4-(tert-butyl-dimethyl-silanyloxy)-thiochroman-6-yl]-hydroxy-methyl}-imidazole-1-sulfonic acid dimethylamide (Intermediate K4) as an oil, 4.12 g.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][CH3:28])[N:26]=2)[N:11]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:10]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[CH2:27]([C:25]1[N:26]=[C:22]([C:12]2[N:11]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:10]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:9]([OH:8])[C:13]=2[OH:14])[S:23][CH:24]=1)[CH3:28]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(-c2nc(CC)cs2)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c(O)c(-c2nc(CC)cs2)n1-c1ccc(OC)cc1
Yield: 64.4 %

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-5-(4-ethylthiazol-2-yl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (30) (70 mg, 0.12 mmol) in MeOH/THF (3:1; 5 mL) was passed through a Thales ‘H-cube’ cartridge (10 Pd/C) at a flow rate of 1 mL/min at 40° C. under H2 (full H2 mode). The output was concentrated in vacuo and the resulting oil was purified by silica gel chromatography (12 g, 0-20% EtOAc in isohexane) to afford ethyl 5-(4-ethylthiazol-2-yl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-086) (30 mg, 63%) as an off-white solid: m/z 389 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1H NMR (400 MHz, DMSO-d6) δ: 9.82 (s, 1H), 8.68 (s, 1H), 7.28-7.19 (m, 2H), 7.06-7.03 (m, 1H), 7.03-6.97 (m, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H), 0.99 (t, J=7.1 Hz, 3H).