Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=C2C(NC(NC2=NC=1)=O)=O.[CH3:13][C:14]1[N:25]=[C:24]2[C:17](=[N:18][C:19]([NH:21][C:22]2=[O:23])=[O:20])[N:16]([CH2:26][C@H:27]([OH:34])[C@H:28]([OH:33])[C@H:29]([OH:32])[CH2:30][OH:31])[C:15]=1[CH3:35].CC(C(O)C[O:41][P:42]([OH:45])([OH:44])=[O:43])=O>>[P:42]([O-:45])([O-:44])([O-:43])=[O:41].[CH3:13][C:14]1[N:25]=[C:24]2[C:17](=[N:18][C:19]([NH:21][C:22]2=[O:23])=[O:20])[N:16]([CH2:26][C@H:27]([OH:34])[C@H:28]([OH:33])[C@H:29]([OH:32])[CH2:30][OH:31])[C:15]=1[CH3:35]
Reactant: CC(=O)C(O)COP(=O)(O)O
Agent: Cc1nc2c(=O)[nH]c(=O)nc-2n(C[C@H](O)[C@H](O)[C@H](O)CO)c1C
Agent: O=c1[nH]c(=O)c2nccnc2[nH]1
Product: O=P([O-])([O-])[O-]

Procedure:
The terms "lumazine synthase" or "LS" are used interchangeably with "6,7-dimethyl-8-ribityllumazine synthase" and refer to a plant or fungal enzyme that catalyzes the condensation of 3,4-dihydroxy-2-butanone 4-phosphate with 4-ribitylamino-5-amino-2,6-dihydroxypyrimidine (RAADP) to yield orthophosphate and 6,7-dimethyl-8-(1'-D-ribityl)-lumazine (DMRL).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][O:43][C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH2:65])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)=[O:45]>CN(C=O)C>[CH3:42][O:43][C:44]([CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH:65][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:57][CH:58]=1)=[O:45]
Reactant: COC(=O)COC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)COC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.2 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid methoxycarbonylmethyl ester (47.8 mg, 124 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (18 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H28N4O6, 481.20. found 481.2.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[O:18]([C:19]1[CH:20]=[CH:21][C:22]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1)C(O)c1ccc(Oc2ccccc2)cc1

Procedure:
Phenyglyoxal monohydrate (200 mg, 1.31 mM) and diphenylether (0.4 ml, 2.62 mM) were dissolved in dichloroethane (3 ml), titanium tetrachloride (0.07 ml, 0.66 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-phenoxybenzoin was obtained as crystal (331.2 mg, 80.7% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Br[C:34]1[N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:36]([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)=[CH:37][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([C:34]2[N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:36]([C:39]3[S:40][CH:41]=[CH:42][N:43]=3)=[CH:37][CH:38]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.44 g, 13.9 mmol) synthesized in Example (1e) and t-butyl 2-bromo-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (5.21 g, 15.8 mmol) synthesized in Example (1g) were dissolved in a mixed solvent of 1,4-dioxane (200 mL) and water (50 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (564 mg, 0.691 mmol) and potassium carbonate (9.67 g, 70.0 mmol) were added, followed by stirring at 50° C. for 3 hours under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (200 mL) was added, and extraction was carried out with ethyl acetate (400 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired compound (7.12 g, yield 88%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH:19]([CH3:24])[C:18]=3[CH:25]=2)=[CH:4][CH:3]=1.[OH:26]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:26])=[CH:6][CH:7]=1
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)OC(=O)N3)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methylphenylmercapto)-butoxy]-4-methyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:5][C:6]=1Br.BrC1C=C(C(O)=O)OC=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:5][CH:6]=1
Reactant: CCOC(=O)c1cc(Br)c(Br)o1
Agent: O=C(O)c1cc(Br)co1
Product: CCOC(=O)c1cc(Br)co1

Procedure:
The preparation of the title compound takes place on analogy to the synthesis of the compound from Example 2A starting with the compound from Example 1A. 19.1 g (89% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][SH:9])=[CH:3][CH:2]=1.Br[CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][S:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OCCBr
Reactant: SCCc1ccncc1
Product: OCCSCCc1ccncc1

Procedure:
Furthermore, by following this method 2-(4-pyridyl)ethyl mercaptan is reacted with 2-bromoethanol to yield 4-[2-(2-hydroxyethylthio)ethyl]pyridine, with 2-bromo-1-propanol to yield 4-[2-(2-hydroxy-1-propylthio)ethyl]pyridine, with 3-bromo-2-butanol to yield 4-[2-(3-hydroxy-2-butylthio)ethyl]pyridine, with ethyl 2-chloropropionate to yield ethyl 2-[2-(4-pyridyl)ethylthio]propionate, with methyl 2-phenyl-2-bromoacetate to yield methyl 2-phenyl-2-[2-(4-pyridyl)ethylthio]acetate, with alpha-bromoacetophenone to yield alpha-[2-(4-pyridyl)ethylthio]acetophenone, and with chloroacetone to yield 2-(4-pyridyl)ethylthioacetone.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]([C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])=[CH:15][C:14]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([NH2:11])[CH2:5][CH2:6][S:7]([CH3:10])(=[O:9])=[O:8]>C1COCC1.O>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([C:4]([NH2:11])([CH2:5][CH2:6][S:7]([CH3:10])(=[O:8])=[O:9])[C:3]([OH:35])=[O:2])=[O:34])=[C:14]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:15]=2)=[O:21])[CH:23]=1
Reactant: COC(=O)C(N)(CCS(C)(=O)=O)C(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)CCC(N)(C(=O)O)C(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
The [4-(3-pyridylcarbonylamino)-2-phenylbenzoyl]-2-amino-4-(methylsulfonyl)butanoic acid methyl ester prepared in Example 203A (43 mg, 0.081 mmol) was dissolved in 3 mL of THF and a solution of LiOH monohydrate was in 1 mL of H2O was added. The reaction mixture was stirred at 25° C. for 1 hour and then was evaporated. Formic acid (1 mL) was added to acidify to pH=3. The reaction was then evaporated once again and 1 mL of H2O was added along with 5 mL of ethyl acetate to dissolve the mixture. The ethyl acetate layer was dried over Na2SO4, filtered and evaporated and the residue was lyophilized from acetonitrile/H2O to give [4-(3-pyridylcarbonylamino)-2-phenylbenzoyl]-2-amino-4-(methylsulfonyl)butanoic acid (36 mg, 88%) as a white solid. 1H NMR (300 mHz, CD3OD) δ 9.12 (d, 1H), 8.70 (d, 1H), 8.42 (dt, 1H), 7.85-7.80 (m, 2H), 7.65-7.40 (m, 8H), 4.50 (m, 1H), 2.90 (s, 3H), 2.88-2.80 (m, 1H), 2.70-2.58 (m, 1H), 2.35-2.20 (m, 1H), 2.10-1.95 (m, 1H). HRMS calcd C24H23N3SO6 MH+ 482.1386, found 482.1373.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[C:10](=[O:32])[N:11]([CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[CH2:12][CH2:13][O:14][C:15]=2[N:16]=1)(=O)C.[OH-].[Na+]>C(O)C>[F:31][C:28]([F:29])([F:30])[C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=1)[CH2:17][N:11]1[C:10](=[O:32])[C:9]2[C:8]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:7][C:6]([CH2:5][OH:4])=[N:16][C:15]=2[O:14][CH2:13][CH2:12]1
Reactant: CC(=O)OCc1cc(-c2ccccc2)c2c(n1)OCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2c(-c3ccccc3)cc(CO)nc2OCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
A mixture of 8-acetoxymethyl-4-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine (Example 37) (4.51 g), ethanol (50 ml), and 4N-NaOH (50 ml) was stirred for 1.5 hours at room temperature. After evaporation of the solvent, water was added to the residue. The pH of the mixture was adjusted to ca.8 using dilute hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the entitled compound as colorless crystals (4.10 g). m.p. 199-201° C. (recrystallized from ethyl acetate-isopropyl ether) NMR(200 MHz, CDCl3) ppm: 3.10(1H,b), 3.71(2H,t,J=5.6 Hz), 4.50(2H,t,J=5.6 Hz), 4.78(2H,s), 4.88(2H,s), 7.20-7.50(6H,m), 7.80(2H,m), 7.87(1H,s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]#[N:11].O.[NH2:14][NH2:15]>CCO>[NH2:11][C:10]1[NH:15][N:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH:9]=1
Reactant: N#CCC(=O)c1ccccc1Br
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2Br)n[nH]1
Yield: 69.6 %

Procedure:
To a solution of 3-(2-bromo-phenyl)-3-oxo-propionitrile (1.8 g, 8.03 mmol) in absolute EtOH (25 mL) was added hydrazine hydrate (2.3 mL, 48.2 mmol). The reaction mixture was refluxed for 23 hours, then cooled and purified directly on silica gel with 0-10% MeOH in CH2Cl2 as eluent to provide 1.33 g (70% yield) of 5-amino-3-(2-bromophenyl)pyrazole as a sticky oil. 1H-NMR (d6-DMSO) δ: 11.7 (broad m, 1H, tautomers), 7.20-7.70 (broad m, 4H), 5.76 (broad m, 1H), 5.03 (broad s, 1H), 4.60 (broad s, 1H); HPLC/MS m/z: 238.0, 240.0 [MH]+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=4[CH3:15])[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(N2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)c1C

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(2,3-dimethylphenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 83% overall yield. FDMS m/e=379 (M+ of free base). α[D]589 =-9.84 (c=0.75, methanol).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([N:12]([CH2:20][C:21](O)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:35][C@@H:36]1[CH2:40][NH:39][C@H:38]([C:41]#[N:42])[CH2:37]1>>[N:1]1([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([N:12]([CH2:20][C:21]([N:39]3[CH2:40][C@@H:36]([F:35])[CH2:37][C@H:38]3[C:41]#[N:42])=[O:22])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:8]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N#C[C@@H]1C[C@H](F)CN1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)[C@H]1CC[C@@H](Cn2cncn2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)OC(=O)N(CC(=O)N1C[C@@H](F)C[C@H]1C#N)[C@H]1CC[C@@H](Cn2cncn2)C1
Yield: 92.4 %

Procedure:
This compound was prepared from [(3R,1S)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentyl-N—BOC-amino]acetic acid (50 g, 154.14 mmol) and (2S,4S)-4-fluoropyrrolidine-2-carbonitrile p-toluenesulfonate (52.96 g, 184.96 mmol) as described in the preparation of its enantiomer (Method C) to give 59.9 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.22-1.36 (m, 2H), 1.44 (s, 9H), 1.62-1.81 (m, 2H), 1.88-2.04 (m, 3H), 2.22-2.27 (m, 1H), 2.34-2.49 (m, 1H), 2.62-2.77 (m, 1H), 3.69-4.01 (m, 3H), 4.13-4.23 (m, 3H), 4.99 (d, J=9.3 Hz, 1H), 5.33 (d, J=51.7 Hz, 0.3H, rotomer), 5.45 (d, J=51.0 Hz, 0.7H. rotomer), 7.92 (s, 1H), 8.08 (s, 0.4H, rotomer), 8.10 (s, 0.6H, rotomer).
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])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[O:21]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[O:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:36])=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)c2cc1OC
Yield: 44.2 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (20 mg, 0.0733 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 4-phenoxyphenyl isocyanate (23 mg, 0.109 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a brown solid (15.7 mg, 44%). 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.48 (m, 1H), 7.33 (m, 5H), 7.07 (m, 1H), 6.99 (m, 4H), 6.41 (br s, NH), 4.32-4.27 (m, 2H), 4.09 (s, 6H), 3.63 (m, 1H), 3.20 (m, 2H), 2.17 (m, 2H), 2.03-1.99 (m, 2H); LC/MS (ESI) calcd mass 484.2, found 485.3 [M+1]+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][C:8]2([O:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:7]1.C[O-].[Mg+2].C[O-].CO.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][C:8]3([O:11][CH2:12][CH2:13][CH2:14][O:15]3)[CH2:7]2)[C:3]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[O:2])[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCC2(C1)OCCCO2)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCC2(C1)OCCCO2)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 65 %

Procedure:
2-(3,4-Dichloro-phenyl)-3-(6,10-dioxa-spiro[4.5]dec-2-yl)-propionic acid methyl ester (1.00 g, 2.68 mmol) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 19 mL, 13.39 mmol), The reaction mixture was then treated with 2-aminothiazole (348.7 mg, 3.48 mmol). The resulting reaction mixture was then heated under reflux for 28 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate, and the filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 25–50% ethyl acetate/hexanes) afforded crude 2-(3,4-dichloro-phenyl)-3-(6,10-dioxa-spiro [4.5]dec-2-yl)-N-thiazol-2-yl-propionamide (768.5 mg) as a yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17](O)=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.C(Cl)(=O)C(Cl)=O.[CH3:29][NH2:30]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([NH:30][CH3:29])=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: CN
Reactant: O=C(O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a solution of 7-((3-chlorobenzyl)oxy)quinoline-3-carboxylic acid (50 mg, 0.16 mmol) in DCM (1.5 mL) was added oxalyl chloride (0.042 mL, 0.48 mmol) followed by 1 drop of DMF. After 30 minutes, methylamine (2M in THF, 1 mL, 2 mmol) was added to the reaction. The reaction was stirred for 14 h. The crude reaction was loaded directly onto a column and purification (FCC, SiO2, 0-10%, MeOH/DCM) afforded the title compound as a white solid (19 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 9.17 (d, J=2.3 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.49 (d, J=2.7 Hz, 2H), 7.38-7.31 (m, 4H), 6.28-6.22 (m, 1H), 5.21 (s, 2H), 3.10 (d, J=4.7 Hz, 3H). [M+H]=327.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:17][CH:16]([CH2:18]Br)[O:15][C:5]2=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][C:7]2([CH3:14])[CH3:13].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:18][CH:16]1[O:15][C:5]2=[C:6]3[C:11](=[C:2]([Br:1])[CH:3]=[C:4]2[CH2:17]1)[NH:10][C:9](=[O:12])[CH2:8][C:7]3([CH3:14])[CH3:13])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CC(=O)Nc2c(Br)cc3c(c21)OC(CBr)C3
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)Nc2c(Br)cc3c(c21)OC(CN=[N+]=[N-])C3
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.4 %

Procedure:
5-Bromo-2-bromomethyl-9,9-dimethyl-2,3,6,7,8,9-hexahydrofuro[2,3-f]quinoline-7-one (1.25 g, 3.21 mmol) was dissolved in dimethylformamide (50 ml). To the resultant solution, sodium azide (1.25 g, 19.3 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was condensed under reduced pressure, and the residue was extracted along with chloroform and water. The organic phase was dried, and condensed under reduced pressure. Recrystallization from chloroform-n-hexane-ether yielded 997 mg of the title compound as pale yellow needles (88.4%).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[F:14][C:15]([F:30])([F:29])[C:16]1[CH:28]=[CH:27][C:19]([O:20]C2CCCCO2)=[CH:18][CH:17]=1.CN(C)[CH:33]=[O:34].Cl>>[OH:20][C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:29])[F:30])=[CH:28][C:27]=1[CH:33]=[O:34]
Reactant: FC(F)(F)c1ccc(OC2CCCCO2)cc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Product: O=Cc1cc(C(F)(F)F)ccc1O
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
At −15° C., an 1.6 N solution of n-butyllithium in hexanes (7.20 ml, 11.5 mmol) was added to N,N,N′,N′-tetramethylethylenediamine (1.72 ml, 11.4 mmol). The reaction mixture was stirred for 10 min at −10° C. 2-(4-(trifluoromethyl)phenoxy)tetrahydropyran (2.0 g, 8.12 mmol) was added. The reaction mixture was stirred for 2 h at −10° C. N,N-Dimethylformamide (0.88 ml, 11.4 mmol) was added. The reaction mixture was stirred for 15 min at −10° C. It was given onto a 6 M hydrochloric acid. This mixture was stirred at room temperature for 16 h. The organic layer was isolated and dried. The solvent was removed in vacuo. 659 mg of 2-hydroxy-5-(trifluoromethyl)benzaldehyde were isolated from the crude mixture by flash chromatography on silica (90 g), using ethyl acetate/heptane 1:10 as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:6]2.[K].C(=O)([O-])[O-].Br[CH2:44][CH2:45][CH2:46][Cl:47]>CN(C=O)C>[Cl:47][CH2:46][CH2:45][CH2:44][N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([C:14]2[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=2)[C:8]1=[O:13]
Reactant: COc1ccc2[nH]c(=O)c(-c3nnn(Cc4cccc(OCc5ccc6ccccc6n5)c4)n3)cc2c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(-c1nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n1)c(=O)n2CCCCl
Temperature: 60 °C
Reaction time: 4 h
Yield: 47.2 %

Procedure:
A mixture of 6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (1.00 g, 2.04 mmol), potassium, carbonate (564 mg, 4.08 mmol), 1-bromo-3-chloropropane (962 mg, 6.12 mmol), and DMF (100 ml) was stirred for four hours at a bath temperature of 60° C. The solvent of the reaction mixture was removed under reduced pressure. Water was then added to the mixture, and the mixture was extracted with chloroform-methanol (10:1). The thus-obtained organic phase was dried over magnesium sulfate anhydrate, and the solvent was removed under reduced pressure. The organic phase was then subjected to silica gel column chromatography (developer: chloroform-methanol (100:1)), purified, and crystallized from a chloroform-diethylether mixture, to thereby obtain the title compound (546 mg, 0.963 mmol, 47.2%) as pale yellow powder.
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19]C1CCCCO1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.O1CCCC1.O>[CH2:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(CCOCCCCCCCCCOC2CCCCO2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCCCCCCCCCOCCc1ccccc1
Yield: 76.1 %

Procedure:
A solution of 2-(9-phenethyloxy-nonyloxy)-tetrahydro-pyran (890 mg, 2.55 mmol) in acetic acid/tetrahydrofuran/water 4:2:1 (23 mL) was stirred at 45° C. for 4 h. After evaporation, the residue was purified by chromatography (SiO2; heptane-ethyl acetate gradient), affording 9-phenethyloxy-nonan-1-ol (513 mg, 76%). Colorless oil, m/e=265.3 ([M+H]+).