Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.Br[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1)[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Reactant: BrCC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A solution of diisopropylamine (0.67 mL, 4.82 mmol) in tetrahydrofuran (30 mL) cooled to −78° C. under an argon atmosphere was treated with a 2.5M solution of n-butyllithium in hexanes (1.93 mL, 4.82 mmol). The reaction mixture was stirred at −78° C. for 15 min. At this time, the reaction was treated with a solution of (4-methanesulfonyl-phenyl)-acetic acid methyl ester (1.00 g, 4.38 mmol) in tetrahydrofuran (6 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The bright yellow solution was allowed to stir at −78° C. for 1 h, after which time, a solution of 2-bromomethyl-tetrahydro-pyran (0.67 mL, 5.26 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 16 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×15 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 70/30 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid methyl ester (157 mg, 11%) as a colorless oil: EI-HRMS m/e calcd for C16H22O5S (M+) 326.1188, found 326.1189.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:18]=[C:19]2[C:24]3[CH2:25][NH:26][CH2:27][CH2:28][C:23]=3[NH:22][C:21](=[O:29])[N:20]2[CH:30]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:26]1[CH2:27][CH2:28][C:23]2[NH:22][C:21](=[O:29])[N:20]3[CH:30]=[C:17]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[F:10])[N:18]=[C:19]3[C:24]=2[CH2:25]1
Reactant: Fc1ccccc1CBr
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CN(Cc1ccccc1F)CC2
Reaction time: 0.75 h

Procedure:
2-Fluorobenzyl bromide (54 uL, 0.45 mmol) was added to a solution of 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (128 mg, 0.45 mmol) and triethylamine (76 uL, 0.54 mmol) in DMF (1 mL) at room temperature. The reaction mixture was stirred for 45 minutes, and then concentrated. Aqueous sodium bicarbonate was added, the aqueous layer extracted twice with 10% methanol/ethyl acetate, and the combined organic layers dried over magnesium sulfate, filtered, concentrated, and triturated with methanol/ether to give 9-(2-Fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (Compound 13) as an off-white solid, m.p. 270°-273° C. Treatment with ethanolic HCl affords the corresponding HCl salt.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])C.CO.C1COCC1.[OH-].[Na+]>O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]([CH3:11])=[N:8]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-n2nc(C)cc2C(=O)O)cc1

Procedure:
To a solution of 2-(4-Methoxy-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (400 mg) in a 1:1:1 mixture of MeOH:THF:water was added 10% NaOH (20 mL). The mixture was heated to reflux and the reaction monitored by TLC and HPLC until hydrolysis was complete. The solution was cooled and concentrated under reduced pressure. The residue was acidified with 10% HCl and extracted with EtOAc. The organic fractions were combined and dried over MgSO4 and concentrated under reduced pressure. The resulting solid was used without further purification (Yield 242 mg). LC-MS (C12H12N2O3 calculated 232) m/z 231 (M−H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH3:7][S:8]([NH:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([NH:23][C:24](=[O:27])[CH2:25][Cl:26])=[C:17]2[OH:22])(=[O:10])=[O:9]>O1CCCC1>[Cl-:26].[OH:22][C:17]1[C:18]2[C:13](=[C:12]([NH:11][S:8]([CH3:7])(=[O:10])=[O:9])[CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[NH:23][C:24]([CH2:25][N:4]1[CH:5]=[CH:6][N+:2]([CH3:1])=[CH:3]1)=[O:27]
Reactant: Cn1ccnc1
Reactant: CS(=O)(=O)Nc1cccc2c(O)c(NC(=O)CCl)ccc12
Solvent: C1CCOC1
Product: C[n+]1ccn(CC(=O)Nc2ccc3c(NS(C)(=O)=O)cccc3c2O)c1
Product: [Cl-]
Yield: 70 %

Procedure:
0.25 ml of N-methylimidazole (3.1 mmol) was introduced into a solution of N-(5-methanesulphonylamino-1-hydroxynaphthalen-2-yl)-2-chloroacetamide obtained above in the preceding step (1 g, 3 mmol) in 20 ml of tetrahydrofuran. The reaction medium was heated under reflux for 8 hours. The precipitate formed was drained, washed abundantly with dioxane and dried under vacuum to constant weight to give 0.86 g of 3-[(1-hydroxy-5-methanesulphonylaminonaphthalen-2-ylcarbamoyl)methyl]-1-methyl-3H-imidazol-1-ium chloride in the form of a brown powder melting at 198° C., with a yield of 70%. The cation mass spectroscopy analysis: m/z=375 of the product obtained was consistent with that of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][N:19]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(F)cn1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Product: O=C(Nc1ccc(F)cn1)c1ccc(F)c([N+](=O)[O-])c1
Yield: 98 %

Procedure:
The product from Example 172a was reacted with 5-Fluoro-pyridin-2-ylamine (165 mg, 1.474 mmol) according to the procedure from Example 172a to provide the title compound (404 mg, 98%).
Reaction SMILES: C([C:4]1[C:5]([O:16][CH2:17][C:18]([Cl:20])=[CH2:19])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[CH3:15])(=O)C.ClC(=C)[CH2:23][O:24]C1C(O)=C2C(C(C)=CC(=O)O2)=CC=1>>[Cl:20][C:18](=[CH2:19])[CH2:17][O:16][C:5]1[C:4]([O:24][CH3:23])=[C:13]2[C:8]([C:9]([CH3:15])=[CH:10][C:11](=[O:14])[O:12]2)=[CH:7][CH:6]=1
Reactant: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1O
Product: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1OC

Procedure:
As shown in FIG. 24, the synthesis pathway for the compounds of the present invention involves starting with the following compound, Compound 1: ##STR5## This starting compound in the synthesis of Compound 2 is 4,5'-dimethyl-8-methoxypsoralen. The synthesis of this precursor compound has been described previously in the literature. See Bender, et al., J. Org. Chem. 44:2176 (1979). Alternatively, the starting compound may be synthesized by the following method: 8-acetyl-7-(2-chloroallyl)oxy-4-methylcoumarin, described in Bender, et al, J. Org. Chem. 48:2709 (1983), is initially oxidized to a phenolic compound, 7-(2-chloro-2-propenyl)oxy-8-hydroxy-4-methylcoumarin, and then methylated, providing 7-(2-chloro-2-propenyl)oxy-8-methoxy-4-methylcoumarin. Claisen rearrangement provides 6-(2-chloro-2-propenyl)-7-hydroxy-8-methoxy-4-methylcoumarin, which is then converted to 4,5'-dimethyl-8-methoxypsoralen.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:32].[Na+].OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[C:23]([C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[Cl:1])[NH:8][CH:7]=[C:6]4[C:11]([OH:32])=[O:12])=[CH:14][CH:15]=2)[CH2:22][CH2:21][CH2:20]1)([OH:25])=[O:24]
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(C(=O)O)CCC4)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(C(=O)O)CCC4)cc3)cc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 31.5 %

Procedure:
To a mixture of 1-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]cyclobutane carboxylic acid (120 mg, 0.30 mmol) in acetonitrile (3 mL) and tert-butanol (3 mL) was added 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (550 mg, 6.00 mmol) and sodium phosphate monobasic (800 mg, 6.00 mmol) in water (3 mL) dropwise via additional funnel. The ice water bath was removed, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give a residue, which was purified by prep-HPLC (Column: Boston Symmetrix ODS-H 150*30 mm*5 μm Mobile phase: from 39% MeCN in water (0.1% TFA) to 39% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min;) to give the title compound (35 mg, 27% yield) as a white solid. MS (ES+) 392.0 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.03 (s, 1H), 7.99 (s, 1H), 7.58 (s, 1H), 7.44-7.38 (m, 4 H), 2.90-2.84 (m, 2 H), 2.62-2.54 (m, 2 H), 2.11-1.97 (m, 1 H), 1.95-1.91 (m, 1 H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.BrC[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)=O>>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[C:6]3=[C:5]([OH:11])[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]3[O:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COc1cc(O)cc(OC)c1
Product: Oc1ccc(-c2coc3cc(O)cc(O)c23)cc1
Yield: 38 %

Procedure:
This compound was prepared using Method B from 3,5-dimethoxyphenol and 2-bromo-1-(4-methoxyphenyl)ethanone: Yield 38% following procedures B.2, B.3 and B.5; m.p. 220° C. (dec.); IR 3460, 3373, 2914, 1635, 1518, 1229, 1133, 1055 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.75 (s, 1H), 9.36 (s, 1H), 9.33 (s, 1H), 7.62 (s, 1H), 7.46 (d, J=8.5 Hz, 2H), 6.75 (d, J=8.5 Hz, 2H), 6.37 (d, J=1.7 Hz, 1H), 6.21 (d, J=1.6 Hz, 1H); 13C-NMR (126 MHz, δ ppm, CD3OD) 160.2, 157.7, 157.5, 153.6, 139.7, 131.4, 125.4, 124.1, 115.9, 109.6, 99.0, 90.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:21][C:18]2[CH:19]=[CH:20][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: CC(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (12 g, 50.7 mmol) was added to a solution of 4-isopropylphenol (8.3 g, 60.8 mmol), and K2CO3 (14.0 g, 101 mmol) in DMF (70 mL). The mixture was heated at 80° C. for 16 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by silica gel chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title compound (13.5 g, 92%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)=[O:6])[CH:2]=[CH2:3].[CH3:39][I:40]>CC(C)=O>[I-:40].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][CH2:33][N+:34]1[CH:38]=[CH:37][N:36]([CH3:39])[CH:35]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCCn3ccnc3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCC[n+]3ccn(C)c3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Reaction time: 8 h

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{3-(imidazol-1-yl)propyl}pyrrolidin-4yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (4.00 g) in acetone (20 ml) was added methyl iodide (4.57 ml) at room temperature and the solution was allowed to stand overnight. The solvent was evaporated to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{3-(3-methyl-1-imidazolio) propyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (5.01 g) as a yellow solid. This compound was immediately used as the starting compound for the next step.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([C:14]1[CH:22]=[CH:21][C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=1)[CH3:13].[Br:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH:34]=[O:35])[CH:25]=1.[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH:34]([C:19]2[S:18][C:17]3[CH:21]=[CH:22][C:14]([CH2:12][CH3:13])=[CH:15][C:16]=3[CH:20]=2)[OH:35])[CH:25]=1
Reactant: O=Cc1cc(Br)c2ccccc2c1
Reactant: CCc1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc2sc(C(O)c3cc(Br)c4ccccc4c3)cc2c1
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 1.44 ml, 2.30 mmol) was added dropwise to a solution of 5-ethylbenzo[b]thiophene (373 mg, 2.30 mmol) in THF (15 ml) at −78° C., and the reaction solution was stirred at the same temperature for 5 minutes. To this mixture, a solution of 4-bromonaphthalene-2-carbaldehyde (515 mg, 2.19 mmol) in THF (5 ml) was added dropwise at −78° C., and the resulting mixture was stirred at the same temperature for two hours and at −20° C. for 30 minutes, and then a saturated ammonium chloride aqueous solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:9)] to obtain the title compound (780 mg, 90%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@@H:23]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]3[OH:25])[N:21]=[CH:22][C:15]=12.C(=O)(O)[O-].[K+].O>CN(C)C=O.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]3[N:20]([C@@H:23]4[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]4[OH:25])[N:21]=[CH:22][C:15]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@H]1O[C@@H](n2ncc3c(S)ncnc32)[C@H](O)[C@@H]1O
Reactant: ClCCCCCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](n2ncc3c(SCCCCCc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Yield: 9.2 %

Procedure:
Crude 5-phenylpentyl chloride (1.3 g) was added to a stirred solution of 4-mercapto-1-β-D-ribofuranosylpyrazolo [3,4-d]pyrimidine (2.0 g) and potassium bicarbonate (0.7 g) in N,N-dimethylformamide. The reaction mixture was heated on a steam bath for 25 hours. An additional 0.7 g of potassium bicarbonate was added and after heating for 1 hour more, the mixture was poured into water. The cooled aqueous mixture was extracted with chloroform. The chloroform soluble material was chromatographed on a silica gel column. The fractions containing the compound were combined and evaporated. Trituration with ether gave 0.4 g of crude product. This was dissolved in ethyl acetate and washed with water. The dried ethyl acetate solution was evaporated and purified by reversed phase chromatography in methanol water (80:20 vol/vol) to give 0.28 g of product m.p. 72°-75° C. (indefinite).
Reaction SMILES: C([NH:4][C@:5]1([C:41](=[O:47])NC(C)(C)C)[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][N:7]([CH2:22][CH:23]2[CH2:32][C:31]3[C:26](=[CH:27][C:28]([Cl:33])=[CH:29][CH:30]=3)[CH2:25][N:24]2C(OC(C)(C)C)=O)[CH2:6]1)(=O)C.[ClH:48].[OH2:49]>>[ClH:33].[ClH:48].[ClH:33].[NH2:4][C@:5]1([C:41]([OH:49])=[O:47])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:22][CH:23]2[CH2:32][C:31]3[C:26](=[CH:27][C:28]([Cl:33])=[CH:29][CH:30]=3)[CH2:25][NH:24]2)[CH2:6]1
Reactant: O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(CC2Cc3ccc(Cl)cc3CN2C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Product: N[C@@]1(C(=O)O)CN(CC2Cc3ccc(Cl)cc3CN2)C[C@@H]1CCCB(O)O
Temperature: 25 °C

Procedure:
In an Ace pressure tube, a solution of tert-butyl 3-({(3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidin-1-yl}methyl)-7-chloro-3,4-dihydroisoquinoline-2(1 H)-carboxylate (280 mg, 0.415 mmol) was treated with concentrated HCl (8 mL) and stirred at room temperature. After 10 min the tube was sealed, and the mixture was heated to ˜118° C. for 16 h. After cooling to room temperature, the solution was carefully diluted with water (20 mL) and washed with methylene chloride (2×15 mL). The aqueous phase was concentrated under reduced pressure, and the resulting residue purified by reverse phase HPLC. Product fractions (mixture of diastereomers) were pooled and concentrated. The residue was reconstituted in 1 M HCl and re-concentrated. The resulting residue was diluted with deionized water and lyophilized to give (3R,4S)-3-amino-1-[(7-chloro-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl]-4-[3-(dihydroxyboryl)propyl]-pyrrolidine-3-carboxylic acid trihydrochloride (mixture of 2 diastereomers, each a racamate) (102 mg, 49%) as a faint yellow amorphous solid. 1H NMR (0.1M DCl in D2O, 400 MHz) δ 7.23 (m, 1 H), 7.15 (m, 2 H), 4.37 (s, 2 H), 4.00 (m, 3 H), 3.84 (m, 2 H), 3.69 (m, 1 H), 3.43 (m, 1 H), 3.22 (m, 1 H), 2.98 (m, 1 H), 2.68 (m, 1 H), 1.60 (m, 1 H), 1.25 (m, 3 H), 0.64 (m, 2 H). ESI+ MS found for C18H27BClN3O4 m/z 378.1 (M−18+H), 360.1 (M−36+H); ESI− MS m/z 376.2 (M−18−H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[C:7]2[O:13][CH:14]=[CH:15][C:6]=2[C:5]=1[O:16][CH3:17])=[O:3].[C:18]1([CH2:24][CH2:25][CH2:26]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:2]([C:4]1[C:9]([O:10][CH2:26][CH2:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([O:11][CH3:12])[C:7]2[O:13][CH:14]=[CH:15][C:6]=2[C:5]=1[O:16][CH3:17])(=[O:3])[CH3:1]
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Reactant: BrCCCc1ccccc1
Product: COc1c(C(C)=O)c(OCCCc2ccccc2)c(OC)c2occc12
Yield: 85.8 %

Procedure:
Khellinone (59 mg, 0.25 mmol) and 3-(phenyl)propylbromide (46 μL, 0.30 mmol) were treated as described under General Procedure A to afford the title compound (76 mg, 85%) as a colourless solid: 1H NMR (300 MHz, CDCl3): δ 2.03 (m, 2H), 2.53 (s, 3H), 2.76 (t, J=7.8 Hz, 2H), 3.97 (s, 3H), 4.03 (s, 3H), 4.08 (t, J=6.3 Hz, 2H), 6.86 (d, J=2.4 Hz, 1H), 7.14-7.30 (m, 5H), 7.56 (d, J=2.4 Hz, 1H). MS (ES+) m/z 355.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: OCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OCCCCO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (5.00 g, 33.3 mmol) in DMF (30 mL) were added 4-bromo-butan-1-ol (6.11 g, 39.9 mmol) and Cs2CO3 (16.2 g, 50.0 mmol). The reaction mixture was stirred at room temperature for 48 hours, then water (100 mL) was added, and the products were extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Solvent was removed and the crude product was purified by the Simpliflash system, using 40% ethyl acetate in hexane as eluent, to give 4-(4-hydroxybutoxy)-3,5-dimethyl benzaldehyde as a colorless liquid. Yield: 0.66 g (7%).
Reaction SMILES: [OH-].[K+].CS(C)=O.[CH:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[CH:9][CH:8]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>O>[N:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:11]1[CH:12]=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: ClCc1ccccn1
Reactant: c1ccc(Nc2ccccn2)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CN(c2ccccn2)c2ccccn2)nc1
Reaction time: 0.75 h
Yield: 55.7 %

Procedure:
To a flask were added 5.2 g pulverized potassium hydroxide and 35 ml dimethylsulfoxide. After adding 3.4 g 2,2′-dipyridylamine, the mixture was stirred under nitrogen for 45 minutes, when 3.3 g 2-(chloromethyl)pyridine hydrochloride was added. After stirring for 1 hour, 100 ml of water was added and the product was extracted with 60 ml of 50% ethyl acetate, 50% hexane. The organic layer was washed with 30 ml water and the solvent was removed. The residue was added to 5 ml hot ethanol, and 20 ml of water was added. After cooling to 5 C, the solid was filtered and washed with water. The product was dissolved in 20 ml hot ethanol and treated with 150 mg activated carbon. After hot filtration through celite, 40 ml of water were added and the mixture was cooled to 5 C. The product was filtered, washed with 20 ml 20% ethanol in water, and dried resulting in 2.9 g of an off-white solid.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:29][CH:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:28])=[CH:5][N:6]=3)=[C:16]([C:17]([F:19])([F:20])[F:18])[O:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 80 %

Procedure:
As described for example 137, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) was converted, using 4-aminotetrahydropyran instead of methylamine (2 M in THF), to the title compound (94 mg, 80%) which was obtained as a white solid. MS: m/e=466.0 [M+H]+.