Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C[O-].[Na+].[CH3:5][C@@H:6]([CH2:9][CH3:10])[CH2:7]Br.[C:11]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH3:5][C@@H:6]([CH2:9][CH3:10])[CH2:7][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CC[C@H](C)CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C[C@@H](C)CC)C(=O)OCC

Procedure:
Sodium (57.5 g, 2.5 mols) was added to ethanol (1 l) to prepare sodium methoxide, followed by adding (S)-2-methylbutyl bromide (317 g, 2.1 mols) and diethyl malonate 400 g, 2.5 mols), refluxing the mixture for 5 hours and distilling off ethanol to obtain oily diethyl (S)-2-methylbutylmalonate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10](O)=[O:11].N#N.B.C1COCC1.C1COCC1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11]
Reactant: O=C(O)CCc1ccccc1Br
Agent: B
Agent: N#N
Solvent: C1CCOC1
Product: OCCCc1ccccc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
3-(2-Bromophenyl)propionic acid (1.15 g, 5.0 mmol) was placed in a 100 mL three-necked flask with magnetic stirrer. The atmosphere was exchanged with N2 (3 times). With ice cooling, a solution of BH3.THF in THF (1.0M, 7.0 mL, 1.4 equiv.) was added dropwise via syringe with stirring over a 15 min period (H2 evolution). The resulting mixture was stirred in the ice bath for 1 h, and residual borane was quenched by cautious addition of water. The solvents were evaporated, and the residue was partitioned between ether (20 mL) and water (20 mL). The aqueous phase was extracted with ether (20 mL). The combined ether layers were washed with brine, dried over Na2SO4, and concentrated to give the alcohol as a clear oil (1.05 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 7.53 (d, 1H, J=7.8 Hz), 7.26-7.22 (m, 2H), 7.09-7.03 (m, 1H), 3.71 (t, 2H, J=6.4 Hz), 2.87-2.82 (m, 2H), 1.94-1.86 (m, 2H), 1.36 (br s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:15])([CH3:14])[O:12][B:11]([OH:16])[C:10]=2[CH:17]=1)=[O:4].[NH:30]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:31]([C:44](O)=[O:45])[CH2:32][CH2:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=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>C(Cl)Cl>[C:50]([O:49][C:47]([NH:30][C@H:31]([C:44]([NH:1][C@H:2]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:15])([CH3:14])[O:12][B:11]([OH:16])[C:10]=2[CH:17]=1)=[O:4])=[O:45])[CH2:32][CH2:33][C:34]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:43])=[O:48])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC1(C)OB(O)c2cc(NC(=O)[C@H](N)CCc3ccc(C(F)(F)F)cc3)ccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a suspension of (R)-2-amino-N-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(4-(trifluoromethyl)phenyl)butanamide (CLXIX) (1.2 g, 2.71 mmol) and Boc-Glu(OBzl)-OH (CLXX) (0.915 g, 2.71 mmol) in DCM (10 mL) was added DIPEA (1.39 mL, 8.13 mmol). To this solution was added HATU (1.03 g, 2.71 mmol) and the mixture was stirred at room temperature overnight. The mixture was washed with 2 N aqueous HCl, 1 M aqueous K2CO3, brine and dried over MgSO4. The solution was evaporated to dryness under vacuum to give (S)-benzyl 4-(tert-butoxycarbonylamino)-5-((R)-1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-4-(4-(trifluoromethyl)phenyl)butan-2-ylamino)-5-oxopentanoate as an orange foam (1.83 g, 2.52 mmol, 93% yield). 1H NMR (DMSO-d6) δ ppm 1.33 (s, 9H), 1.4 (s, 6H), 1.8-1.88 (m, 1H), 1.9-1.96 (m, 2H), 2.08 (brs, 1H), 2.42 (brs, 2H), 2.6-2.66 (m, 1H), 2.7-2.76 (m, 1H), 3.98-4.05 (m, 1H), 4.4 (brs, 1H), 5.07 (s, 2H), 7.1 (brs, 1H), 7.28-7.34 (m, 6H), 7.37-7.44 (m, 2H), 7.55-7.63 (m, 3H), 7.89 (s, 1H), 8.34 (brs, 1H), 9.0 (s, 1H), 9.86 (s, 1H); 19F NMR (DMSO-d6) δ ppm −60.11 (s, 3F); ESIMS found for C37H43BF3N3O8 m/z 726.7 (M+H).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1C1N=NNC=1)(=O)C.N.OO.[C@@H]1([N:36]2[N:40]=[C:39]([C:41]([NH2:43])=[O:42])[CH:38]=[N:37]2)O[C@H](CO)[C@@H](O)[C@H]1O>CC(O)C>[C@@H:6]1([N:37]2[CH:38]=[C:39]([C:41]([NH2:43])=[O:42])[N:40]=[N:36]2)[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: NC(=O)c1cnn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2c[nH]nn2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Agent: OO
Solvent: CC(C)O
Product: NC(=O)c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)nn1

Procedure:
4-Cyano-1-(2,3,5-tri-O-acetyl-β -D-ribofuranosyl-1,2,3-triazole (8). (0.35 g, 0.001 mol) was added to 15% aqueous ammonia (30 ml) and 30% hydrogen peroxide (3 ml). The solution was stirred 4 hr before additional hydrogen peroxide was added. The procedure and product isolation was identical to that used in method 2 for compound 4. The compound was dissolved in hot 2-propanol; cooling of the solution and filtering provided 30 mg of crystalline 5 which was identical to an authentic sample prepared by the procedure of Alonso, et al. J. Heterocyclic Chem. 7, 1269 (1970).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([NH:55][CH:56]=[O:57])[CH:49]=1)[CH2:10][N:11]=[CH:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:27][CH2:26]2)=[O:22])=[C:15]([CH3:47])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CC1CCCO1>[Si:1]([O:8][C@H:9]([C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([NH:55][CH:56]=[O:57])[CH:49]=1)[CH2:10][NH:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:29][CH2:30]2)=[O:22])=[C:15]([CH3:47])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Solvent: CC1CCCO1
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Reaction time: 6 h

Procedure:
To a hydrogenation flask was added biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylimino]methyl}-2,5-dimethyl-phenylcarbamoyl)ethyl]piperidin-4-yl ester (4.6 g) and 2-methyltetrahydrofuran (50 mL). The resulting mixture was stirred until the solid dissolved (about 5 min.) and then the mixture was purged with nitrogen. Platinum on carbon (920 mg, 5 wt. %, support activated carbon) was added and the mixture was hydrogenated at 50 psi (Parr shaker) for 6 hours. The mixture was then filtered through Celite and the Celite was washed with 2-methyltetrahyrofuran (10 mL). To the filtrate was added a thiopropyl-modified silica gel (20% of weight of solution, Silicycle) and this mixture was stirred at 25° C. to 30° C. for 3 hours. The mixture was then filtered through Celite and concentrated to remove the solvent. The residue was dissolved in methanol (5 mL per gram of residue) and then the resulting solution was added slowly to a vigorously stirred 1:1 mixture of saturated aqueous sodium bicarbonate and water (40 mL per gram of residue). The resulting off-white slurry was stirred for 20 minutes and then filtered. The filter cake was washed with water (20 volumes), air dried for 3 hours and then dried in vacuum at room temperature overnight to provide biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylamino]methyl}-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (80% recovery, about 96% purity).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C@@H:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:27](=O)[CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:26][O:25][C:19]1[CH:18]=[C:17]2[C:22]([CH2:23][CH2:24][C@@H:15]([N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:27][CH2:28][CH3:29])[CH2:16]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)C[C@H](NC1CCN(C(=O)OC(C)(C)C)CC1)CC2
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(C1CCNCC1)[C@@H]1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 141.3 %

Procedure:
To a solution of 4-((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (9.7 g, 23.4 mmol) and propionaldehyde (2.0 mL, 28.1 mmol) in dichloroethane (150 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (10.9 mg, 51.5 mmol) in a single portion. The reaction was stirred at room temperature for 24 h then concentrated in-vacuo. The residue was partitioned between EtOAc (175 mL) and 5% aq. KOH (150 mL). The aqueous phase was extracted twice more with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford 10.0 g of the protected amine, which was treated with trifluoroacetic acid as described herein to afford ((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4yl-propyl-amine (7.0 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(COC)OC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:26](=[O:27])[NH:25][C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=1)[C:9]#[N:10]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: N#CCC(=O)c1ccc[nH]1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: N#CC(C(=O)Nc1ccc(Cl)cc1)C(=O)c1ccc[nH]1
Reaction time: 8 h

Procedure:
To the solution of 6.7 g of 2-pyrroloylacetonitrile in 25 ml of glyme and 5.5 g of Et3N is added a solution of 8.6 g of 4-chlorophenyl isocyanate in 25 ml of glyme. After the exothermic reaction, the mixture is let stand overnight. Part of the solvent is evaporated and the cooled residue is poured into a solution of 10 ml of 6N HCl in 250 ml of water. After the addition of some methanol, the crude material is collected. It is dissolved in dilute NaOH solution, the solution is treated with charcoal, filtered, and acidified with 6N HCl. The reprecipitated product is collected, washed with water, and triturated with methanol to give solid, m.p. 219°-221°. Recrystallization from methanol gives β-oxo-α-(4-chlorophenyl carbamoyl)-β-(2-pyrrolyl)propionitrile, m.p. 223°-5°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.Cl.[F:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1>>[F:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:11]1
Reactant: FC1CCNC1
Reactant: O=Cc1ncc[nH]1
Agent: Cl
Product: FC1CCN(Cc2ncc[nH]2)C1

Procedure:
The title compound was prepared from 2-imidazolecarboxaldehyde and 3-fluoropyrrolidine hydrochloride using the synthetic procedure described for Intermediate 5.
Reaction SMILES: [NH2:1][C@H:2]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][C:14]3=[CH:16][N:17]=[C:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[N:13]3[C:12]2=[O:28])[CH2:7][CH2:6]1)=[O:4].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>C(#N)C>[Si:21]([O:20][CH2:19][C:18]1[N:13]2[C:12](=[O:28])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3]([C@H:2]([NH:1][C:41]([NH:40][C:37]4[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=4)=[O:42])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:4])[CH2:6][CH2:7]3)[CH2:15][C:14]2=[CH:16][N:17]=1)([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23]
Reactant: CC(C)(C)[C@@H](N)C(=O)N1CCC(N2Cc3cnc(CO[Si](C)(C)C(C)(C)C)n3C2=O)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CC#N
Product: CC(C)(C)[C@@H](NC(=O)Nc1ccc(Cl)cc1)C(=O)N1CCC(N2Cc3cnc(CO[Si](C)(C)C(C)(C)C)n3C2=O)CC1
Yield: 86.5 %

Procedure:
To a solution of 2-(1-((2R)-2-amino-3,3-dimethylbutanoyl)-4-piperidinyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one (0.33 g) obtained in Example 83k) in acetonitrile was added 4-chlorophenyl isocyanate (0.11 g), and then mixed at room temperature for 1 hour. Acetonitrile was distilled off under reduced pressure, and then the residue was purified with silica gel column (ethyl acetate) to obtain the title compound as a colorless solid (0.38 g, 85%).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][NH:9][CH2:10][C:11]1([N:17]([CH3:19])[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)=O>[CH:5]([N:9]([CH3:8])[CH2:10][C:11]1([N:17]([CH3:19])[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7]
Reactant: CNCC1(N(C)C)CCCCC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CN(C=O)CC1(N(C)C)CCCCC1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
Formic acid (6.9 g. 0.15 mole) and acetic anhydride (15.3 g, 0.15 mole) were mixed without cooling and kept at room temperature for 1 hr. 1-methylaminomethylcyclohexyldimethylamine (5.9 g, 0.034 mole) was dissolved in formic acid (12 ml) and the formylating mixture (16 ml) added slowly. This produced vigorous effervesence and a temperature rise to 75°. The mixture was then left at room temperature for 2 hr. and then heated on a water bath at 55° for 0.75 hr. The solvents were removed under reduced pressure to give an amber oil (5.32 g, 77.7%) which crystallised as colourless prisms of 1-(N-formyl-1-methylaminomethyl) cyclohexyldimethylamine from light petroleum (b.p. 60°-80° ), m.p. 59°-60°.
Reaction SMILES: COC1C=CC([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=CC=1.C(Br)C>CC(C)=O>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][NH2:9]
Reactant: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Solvent: CCBr
Solvent: CC(C)=O
Product: NCCCOc1ccc2ccccc2c1

Procedure:
A mixture of N-(4-methoxyphenyl)-[3-(naphthalen-2-yloxy)propyl]amine (0.5 gm, 0.002 mole) and ethyl bromide(0.52 ml, 0.003 mole) was taken in dry acetone (40 ml). It was refluxed for 12 hrs and the progress of reaction checked by TLC. Reaction mixture was filtered and the filtrate was concentrated to get oily compound which was further crystallized by benzene hexane mixture to get N-(4 methoxyphenyl)-N-ethyl [3-(naphthalen-2-yloxy)propylamine, crystallized as yellow oil, (yield 0.64 gm, 94.6%).
Reaction SMILES: [F:1][C:2]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:3]=1[O:4][C:5]1[C:19]([C:20]2[C:21]3[CH:30]=[CH:29][N:28]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:22]=3[C:23](=[O:27])[N:24]([CH3:26])[CH:25]=2)=[CH:18][C:8]2[N:9](C3CCCCO3)[N:10]=[N:11][C:7]=2[CH:6]=1.Cl.O>CO>[F:1][C:2]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:3]=1[O:4][C:5]1[C:19]([C:20]2[C:21]3[CH:30]=[CH:29][N:28]([S:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)(=[O:33])=[O:32])[C:22]=3[C:23](=[O:27])[N:24]([CH3:26])[CH:25]=2)=[CH:18][C:8]2[NH:9][N:10]=[N:11][C:7]=2[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc5c(cc4Oc4ccc(F)cc4F)nnn5C4CCCCO4)cn(C)c(=O)c32)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc5[nH]nnc5cc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Temperature: 20 °C
Reaction time: 22 h

Procedure:
A solution of 4-[5-(2,4-difluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-benzotriazol-6-yl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.077 g, 0.12 mmol) in methanol (0.34 mL) was treated with 6.0 M hydrogen chloride in water (0.102 mL, 0.610 mmol) and stirred at 20° C. for 22 h. The reaction mixture was concentrated to give a crude residue that was used immediately without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:17]1[CH2:22][CH2:21]O[CH2:19][CH2:18]1>[Pd]>[O:17]1[CH:22]=[CH:21][C:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:18]1
Reactant: C1COCCO1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=[N+]([O-])c1ccc(-c2ccoc2)cc1
Reaction time: 1.67 h

Procedure:
200 mg 4-bromonitrobenzene, 110.8 mg furan-3-boric acid and 162 mg palladium/C are dissolved in 3 mL 1,4-dioxane. Then 965.3 mg caesium carbonate (dissolved in 586 μL water) are added. The reaction is completed in the microwave (110° C.) after 100 min. After aqueous working up the mixture is extracted with ethyl acetate and died on magnesium sulphate. The solvent is eliminated in vacuo. This crude product is used in the following reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:20](Br)[CH3:21]>CN(C)C=O>[O:12]1[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[NH:1][CH2:21][CH2:20]1
Reactant: CC(Br)Br
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)NCCO2
Temperature: 110 °C
Reaction time: 5 h

Procedure:
5.16 g of methyl 3-amino-4-hydroxybenzoate are dissolved in 100 ml of dimethylformamide in a 500 ml round-bottomed flask. 17.06 g of potassium carbonate and then 7.98 ml of dibromoethane are subsequently added. The reaction medium is heated at 110° C. with stirring for five hours. After evaporating the solvent, water and ethyl acetate are added. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined and then dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a heptane/ethyl acetate 6/4 mixture. 3.61 g of methyl 3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:18])[C:16]=1[OH:17])[CH2:13][CH:12]1[CH2:19][CH2:20][C:9]2([O:21][CH2:22][CH2:23][OH:24])[CH2:10][CH2:11]1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:14]([C:15](=[O:18])[C:16]=1[O:17][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:13][CH:12]1[CH2:19][CH2:20][C:9]2([O:21][CH2:22][CH2:23][OH:24])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(OCCO)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(OCCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of 5-hydroxy-1-(2-hydroxyethoxy)-6-oxo-3,7-diazatricyclo[7.2.2.02,7]trideca-2,4-diene-4-carboxylic acid ethyl ester (203 mg, 0.600 mmol) in DMF (1 mL) was added K2CO3 (249 mg, 1.80 mmol) and (bromomethyl)benzene (103 mg, 0.600 mmol) and the mixture stirred at room temperature overnight under N2. Additional (bromomethyl)benzene (206 mg, 1.2 mmol, 2 eq.) and K2CO3 (166 mg, 1.2 mmol, 2 eq.) were added and the mixture stirred overnight. The mixture was concentrated in vacuo to remove most of DMF, and the residue was diluted with ethyl acetate (15 mL),washed with water followed by brine, then dried (Na2SO4) and concentrated to provide an amber oil which was purified by silica gel column chromatography (18 g SiO2, 45% ethyl acetate/CH2Cl2) to gave the title compound (141 mg, 0.329 mmol, 55% yield) as an amber oil; HPLC: retention time=2.18 min (area percent=92%); LCMS: m/z 429 (M+H); 1H NMR (500 MHz, CDCl3) δ ppm 1.28 (3H, t, J=7.2 Hz), 1.63 (2H, ddd, J=14.3, 7.5, 7.2 Hz), 1.83-1.94 (2H, m), 2.06 (4H, t, J=7.6 Hz), 2.42 (1H, brs), 3.59 (2H, t, J=4 Hz), 3.70 (2H, d, J=4 Hz), 4.05 (2H, d, J=4.0 Hz), 4.31 (2H, q, J=7.2 Hz), 5.22 (2H, s), 7.27 (1H, t, J=7.4 Hz), 7.32 (2H, t, J=7.2 Hz), 7.46 (2H, d, J=6.7 Hz); 13C NMR (126 MHz, CDCl3) δ ppm 14.1, 23.2, 27.6, 30.5, 53.6, 62.1, 62.2, 65.3, 74.5, 76.7, 128.3, 128.5, 128.6, 136.8, 140.0, 142.4, 159.2, 161.3, 163.9.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O:7][C:8]([C:10]1(Cl)[C:14](=[O:15])[CH:13]=[CH:12][S:11]1)=[O:9]>C(Cl)Cl>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:13][C:14]=1[OH:15])=[O:9]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2ccnc2)cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
Imidazole (710 mg, 10.4 mmol, 2 Eq.) and 2-Chloro-3-oxo-2,3-dihydrothiophene-2-carboxylic acid methyl ester (1.0 g, 5.19 mmol, 1.0 Eq.) were dissolved in anhydrous DCM (25 mL) and stirred at ambient temperature for 18 hours. The crude reaction mixture was partitioned between EtOAc (50 mL) and brine (50 mL), The aqueous phase was extracted with EtOAc (3×20 mL) and the combined organice extracts washed with brine (1×10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purifed by column chromatography (5% MeOH/DCM) and recrystalised from EtOAc/hexane to give the sub-title compound as a yellow powder (692 mg, 3.09 mmol 59%); 1H NMR (400 MHz, d-6 DMSO) δ 3.77 (3H, s), 7.02 (1H, s), 7.14 (1H, d), 7.74 (1H, d), 8.28 (1H, d), 10.82 (1H, br s).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]2[O:9][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[CH3:17].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>CN(C)C=O>[Si:25]([O:1][C:2]1[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]2[O:9][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[CH3:17])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(C)c2c(c(C)c1O)SC(c1ccccc1)O2
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(c1ccccc1)O2
Yield: 84 %

Procedure:
2.6 g of 5-hydroxy-4,6,7-trimethyl-2-phenyl-1,3-benzoxathiole, 1.3 g of imidazole and 2.9 g of t-butyldimethylsilyl chloride were dissolved in 20 ml of dimethylformamide, and the mixture was reacted for 24 hours at room temperature. At the end of this time, the reaction mixture was poured into water. The separated product was extracted with benzene, and the extract was washed with a 5% w/v aqueous solution of ammonia and then with water and dried over anhydrous sodium sulfate. The solvent was evaporated off and the product thus obtained was purified by silica gel column chromatography. From the fraction eluted with a 10:1 by volume mixture of cyclohexane and benzene were obtained 3.1 g of the title compound, melting at 95°-98° C.