Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26]Br>C(Cl)(Cl)(Cl)Cl>[Br:26][CH:17]([CH3:18])[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[O:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:8][C:9]=2[CH:15]=1)=[O:19]
Reactant: CCC(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)C(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
1-(2,2-Diphenyl-benzo(1,3)dioxol-5-yl)-propan-1-one (the compound of Preparation 42, 4.70 g, 14.23 mmol) was dissolved in carbon tetrachloride (60 mL) and bromine (0.74 mL, 14.36 mmol in 10 mL of carbon tetrachloride) was added dropwise. The reaction was stirred at ambient temperature 30 min and then it was extracted with saturated aqueous bicarbonate solution. The organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated to afford 5.58 g (96%) of 2-bromo-1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-propan-1-one as a dark orange oil which had: NMR δ7.68-7.37 (m, 12 H), 6.95 (d, J=8.3 Hz, 1 H), 5.21 (q, J=6.7 Hz, 1 H), 1.88 (d, J=6.6 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][CH2:13][CH2:12][CH2:11]2.[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24]O)=[CH:19][N:18]=1>>[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24][C:8]2[CH:9]=[C:10]3[C:15](=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[NH:14][CH2:13][CH2:12][CH2:11]3)=[CH:19][N:18]=1
Reactant: COCCOc1cccc2c1NCCC2
Reactant: Nc1ncc(CO)c(N)n1
Product: COCCOc1cc(Cc2cnc(N)nc2N)cc2c1NCCC2

Procedure:
The procedure of Example 1 was used to react 1,2,3,4-tetrahydro-8-methoxyethoxyquinoline (3.11 g) with 2,4-diamino-5-hydroxymethylpyrimidine, and 2,4-diamino-5-(1,2,3,4-tetrahydro-8-(2-methoxyethoxy)-6-quinolylmethyl)pyrimidine was isolated and purified as in this example. The free base was recrystallized from absolute ethanol; m.p. 149°-151° C. NMR (Me2SO-d6) δ 1.76 (m, 2, CH2), 2.61 (tr, 2, CH2), 3.22 (m, 2, CH2), 3.31 (s, 3, OMe), 3.39 (s, 2, bridge CH2), 3.65 (m, 2, CH2CH2O), 3.97 (m, 2, OCH2CH2), 4.60 (br. s., 1, NH), 5.60 and 5.90 (2 br s, 4, (NH2)2), 6.36 (d, 1, J=1-2, Ar), 6.53 (d, 1, J=1- 2, Ar), 7.45 (s, 1, pyrimidine-6-H). Anal. Calcd. for C17H23N5O2 : C, 61.99; H, 7.04; N, 21.26. Found: C, 61.82; H, 7.06; N, 21.25.
Reaction SMILES: C1CO[C:3]([C@@H:5]2[C@:22]3([CH3:23])[C@H:8]([C@H:9]4[C@H:19]([C:20](=[N:24]O)[CH2:21]3)[C@:17]3([CH3:18])[C@H:12]([CH2:13][CH:14]=[CH:15][CH2:16]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6]2)([CH3:4])[O:2]1.[Na]>C(O)CC>[NH2:24][C@@H:20]1[CH2:21][C@@:22]2([CH3:23])[C@@H:8]([CH2:7][CH2:6][C@@H:5]2[C:3](=[O:2])[CH3:4])[C@H:9]2[C@H:19]1[C@:17]1([CH3:18])[C@@H:12]([CH2:11][CH2:10]2)[CH2:13][CH:14]=[CH:15][CH2:16]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5CC=CC[C@]5(C)[C@H]4C(=NO)C[C@]23C)OCCO1
Agent: [Na]
Solvent: CCCO
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3[C@H](N)C[C@]12C
Yield: 110.9 %

Procedure:
A solution of 20,20-ethylenedioxy-5α-pregn-2-en-11-one 11-oxime (9.36 g) in propan-1-ol (215 ml) was heated at reflux and sodium (8 g) was added over 2 hours. When all the sodium was consumed the propan-1-ol was removed by distillation. The residue was extracted with ether (x 3) and these extracts were extracted with 2 M-HCl solution (x 3). The extracts were washed with ether and brought to pH 9 with 0.88 NH3 solution. The mixture was extracted with ether (x 2) and the extracts were washed with water, dried and evaporated to leave a solid (8.77 g) which was crystallised from ethyl acetate/petrol to give the title compound (6.15 g) in two crops. A portion was recrystallised from ethyl acetate/petrol, m.p. 127°-129° C., [α]D +121°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)cc(CCCBr)c1
Reaction time: 3 h
Yield: 86.4 %

Procedure:
Compound 36-2 (2.36 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (4.19 g) and N-bromosuccinimide (2.81 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.82 g) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N:48]3[C:52]([CH3:53])=[N:51][N:50]=[N:49]3)[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:45])=[O:46])=[C:40]([N:48]3[C:52]([CH3:53])=[N:51][N:50]=[N:49]3)[CH:39]=2)[C:35]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1nnnn1-c1cc(C(CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1cc(C(CC2CCCC2)C(=O)Nc2nccs2)ccc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A solution of triphenylphosphine (100 mg, 0.38 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (68 mg, 0.38 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (85 mg, 0.22 mmol) in methylene chloride (3 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (55 mg, 0.55 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and a 1N aqueous hydrochloric acid solution (25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 to 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide (42 mg, 41%) as a white solid: mp 148-154° C.; EI-HRMS m/e calcd for C20H24N6O3S2 (M+) 460.1351, found 460.1356.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:9]([CH3:15])=[N:10][CH:11]=[CH:12][C:13]=1[Br:14])C(=O)C)(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO>[Br:14][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:15])[C:8]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1c(Br)ccnc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1c(Br)ccnc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of N-acetyl-N-(4-bromo-2-methylpyridin-3-yl)acetamide (0.95 g, 3.50 mmol) in methanol (14.02 mL) was added 1M NaOH (0.876 ml, 0.876 mmol) and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with 1N HCl (400 uL) and then concentrated under vacuum to give a residue that was purified on silica column chromatography eluting with (chloroform:methanol, 97:3) Concentration of the product fractions gave N-(4-bromo-2-methylpyridin-3-yl)acetamide (0.7 g, 3.06 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.04-2.10 (m, 3H) 2.39 (s, 3H) 7.49-7.60 (m, 1H) 8.12-8.26 (m, 1H) 9.65-9.83 (m, 1H). MS [M+H] found 229.1.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[O:2].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>CN(C)C1C=CN=CC=1.C(#N)C.CCOC(C)=O>[C:12]([O:16][C:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
5-Formylindole (1.45 g, 10.0 mmol) and 4-dimethylaminopyridine (1.47 g, 12.0 mmol) were dissolved in acetonitrile (20 mL) with stirring at ambient temperature. Once dissolution was complete, the reaction mixture was cooled to −10° C. with stirring. Di-t-butylcarbonate (2.18 g, 10.0 mmol) was added in one portion. Stirring was continued for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and the organic solution was washed successively with water (20 mL), a 1N HCl solution (10 mL), a saturated NaHCO3 solution (20 mL) and brine (20 mL). The organic solution was dried over MgSO4 and filtered. Solvent was removed in vacuo from the filtrate to provide a pale yellow oil (2.45 g, 100% yield): 1H NMR (CDCl3, 300 MHz): 10.1 (s, 1H), 8.31 (d, 1H, J=8), 8.12 (s, 1H), 7.87 (dd, 1H, J=8, 1), 7.70 (d, 1H, J=4), 6.71 (d, 1H, J=4), 1.71 (s, 9H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:17])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]=[C:6]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1>CO.[Pd]>[ClH:1].[CH3:2][N:3]([CH3:17])[CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)CC1CCCC=C1c1cccnc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C[C@@H]1CCCC[C@@H]1c1cccnc1
Reaction time: 8 h
Yield: 34.8 %

Procedure:
6.90 g dimethyl-(2-pyridin-3-yl-cyclohex-2-enylmethyl)amine hydrochloride were dissolved in 70 ml methanol and hydrogenated in the presence of 1.04 g palladium-on-active charcoal (10 percent by weight) for five hours under a hydrogen pressure of 2 bar. The mixture was then filtered, the filtrate was concentrated in vacuo, the residue was converted into the base with two molar sodium hydroxide solution and a mixture of equal volumes of ethyl acetate and tetrahydrofuran and the base was extracted with ethyl acetate. After drying and concentration, the residue (4.47 g) was chromatographed on silica gel with a mixture of equal volumes of methanol, ethyl acetate and n-hexane. The main fraction (3.72 g) was dissolved in approx. 40 ml acetone/ethanol (V/V=9:1), and half a molar equivalent of water and one molar equivalent of chlorotrimethylsilane were added. After the mixture had been stirred overnight, it was concentrated to dryness, the residue was treated in an ultrasonic bath with 72 ml THF and 18 ml ethanol for 30 minutes, the suspension was stirred overnight and filtered with suction and the residue was dried. 2.42 g cis-dimethyl-(2-pyridin-3-yl-cyclohexylmethyl)amine hydrochloride with a melting point of 219-222° C. were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]3[CH2:30][CH2:31][C:32](=[O:33])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[NH:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1>CN(C)C=O>[O:19]=[C:13]1[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=2)[C:11]2[CH2:30][CH2:31][C:32](=[O:33])[C:10]=2[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:14]1[CH2:15][C:16](=[O:18])[N:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Reactant: C1CSCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)N2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetic acid (example 4, 30 mg, 66 μmol) and triethylamine (30 μL, 0.22 mmol) in N,N-dimethylformamide (1.25 mL) is treated with N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (21 mg, 66 μmol) and stirred at room temperature for 15 min. This mixture is then added to a solution of thiomorpholine (13 mg, 0.13 mmol) in N,N-dimethylformamide (0.25 mL) and stirred for 72 h. The mixture is filtered and the filtrate is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of methanol in water, 0.1% NH3). Yield: 20 mg; ESI mass spectrum [M+H]+=541; Retention time HPLC: 1.17 min (001_CA03).
Reaction SMILES: [Cl:1][C:2]1[C:7](OC2C=CC=CC=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>O1CCOCC1>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=1[NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)c(Cl)c1Oc1ccccc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(Cl)c1NCc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 5 gm of 2-chloro-4-nitro-1,3-diphenoxy-benzene, 10 ml of dioxane and 6 gm of 4-chlorobenzylamine was stirred for 12 hours at 80° C. Thereafter, the reaction mixture was evaporated, the residue was taken up in chloroform, the resulting solution was extracted with 1 N sodium hydroxide, and the organic phase was dried with sodium sulfate. The chloroform was distilled off, and the residue was recrystallized from ethanol, yielding 4.7 gm (82.7% of theory) of the title compound, m.p. 95°-96° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.N[CH2:31]C1C=CC(C(OC)=O)=CC=1C>>[F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][C:29]=2[CH3:31])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Reactant: COC(=O)c1ccc(CN)c(C)c1
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)c(C)c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 3 of Example 1) and methyl 4-(aminomethyl)-3-methylbenzoate: 1H-NMR (CDCl3) δ 8.36 (1H, dd, J=8.2, 3.1 Hz), 8.25–8.18 (1H, m), 8.04 (1H, d, J=3.1 Hz), 7.85–7.81 (2H, m), 7.37 (1H, d, J=7.7 Hz), 7.15–7.07 (4H, m), 4.73 (2H, d, J=5.8 Hz), 3.89 (3H, s), 2.40 (3H, s); MS (ESI) m/z 413 (M+H)+, 411 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:14][OH:15])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(C(=O)C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=NO)C(C)C)cc1
Reaction time: 4 h

Procedure:
3.2 g of 5A, 7.4 g of hydroxylamine hydrochloride, 40 ml of ethanol and 80 ml of water were mixed. 4.4 g of sodium hydroxide was added to the stirred mixture at room temperature. The mixture was stirred for 4 hours at reflux temperature, cooled, poured into cold dilute hydrochloric acid and extracted with methylene chloride. The extract was dried (MgSO4) and stripped of solvent and the product was chromatographed (silica gel, methylene chloride/ether) to give 1-(4-methylphenyl)-2-methyl-1-propanone oxime (5B), as a liquid, boiling point not determined.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[NH:11][C:10]=2[CH3:19])=[CH:5][CH:4]=1.[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:19])=[C:9]2[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccc(-c2c(C)[nH]c3ccc(O)cc23)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(-c3ccc(OC)cc3)c2c1

Procedure:
This compound was prepared from 3-(4-methoxyphenyl)-2-methyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester analogously to Example 10.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:4]=2[N:3]=1.[Cl:20]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Br:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:4]=3[N:3]=[C:2]2[Cl:20])=[CH:7][CH:8]=1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Br)cc12
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Product: Clc1nc2c3ccccc3oc2c2ccc(Br)cc12

Procedure:
The procedure was similar to step S19C, while the starting material was 20B in stead of 19B.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:19]([CH2:20][C:21](OCC)=[O:22])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Li+]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:19]([CH2:20][CH2:21][OH:22])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cn1c(Nc2ccc([N+](=O)[O-])cc2)nc2cccnc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Nc2nc3cccnc3n2CCO)cc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
To a suspension of ethyl {2-[(4-nitrophenyl)amino]-3H-imidazo[4,5-b]pyridin-3-yl}acetate (3.6 g) in THF (120 mL) was added lithium borohydride (0.77 g) at room temperature, and the mixture was refluxed for 2 h. The mixture was cooled to room temperature, quenched with water and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 50%-100% AcOEt in hexane) to give the title compound (2.2 g).
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:3]=1[CH2:4][NH:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]1[N:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][N:33]=1.[C:46](Cl)(=[O:48])[CH3:47]>N1C=CC=CC=1>[F:1][C:2]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:3]=1[CH2:4][N:5]([CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:9][N:8]1[C:32]1[N:33]=[CH:34][C:35]([CH2:38][CH2:39][CH3:40])=[CH:36][N:37]=1)[C:46](=[O:48])[CH3:47]
Reactant: CC(=O)Cl
Reactant: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CNCc2cc(F)ccc2F)nc1
Solvent: c1ccncc1
Product: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN(Cc2cc(F)ccc2F)C(C)=O)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
160 mg (0.258 mmol) (2S,4R)-(2,5-Difluoro-benzyl)-[1-(5-propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl]-amine in 2 ml pyridine were treated with 37 μl (0.52 mmol) acetyl chloride at 0° C. The solution was stirred at RT for 1.5 h, poured on ice water and was extracted with EtOAc. The combined organic layers were washed with 1N HCl and brine, dried over Na2SO4 and were evaporated. Column chromatography with EtOAc:hexane 1:2 to 1:1 yielded 170 mg (quant) (2S,4R)-N-(2,5-Difluoro-benzyl)-N-[1-(5-propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl]-acetamide as white foam.
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:32])=[CH:13][C:14]([OH:31])=[C:15]([CH:30]=3)[C:16]([NH:18][CH2:19][C:20]3[CH:25]=[C:24]([O:26]C)[CH:23]=[CH:22][C:21]=3[O:28]C)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.CO>ClCCl>[C:1]12([C:11]3[C:12]([OH:32])=[CH:13][C:14]([OH:31])=[C:15]([CH:30]=3)[C:16]([NH:18][CH2:19][C:20]3[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=3[OH:28])=[O:17])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COc1ccc(OC)c(CNC(=O)c2cc(C34CC5CC(CC(C5)C3)C4)c(O)cc2O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1cc(O)ccc1O)c1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.9 %

Procedure:
5-Adamantan-1-yl-N-(2,5-dimethoxybenzyl)-2,4-dihydroxybenzamide (0.27 g) is dissolved in dichloromethane (3 mL). After adding BBr3 (1.7 mL in CH2Cl2 1.0 M solution, 3 eq.) and stirring at room temperature for 2 hours, methanol (5 mL) is added and extraction is carried out using water and dichloromethane. The organic layer is dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography to obtain 0.02 g of the target compound as white solid.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[N:10]([CH2:13]O)[C:9](=[O:15])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:11](=[O:12])[N:10]([CH2:13][Cl:18])[C:9](=[O:15])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1on(-c2ccccc2)c(=O)n1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=c1on(-c2ccccc2)c(=O)n1CCl
Reaction time: 2 h

Procedure:
2-Phenyl-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (7.6 grams; 0.0365 mole) dissolved in chloroform (40 ml) and thionyl chloride (8.68 grams; 0.073 mole) dissolved in chloroform (10 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux with stirring for a period of about 2 hours. After this time the reaction mixture was stripped of solvent under reduced pressure, leaving a solid residue. This residue was dissolved in toluene and was distilled to remove unreacted starting material. The remaining product was recrystallized from a hexane-ether mixture to yield the desired product 2-phenyl-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione.