Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27]2)=[CH:22][CH:21]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:32](=[O:33])[CH2:31][C:28]1[CH:29]=[CH:30][N:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1ccn(-c2ccc(F)cc2)c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccn(-c2ccc(F)cc2)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of (S)-(−)-4-benzyl-2-oxazolidinone (710 mg, 4 mmol) in dry THF (10 mL) at −78° C. was added n-butyllithium (2.5 mL of 1.6 M in hexanes). In a separate reaction vessel, to a solution of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid (920 mg, 4.2 mmol) and triethylamine (0.7 mL, 5 mmol) in dry THF (20 ml) at −78° C. was added dropwise pivaloyl chloride (0.5 mL, 4 mmol). After stirring at −78° to 0° C. over 1 hour, then recooling to −78° C., the above solution was added via cannula. The resultant mixture was allowed to warm to ambient temperature over 17 hours, then partitioned with EtOAc and aqueous NH4Cl. The separated aqueousueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to an oil, which was purified via flash column chromatography with 15-20% EtOAc/hex gradient eluant. The oily product crystallized from benzene to give 1.04 g (69%) of 1-(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-ethanone as a solid, mp 106-8° C. 1H NMR: δ 7.36-7.25 (m, 5H), 7.17-7.07 (m, 4H), 7.04 (s, 1H), 6.98 (t, 1H, J=2.6 Hz), 6.35 (dd, 1H, J=1.8, 2.6 Hz), 4.72-4.67 (m, 1H), 4.28-4.14 (m, 4H), 3.28 (dd, 1H, J=3.3, 3.6 Hz), 2.79 (dd, 1H, J=9.4, 13.4 Hz). Anal. Calculated for C22H19N2O3F: C, 69.83; H, 5.06; N, 7.40. Found: C, 69.80; H, 5.07; N, 7.30.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:18]([C:22]1[CH:23]=[CH:24][C:25]([OH:35])=[C:26]([C:28]2[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)[CH:27]=1)([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C.C(O)(=O)C.C(N)CN.S([O-])(O)=O.[Na+]>CO>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([OH:35])=[C:26]([C:28]2[O:32][C:31]([CH:33]=[C:6]3[S:5][C:4](=[S:7])[N:3]([NH:8][C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=4[C:11]([OH:13])=[O:12])[C:2]3=[O:1])=[CH:30][CH:29]=2)[CH:27]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(O)c(-c2ccc(C=O)o2)c1
Reactant: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: NCCN
Product: CC(C)(C)c1ccc(O)c(-c2ccc(C=C3SC(=S)N(Nc4ccccc4C(=O)O)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A mixture of 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (0.078 g, 0.29 mmol), 5-(5-tert-butyl-2-hydroxy-phenyl)-furan-2-carbaldehyde and (0.075 g, 0.31 mmol) and ethylenediamine diacetate (0.056 g, 0.031 mmol) in methanol (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into stirred 0.6 N aq sodium hydrogensulfite (50 mL). The mixture was vigorously stirred for 30 min. The solid product was filtered off and washed on funnel successively with 0.6 N aq sodium hydrogensulfite (1 mL), water (2×2 mL), ether (2×1 mL) and hexanes (2 mL). The material was dried in a vacuum oven at 65° C. for 17 h to afford 2-{5-[1-[5-(5-tert-Butyl-2-hydroxy-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-ylamino}-benzoic acid (135 mg, 94%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.37 (9H, s), 6.98 (1H, d, J=8.4 Hz), 7.23 (1H, d, J=3.6 Hz), 7.34 (1H, dd, J=8.8, 2.8 Hz), 7.39 (1H, d, J=3.6 Hz), 7.70 (2H, m), 7.74 (1H, s), 7.94 (1H, d, J=2.4 Hz), 8.01 (1H, m), 8.07 (1H, m). LC/MS. APCI 493.1, HPLC 100%.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=1.O.Cl>C(OCC)C.C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]([C:11]([OH:16])([CH3:1])[C:12]([F:14])([F:15])[F:13])[CH:8]=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: O=C(c1cccc(Br)c1)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1cccc(Br)c1)C(F)(F)F

Procedure:
Under argon and with stirring, 22.7 ml (22.7 mmol) of a 1 M solution of methylmagnesium bromide in diethyl ether were added dropwise at 0° C. to a solution of 5.22 g (20.6 mmol) of 1-(3-bromophenyl)-2,2,2-trifluoroethanone in 40 ml of anhydrous THF. After the addition had ended, the reaction mixture was stirred at 0° C. for another 30 min. Then—still at 0° C.—excess Grignard reagent was hydrolyzed by careful addition of water. The mixture was then adjusted to a pH of about 5 by addition of 2 M hydrochloric acid. The phases were separated and the aqueous phase was extracted twice with in each case about 20 ml of diethyl ether. The combined organic phases were dried over magnesium sulphate, filtered and evaporated to dryness on a rotary evaporator. This gave 5.32 g (95% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH:17]=O.N1CCCC1>CO>[Cl:1][C:2]1[C:3]2[C:10](=[CH:17][C:13]3[S:12][CH:16]=[CH:15][N:14]=3)[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=Cc1nccs1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2ncnc(Cl)c2C1=Cc1nccs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
Combine 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.3 g; 0.0017 mol), thiazole-2-carbaldehyde (0.23 mL, 0.0026 mol) in methanol (1.5 mL). Add drop-wise pyrrolidine (0.073 mL; 0.0008 mol). Stir at RT for 15 min. Filter the solids to give the title compound (0.35 g; 76.08%).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([OH:11])[C:8]([Br:12])=[C:7]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:6]=1)C.[OH-].[Na+]>C(O)C.O>[Br:12][C:8]1[C:9]([OH:11])=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[CH:6][C:7]=1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]
Reactant: CCOC(=O)c1cc(O)c(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(O)c(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Yield: 18.2 %

Procedure:
A solution of 25.6 g (59 mmol) of 4-bromo-3-[2-(2,4-dichlorophenyl)ethoxy]-5-hydroxybenzoic acid ethyl ester in 300 ml of ethanol and 2.36 g (65 mmol) of sodium hydroxide in 15 ml of water was stirred at room temperature for 12 h. The solvent was removed and the residue was distributed between water and ethyl acetate. The aqueous solution was acidified with 1 N HCl and the precipitate was filtered to give 4.35 g (31%) of the title compound.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH2:11]CS([O-])(=O)=O)[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.[Na+].[I-].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.CCOC(C)=O>[N:19]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]2[CH2:4][O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)([O-])CCc1ccc2c(c1)B(O)OC2
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccc2c(c1)B(O)OC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 131 %

Procedure:
To the solution of (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methylmethanesulfonate (CIX) (0.48 g, 1.98 mmol) in DMF (20 mL) was added NaI (0.06 g, 0.40 mmol) and NaN3 (0.15 g, 2.38 mmol). The mixture was stirred at 60° C. overnight. The reaction mixture was diluted with EtOAc, washed with 10% aqueous Na2S2O3, brine, dried over anhydrous MgSO4, and concentrated under vacuum to give 6-(azidomethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CX) (0.49 g, impure). The crude product was used without further purification for step 7.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH3:6])[CH2:3]O.[CH3:7][S:8](Cl)(=[O:10])=[O:9]>>[CH2:5]([C@@H:2]1[CH2:3][CH2:7][S:8](=[O:10])(=[O:9])[NH:1]1)[CH3:6]
Reactant: CC[C@@H](N)CO
Reactant: CS(=O)(=O)Cl
Product: CC[C@@H]1CCS(=O)(=O)N1

Procedure:
Using (R)-2-amino-1-butanol (1.78 g) and methanesulfonyl chloride (3.2 mL) and by the reaction and treatment in the same manner as in Preparation Example 1, the title compound (1.54 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([C:22](=O)[CH3:23])[CH:10]=[CH:11][C:12]=2[S:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.CO.C([BH3-])#[N:28].[Na+].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH:22]([NH2:28])[CH3:23])[CH:10]=[CH:11][C:12]=2[S:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccc(S(=O)(=O)N2CCOCC2)c(-c2ccc(Cl)s2)c1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(N)c1ccc(S(=O)(=O)N2CCOCC2)c(-c2ccc(Cl)s2)c1
Yield: 43.5 %

Procedure:
To a solution of the compound yielded from step 3 (2.2 g, 5.7 mmol) in MeOH (30 mL) ammonium acetate (4.39 g, 57.0 mmol) and sodium cyanoborohydride (358 mg, 5.7 mmol) were added. The reaction mixture was refluxed for 4 h. After that the mixture was acidified with trifluoroacetic acid to pH=2 and then evaporated to dryness. Purification of the crude product by prep-HPLC and lyophilization of the relevant fractions gave the desired product (0.96g, 34%).
Reaction SMILES: [OH-].[Li+].O.[Br:4][C:5]1[C:6]([CH3:23])=[CH:7][C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11]>O1CCCC1>[Br:4][C:5]1[C:6]([CH3:23])=[CH:7][C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:14]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc(Br)c(C)cc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2ccccc2)c(C(=O)O)cc1Br
Temperature: 40 °C

Procedure:
Lithium hydroxide (0.29 g, 12.08 mmol) and water (4 ml) were added to a solution of methyl 5-bromo-4-methyl-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 8; 1.35 g, 4.03 mmol) in tetrahydrofuran (20 ml). The reaction was heated at 40° C. for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water (20 ml) and ethyl acetate (30 ml). The aqueous layer was acidified to pH2 using 2N HCl. The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a white solid. 1.26 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=1)[O:10][C:9]([C:21]([OH:23])=O)=[CH:8][C:7]2=[O:24].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:30]=[CH:29][C:28]=1[NH2:39]>>[CH3:25][O:26][C:27]1[CH:32]=[C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH:30]=[CH:29][C:28]=1[NH:39][C:21]([C:9]1[O:10][C:11]2[C:6]([C:7](=[O:24])[CH:8]=1)=[CH:5][C:4]([O:3][CH3:2])=[CH:13][C:12]=2[N:14]1[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1)=[O:23]
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Reactant: COc1cc(N2CCOCC2)ccc1N
Agent: Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCOCC4)cc3OC)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and commercially available 2-methoxy-4-morpholin-4-yl-phenylamine (SALOR) as prepared in Example 12, yielding a yellow solid. (55 mg=38%), LCMS-m/z=510.5.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[S:6][CH:7]=1.Br[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1>>[F:20][C:2]([F:19])([F:1])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:22]3[CH:23]=[N:24][CH:25]=[N:26][CH:27]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: Brc1cncnc1
Reactant: Cc1ccc(N)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, light yellow solid, MS (ISP): m/e=381.0 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide in accordance with the general method of example 20 using 5-bromopyrimidine instead of 3-bromo-pyridine.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.[N:24]([C:27]1[C:28]([Cl:47])=[CH:29][C:30]([F:46])=[C:31]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])[CH:32]=1)=[N+]=[N-].O.[C:49](O)(=[O:51])[CH3:50]>>[CH3:50][C:49]1[O:51][C:32]2[C:31]([N:33]3[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]3=[O:45])=[C:30]([F:46])[CH:29]=[C:28]([Cl:47])[C:27]=2[N:24]=1
Reactant: CC(=O)O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N=[N+]=[N-])c(Cl)cc2F)c1=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: O
Product: Cc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere a stirred solution of 4.0 grams (28 mmole) of phosphorus pentoxide and 10 mL (47 mmole) of hexamethyldisiloxane was heated at 90° C. for 30 minutes. To this was added dropwise during a 5.0 minute period a solution of 0.80 gram (2.2 mmole) of 3-(5-azido-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione in 5.0 mL of acetic acid. Upon completion of the addition the reaction mixture was heated at reflux for 5.0 hours, cooled to ambient temperature, and poured into 50 mL of water. The reaction mixture was extracted with three 25 mL portions of ethyl acetate. The combined extracts were washed with 50 mL of aqueous saturated sodium bicarbonate solution and 50 mL of aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.7 gram of a residual oil, which was subjected to column chromatography on silica gel. Elution was accomplished with 3:1 heptane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.40 gram of an oily white solid, 3-(2-methyl-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, m.p. 64°-66° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8]C1C(OC)=CC(C(Cl)=O)=CC=1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22]CCN1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([NH2:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NC(=O)c1ccccc1

Procedure:
First, 4-benzyloxy-3,5-dimethoxybenzoic acid chloride represented by Formula 85 (61.30 mg, 0.200 mmol) prepared in Preparative Example 1 and 4-(2-aminoethyl)morpholine represented by Formula 99 (31.22 mg, 0.240 mmol) were prepared in 0.2 M solution, respectively, using a toluene solvent. After adding 1M sodium carbonate solution and 0.2 M acyl chloride solution to the above solutions, the mixture was vigorously shaken and agitated at room temperature overnight. After terminating the reaction, an aqueous layer was discarded using a tip while an organic layer was moved to a cartridge tube (6 mL, benzenesulfonic acid, 904030-WJ, UCT) using ethyl acetate. Impurities were removed using methanol (15 mL), while separation and purification using an elute solution (ethyl acetate/methanol/triethylamine, 20:2:1, v/v/v) was conducted to produce a benzamide compound represented by Formula 7 as a desired product (VVZ-006; 79.10 mg, 98.8% yield).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(N(CC)CC)C>ClCl.O>[C:13]([NH:1][C:2]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2(N)CC2)cc1
Agent: ClCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(NC(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.1 %

Procedure:
To a stirred suspension of Compound 7 (1.25 g, 7.66 mmol) in CH2 Cl2 (40 ml) was added acetic anhydride (860 mg, 8.42 mmol) and triethylamine (2.32 g, 22.98 mmol) at room temperature. The reaction mixture was stirred at room temperature for 22 h. The mixture was diluted with H2O (50 ml) and stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with 10% HCl aq., sat. NaHCO3 aq. and brine, dried (MgSO4) and concentrated in vacuo to give crude product (1.58 g, quant.), which was recrystallized from hexane-ethyl acetate to give Compound 8 (1.26 g, 80%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=2[NH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=2[NH:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reaction time: 0.65 h
Yield: 77.6 %

Procedure:
To a mechanically stirred 16° C. pyridine (270 mL) solution of 1-[4-phenylmethoxy-3-aminophenyl]ethanone (57.4 g, 238 mmol) under N2, was added methanesulfonyl chloride (18.6 mL, 240 mmol). After 39 minutes, the completed reaction was quenched with 1.8 L H2O and the resulting suspension stirred for ~2 hours before filtration. The collected solids were washed with H2O (2×250 mL=500 mL) and partially air dried. These solids were dissolved in CHCl3 (450 mL), the aqueous phase removed and heptane (475 mL) added with stirring. The resulting fine suspension was filtered after ~15 minutes, washed with hexane and dried in vacuo at 55° C. to give 59 g (78%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:8])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[NH2:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:11]([CH:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH3:14])=[O:13])[CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29]1)=[O:24]
Reactant: CC(NC(=O)c1ccc(Cl)s1)C(=O)O
Reactant: Nc1ccc(C(=O)N2CCCC2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccc(Cl)s1)C(=O)Nc1ccc(C(=O)N2CCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1a from 2-[(5-chloro-thiophene-2-carbonyl)-amino]-propionic acid and 3-chloro-4-(pyrrolidin-1-yl-carbonyl)-aniline with TBTU and NMM in DMF.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:8]([CH3:9])[C:7]([CH2:10][OH:11])=[N:6][CH:5]=1.I[CH3:13]>C1COCC1.CCOC(C)=O>[Br:3][C:4]1[N:8]([CH3:9])[C:7]([CH2:10][O:11][CH3:13])=[N:6][CH:5]=1
Reactant: Cn1c(Br)cnc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1ncc(Br)n1C
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
NaH (60%, 30 mg) was added to a solution of (5-bromo-1-methyl-1H-imidazol-2-yl)methanol (120 mg, 0.63 mmol) in THF (4 mL). After stirring for 15 minutes, iodomethane (35 uL, 0.57 mmol) was added. The resulting solution was stirred at 60° C. under microwave irradiation for 60 minutes. The reaction mixture was diluted with EtOAc, filtered and concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with EtOAc to give the title compound as light brown oil (32 mg, 25%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with benzoyl chloride (9.1 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[Cl-].[NH4+].S([O-])([O-])(=O)=O.[Mg+2]>O.C(OCC)(=O)C.O1CCCC1>[C:16]([O:15][C:13]([NH:12][C@H:8]([CH2:9][OH:10])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])=[O:14])([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
2.0 g of (S)-4-t-butoxy-2-(t-butoxycarbonylamino)-4-oxobutanoic acid and 14 mL of tetrahydrofuran were added to 50 mL flask and then the resulting reaction solution was cooled to 0° C. While the reaction solution was stirred, 1.0 mL of 4-methylmorpholine was dropped, and after 10 minutes, 1.2 mL of isobutylchloroformate was dropped, and then stirred for 1 hour. The produced solid was filtered with diatomite, was washed with 14 mL of tetrahydrofuran, and then the filtrate was cooled to 0° C. 523 mg of sodium borohydride was added to the cooled filtrate, and stirred for 4 hours while the reaction temperature was naturally increased to room temperature. After completing the reaction, the reaction solution was cooled to 0° C. and then 10 mL of ammonium chloride aqueous solution was dropped. 20 mL of ethyl acetate and 10 mL of water were added and then stirred for 10 minutes. An organic layer was isolated, dehydrated with magnesium sulfate and then concentrated under reduced pressure. A concentrated residue was isolated with column chromatography (n-hexane:ethyl acetate=2:1) and then concentrated under reduced pressure to obtain 1.86 g of a title compound.
Reaction SMILES: [C:1](#[N:3])C.[Cl:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>CCOCC>[Cl:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](=[O:9])[C:1]#[N:3]
Reactant: O=C(Cl)c1ccccc1CCl
Reactant: CC#N
Solvent: CCOCC
Product: N#CC(=O)c1ccccc1CCl
Reaction time: 4 h
Yield: 79.5 %

Procedure:
A mixture of 98% cuprous cyanide (2.01 g), acetonitrile (40 ml) and 2-chloromethylbenzoyl chloride (3.79 g) was heated under reflux with stirring for 4 hours. After the mixture was cooled by allowing it to stand, the mixture was diluted with ether, the precipitated insoluble materials were filtered off, and then the filtrate was washed successively with a saturated aqueous solution of sodium bicarbonate, water and saturated brine. The ether layer thus obtained was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain the crude product (3.49 g). The crude product was crystallized from ether-haxane to give the title compound (2.85 g, yield: 79.5%, white crystals).