Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:35][CH2:36][S:37][CH3:38])[NH:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15][S:16][CH2:17][CH3:18])=[CH:9][C:8]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33].O.[OH-].[Li+:42]>>[Li+:42].[CH:21]1([CH2:20][CH2:19][CH:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O-:39])=[O:2])[CH2:35][CH2:36][S:37][CH3:38])=[O:34])=[C:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[CH:9]=2)[CH2:15][S:16][CH2:17][CH3:18])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCSCC(CCC1CCCCC1)Cc1ccc(C(=O)N[C@@H](CCSC)C(=O)OC)c(-c2ccccc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCSCC(CCC1CCCCC1)Cc1ccc(C(=O)N[C@@H](CCSC)C(=O)[O-])c(-c2ccccc2C)c1

Procedure:
The product from Example 1300C (46.5 mg, 0.08 mmol) was allowed to react with lithium hydroxide monohydrate (4 mg, 0.08 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 0.75-0.88 (m, 2H), 1.08-1.38 (m, 10H), 1.53-2.01 (m, 14H), 2.15 (m, 1H), 2.39-2.49 (m, 4H), 2.57-2.75 (m, 2H), 3.32 (d, partially buried under water peak 2H), 3.66 (m, 1H), 6.86 (d, J=6 Hz, 1H), 6.95 (m, 1H), 7.12-7.26 (m, 4H), 7.47 (d, J=8 Hz, 1H); MS (APCI(−)) m/z: (M−H)− 554; Anal. Calcd for C32H44LiNO3S2.1.75 H2O: C, 64.78; H, 8.07; N, 2.36. Found: C, 64.75; H, 7.40; N, 2.20.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[NH2:10][OH:11]>CO>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][OH:11])=[CH:4][N:3]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: NO
Solvent: CO
Product: Cc1ccc(C=NO)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 6-methylnicotinaldehyde (1.67 g, 13.79 mmol) in 27.6 mL MeOH, hydroxylamine (50% weight in water, 0.87 mL, 14.2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then at 40° C. for an additional 2 h. The reaction mixture was concentrated to obtain 1.76 g (94%) of the title compound as a light brown solid. HPLC: retention time=0.20 min.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:17]=[C:16]([O:28][CH3:29])[N:15]=2)[CH2:10][CH:9]1[C:30](=[O:42])[NH:31][C:32]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][CH:33]1[CH:35]=[CH2:36])=[O:7])(C)(C)C.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:40]([O:39][C:37]([C:32]1([NH:31][C:30]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[N:17]=[C:16]([O:28][CH3:29])[N:15]=3)[CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:42])[CH2:34][CH:33]1[CH:35]=[CH2:36])=[O:38])[CH3:41]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccc(OC)cc3)nc(OC)n2)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccc(OC)cc3)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Yield: 130.2 %

Procedure:
Compound 16b (1.11 g, 1.9 mmol) was treated with triethylsilane (0.55 g, 4.75 mmol) and TFA (30 ml) according to the procedure described in Example 13 step b which gave the crude title compound, (1.3 g), (M+H)+526.
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:16])[NH:4][C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[N:6]=1.Cl.[CH3:18][OH:19]>C(Cl)(Cl)Cl>[CH3:1][N:2]=[C:3]([NH2:16])[NH:4][C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:15])[O:19][CH3:18])[N:6]=1
Reactant: CO
Reactant: CN=C(N)Nc1cnn(CCCCC#N)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN=C(N)Nc1cnn(CCCCC(=N)OC)n1

Procedure:
A solution of 5-[4-(2-methylguanidino)-1,2,3-triazol-2-yl]valeronitrile (0.8 g.) in a mixture of chloroform (15 ml.) and MeOH (5 ml.) was saturated at 0° with hydrogen chloride gas and the mixture maintained at 0° for 3 days. The mixture was evaporated to dryness and the residue basified with cold sodium carbonate solution and extracted witn chloroform. The extract was dried and evaporated to give methyl 5-[4-(2-methylguanidino)1,2,3-triazol-2-yl]valerimidate as a yellow oil (1.07 g.).
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16](F)(F)F)=[CH:11][CH:10]=2)[CH2:4]1.[C:20]([O-:23])(=[O:22])[CH3:21].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[C:20]([O:23][CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH2:4]1)(=[O:22])[CH3:21]
Reactant: CC(=O)[O-]
Reactant: O=C1OC(CCl)CN1c1ccc(SC(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(N2CC(COC(C)=O)OC2=O)cc1
Temperature: 0 °C
Yield: 81.3 %

Procedure:
A mixture of 15 g of II (R1 =CH3, X=Cl), 50 g of potassium acetate, a catalytic amount of 18-crown-6, and 60 ml of dimethylformamide was heated under nitrogen atmosphere at 130° C. for 5 hours. The mixture was poured into ice water and the solid precipitate was collected by filtration. The solid was recrystallized from 1-chlorobutane to give 11 g of 5-acetoxymethyl-3-(4-methylthiophenyl)-2-oxazolidinone (XV, R1 =CH3).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)=[O:8])[CH2:2][CH3:3]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Propoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Propoxy-N-(4-nitro-3-trifluromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH2:19]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH3:19][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(-c2nc3ccc(OC)cc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
2-(4-Aminophenyl)-6-methoxybenzothiazole (43, 779 mg, 3.04 mmol) and paraformaldehyde (487 mg, 15.2 mmol) were dissolved in methanol and then added to 0.5 M NaOMe in methanol (30 mL, 15.2 mmol). The resulting reaction mixture was agitated for 4 hours at room temperature and, after adding NaBH4 (1.0 g, 26.5 mmol), heated for 1.5 hours under reflux. After removing methanol by distilling under reduced pressure, the residue was dissolved in ethyl acetate (100 mL) and water was added thereto. After extracting the organic compound with ethyl acetate, removing water using sodium sulfate and removing the solvent under reduced pressure, column chromatography yielded the target compound 2-[4-(N-monomethyl)aminophenyl)-6-methoxybenzothiazole (44, 588 mg, 72%) as yellow solid.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)=O.C(O)C.C1C=CC=CC=1>[Pd].O>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: c1ccccc1
Solvent: O=CO
Product: c1ccc(CCc2ccccc2)cc1
Yield: 92.4 %

Procedure:
To a dry, nitrogen-filled 250 ml single-necked round-bottom flask fitted with a nitrogen inlet and magnetic stirring bar was added 11.8 g (65.5 mmol) of stilbene, 11 g (240 mmol) formic acid, 5 g of 10% Pd on activated carbon (4.7 mmol Pd), 60 ml of absolute ethanol and 100 ml of dry benzene. The reaction vessel was placed in a sonicator so that the liquid level inside the flask matched that of the bath water and in the location that produced the maximum cavitation in the flask. After 1 h the flask was removed and the contents filtered. The solid was washed with chloroform and the combined filtrates concentrated on a rotary evaporator. The residual soild was recrystallized (ethanol-pentane) to give 11.03g (92.5% yield) of bibenzyl mp 51°-51.5° (lit 52.5) (8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][N:16]([C:18]([N:20]2[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)=[O:19])[CH2:15][CH:14]([C:26](O)=[O:27])[CH2:13]1.O[N:30]=[C:31]([O:33][CH2:34][CH3:35])[NH2:32]>>[CH2:34]([O:33][C:31]1[N:32]=[C:26]([CH:14]2[CH2:13][CH:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])[CH2:17][N:16]([C:18]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[O:19])[CH2:15]2)[O:27][N:30]=1)[CH3:35]
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2F)CN(C(=O)N2CCSCC2)C1
Reactant: CCOC(N)=NO
Product: CCOc1noc(C2CC(c3ccc(C(F)(F)F)cc3F)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 4, 254 mg (0.405 mmol) of the compound from Example 90A and 63 mg (0.607 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were reacted. Yield: 70 mg (35% of theory).
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:44]=[C:43]([F:45])[C:42](OC)=[CH:41][C:40]=3[F:48])[CH2:35][CH2:34]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]2[CH2:34][CH2:35][N:36]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=3[F:48])[CH2:37][CH2:38]2)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: COc1cc(F)c(N2CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCN(c2cc(F)ccc2F)CC1
Yield: 88.1 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 1-(4-chlorobenzenesulfonyl)-4-(2,5-difluoro-4-methoxyphenyl)-piperazine (395 mg). The resulting crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=2:1) to provide 1-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)-piperazine (322 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[C:7]([Cl:12])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:7]1[N:8]([CH3:11])[N:9]=[C:10]2[C:6]=1[CH:5]=[CH:4][CH:3]=[C:2]2[C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][C:18]=1[Cl:20]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cn1nc2c(Br)cccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1Cl
Temperature: 88 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A mixture of 7-bromo-3-chloro-2-methyl-2H-indazole (0.079 g, 0.32 mmol), 2,4-dichlorophenyl boronic acid (0.122 g, 0.641 mmol), 2 mL of ethylene glycol dimethyl ether, 2 mL of a 2 M aqueous Na2CO3 solution, and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.010 mmol) was stirred at 88° C. overnight, then diluted with 10 mL of ethyl acetate. The mixture was washed with two 5 mL portions of a saturated aqueous NaCl solution, dried, filtered, and concentrated to a yellow oil. Column chromatography (0→5% EtOAc/hexanes) afforded of 3-chloro-7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole (26: R=Me; Ar=2,4-dichlorophenyl; 0.063 g; 63%) as a white solid.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[O:27]([CH2:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:27]([CH2:34][C:35]([N:21]1[CH2:20][CH2:19][C:16]2([C:15](=[O:24])[N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=3)[CH2:18][CH2:17]2)[CH2:23][CH2:22]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and phenoxy-acetyl chloride. White solid. MS (ESI): 449.2 (MH+).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]O.O>ClCCl>[N+:1]([O-:4])([O:3][CH2:14][CH2:13][CH2:12][CH2:11][Br:10])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: OCCCCBr
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])OCCCCBr
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
In reactor cooled to −5 to 5° C., nitric acid fuming (8.5 g-135 mmol) was slowly added to a solution of 98% sulfuric acid (13.0 g-130 mmol) in dichloromethane (18.0 g-212 mmol). 4-bromobutanol (10.2 g-66.6 mmol) was then added to this mixture and the reaction medium was stirred at −5 to 5° C. over a period of 2-5 hours. The mixture was poured into cold water (110 g) keeping the temperature between −5° C. and 3° C. After decantation, the upper aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water, adjusted to pH=6-7 by addition of 27.65% sodium hydroxide, washed with brine and dried over magnesium sulfate. Dichloromethane was distilled off under vacuum and crude 4-bromobutyl nitrate (12.7 g-64.1 mmol) was recovered in a yield of about 96%.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].Br[CH2:18][C:19]1[CH:20]=[C:21]([B:25]([OH:27])[OH:26])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+].[Cl-].Cl>CN(C=O)C.CCOCC>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][CH2:18][C:19]1[CH:20]=[C:21]([B:25]([OH:27])[OH:26])[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Reactant: OB(O)c1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1nnc2c(Br)c(OCc3cccc(B(O)O)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (Example 1-2) (704 mg, 2.478 mmol, 1.0 equiv.), 3-bromomethylphenylboronic acid (11) (639 mg, 2.97 mmol, 1.2 equiv.) and cesium carbonate (969 mg, 2.97 mmol, 1.2 equiv.) were suspended in anhydrous DMF (6043 μl). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with Et2O, and acidified with aqueous saturated NH4Cl and HCl (1N) to pH 2. The organic layer was dried over MgSO4, filtered and concentrated to provide the titled compound. LRMS m/z (M+H) 418.0 and 420.0 (intensity ratio ˜1:1) found, 418.1 and 420.1 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:18][C@H:19]([N:21]([C@@H](C3C=CC=CC=3)C)[CH2:22][CH2:23][CH3:24])[CH3:20])[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:5][CH:4]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:18][C@H:19]([NH:21][CH2:22][CH2:23][CH3:24])[CH3:20])[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: CCCN([C@H](C)Cc1cccc(NC(=O)c2ccc(OC)cc2)c1)[C@H](C)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCN[C@H](C)Cc1cccc(NC(=O)c2ccc(OC)cc2)c1
Temperature: 25 °C

Procedure:
(R,R)-N-{2-[3-(4-methoxyphenylcarbonylamino)phenyl]-1-methylethyl}-N-propyl-(1-phenylethyl)amine (0.98 g) was dissolved in ethanol (100 ml) and added to 10% palladium on carbon (0.1 g). To this mixture was added ammonium formate (1.2 g), and the mixture heated at reflux for 2 hours, cooled to room temperature, and filtered. The filtrate was evaporated in vacuo, and the residue was partitioned between ethyl acetate and dilute sodium hydroxide. The organic layer was dried over sodium sulfate, filtered, and the solvent removed in vacuo to give [(R)-N-{2-[3-(4-methoxyphenylcarbonylamino)phenyl]-1-methylethyl}propylamine.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=C(SC)N=[C:10](N3CCOC[C@@H]3C)[CH:9]=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]2[CH3:47])[N:25]=1.CC1(C)C(C)(C)OB(C2C=CC(N)=CC=2)O1>>[F:36][C:34]1[CH:33]=[CH:32][C:31]([S:37]([CH3:40])(=[O:39])=[O:38])=[C:30]([C:28]2[N:27]=[C:26]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]3[CH3:47])[N:25]=[C:24]([C:2]3[CH:3]=[CH:4][C:8]([NH2:13])=[CH:9][CH:10]=3)[CH:29]=2)[CH:35]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Agent: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Yield: 58 %

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-2-yl)-3-methylmorpholine (intermediate 16) (451 mg, 1.17 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (256 mg, 1.17 mmol). The mixture was purified using flash chromatography (30-100% EtOAc in petroleum ether 40-60) to afford the title compound (298 mg, 58%)
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=O)[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[O:20][CH:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22].C(O)(=O)C>O>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[C:10](=[O:11])[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=3[C:7]2=[O:9])=[CH:15][C:14]=1[O:20][CH:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: CCOC(=O)C(C)Oc1cc(N)ccc1Br
Reactant: O=C1OC(=O)C2CCCCC12
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.88 g. of 1.52 g. of cyclohexane-1,2-dicarboxylic anhydride 2.88 g. of 4-bromo-3-(1-ethoxycarbonylethyloxy)aniline (nD25 =1.5590) and 10 ml. of acetic acid was refluxed with stirring for 2 hours and the reaction mixture was cooled to room temperature and water was added. The precipitate was separated by a filtration and was recrystallized from a mixture of benzene-cyclohexane to obtain 3.89 g. of Compound No. 18 shown in Table 1.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:14])[C:10](OC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>CO>[CH2:1]([O:8][C@H:9]([CH3:14])[C:10]([NH:16][NH2:17])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)OCc1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: C[C@@H](OCc1ccccc1)C(=O)NN
Yield: 64 %

Procedure:
A mixture of (R)-methyl 2-(benzyloxy)propanoate (1 g, 5.15 mmol), hydrazine monohydrate (250 ul) in MeOH (14 mL) was refluxed 3 hours. Solvent was removed under reduced pressure and the residue was purified on silica gel. Elution with EtOAc yielded title compound (640 mg, 64%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=2[CH:21]=1)[C:5]([NH:7][C:8]1[CH:19]=[CH:18][C:11]([C:12]([O:14]CC=C)=[O:13])=[CH:10][CH:9]=1)=[O:6].N1CCOCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:1][O:2][N:3]=[C:4]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=2[CH:21]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:18][CH:19]=1)=[O:6]
Reactant: C=CCOC(=O)c1ccc(NC(=O)C(=NOC)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Product: CON=C(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.4 g (3.1 mmol) of the ester prepared in (a), 190 mg (0.16 mmol) of tetrakis(triphenylphosphine)-palladium(O) and 50 ml of TEF were introduced into a three-necked flask under a nitrogen stream. 2.7 ml (31 mmol) of morpholine were then added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction medium was evaporated to dryness, taken up in water, acidified to pH 1, and extracted with ethyl ether, the organic phase was decanted off, washed with water, dried over magnesium sulfate and evaporated. The residue obtained was triturated in 50 ml of dichloromethane, filtered and dried. 1.2 g (95%) of 4-[α-methoxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido]benzoic acid of melting point 208°-209° C. were recovered.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.C(=O)(O)[O-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: CCCc1c2c(c(O)c3c(=O)cc(C(=O)OCC)oc13)CCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c2c(c(O)c3c(=O)cc(C(=O)O)oc13)CCCC2
Yield: 81.8 %

Procedure:
A refluxing solution of ethyl 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (45.4 g) in ethanol (600 ml) was stirred whilst adding a solution of sodium bicarbonate (11.5 g) in water (300 ml) over 15 minutes. After refluxing a further 4 hours, an additional quantity of sodium bicarbonate solution (1.5 g in 30 ml water) was added and the mixture refluxed for a further 1 hour. The hot solution was acidified with dilute hydrochloric acid and the yellow precipitate filtered off. The damp solid was recrystallised from acetone to give 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid (34.0 g) mp 265°-268°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:22])[CH:17]([C:35]([OH:37])=O)[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH2:42]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:25][CH2:24]3)=[O:22])[CH:17]([C:35](=[O:37])[NH:42][CH2:41][C:40]([O:39][CH3:38])=[O:43])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Reactant: COC(=O)CN
Product: COC(=O)CNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 76 %

Procedure:
Using an analogous procedure to that described in Example 20, 4-(6-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine was reacted with glycine methyl ester to give 4-(6-bromonaphth-2-ylsulphonyl)-2-[N-(methoxycarbonylmethyl)carbamoyl]-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 76% yield as a glass;