Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:46]2[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:41])([CH3:40])[C:36]([OH:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=2)[C:24]([CH3:42])=[N:23][C:22]=1[CH2:43][CH2:44][CH3:45]>O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]2[NH:3][C:4](=[O:7])[O:5][N:53]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:41])([CH3:40])[C:36]([OH:39])([CH3:37])[CH3:38])=[CH:30][CH:29]=2)[C:24]([CH3:42])=[N:23][C:22]=1[CH2:43][CH2:44][CH3:45]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.97 g), sodium hydrogen carbonate (1.40 g) and dimethyl sulfoxide (7 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-({1-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.77 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.71 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:8][CH:7]=1)=[O:4].[K+].[N+:21]([O-])([OH:23])=[O:22]>C(OCC)C>[CH3:1][O:2][C:3]([CH2:5][C:6]1[C:15]2[C:10](=[C:11]([N+:21]([O-:23])=[O:22])[CH:12]=[CH:13][CH:14]=2)[C:9]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Cc1ccc(S(=O)(=O)[O-])c2ccccc12
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)Cc1ccc(S(=O)(=O)O)c2c([N+](=O)[O-])cccc12
Temperature: -15 °C
Reaction time: 2 h

Procedure:
Potassium 1-(methoxycarbonylmethyl)-4-naphthalene sulfonate (10 g, 31.4 mmol) was added portionwise over 30 minutes to 90% nitric acid, which was cooled in a methanol/ice bath to approximately -15° C. After 2 hours, the bath temperature had reached -10° C. and diethyl ether (200 mL) was added to the mixture. The precipitated solid was filtered, washed with ether (100 mL) and isopropanol (20 mL), and dried under a stream of nitrogen to give the title compound as an approximately 70:30 mixture of the 5- and 8-nitro isomers (approximately 12 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=1[C:39]1[O:43][CH:42]=[N:41][CH:40]=1)[NH2:35]>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:35][C:34]2[CH:36]=[CH:37][C:38]([C:39]3[O:43][CH:42]=[N:41][CH:40]=3)=[C:32]([O:31][CH3:30])[CH:33]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: COc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)ncc2C(N)=O)ccc1-c1cnco1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-methoxy-4-(oxazol-5-yl)aniline in step 1. MS: 424.5 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C

Procedure:
To a well-stirred, 0° C. solution of methyl 2,4-dihydroxybenzoate (50 g, 300 mmol) in acetone (1000 mL) was added K2CO3 (150 g, 1000 mmol) and benzyl bromide (39 mL, 330 mmol). The solution was allowed to warm to ambient temperature over 48 h. The mixture was filtered through celite and the filtrate solvent was removed under reduced pressure. The residue was dissolved in EtOAc (1000 mL) and washed with water (250 mL) and saturated aqueous NaHCO3 (500 mL). The EtOAc layer was dried (MgSO4), filtered, and the EtOAc was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 5:1 hexanes:EtOAc as eluant. Methyl 4-benzyloxy-2-hydroxybenzoate was obtained as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:14].[O:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:22]([OH:23])=[C:19]([O:20][CH3:21])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:22]=1[O:23][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:14])[CH:16]=[O:15]
Reactant: Cc1nc(-c2ccccc2)sc1CCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1sc(-c2ccccc2)nc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
A mixture of 5-chloromethyl-4-methyl-2-phenyl-1,3-thiazole (2.30 g), vanillin (1.49 g), potassium carbonate (1.35 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]benzaldehyde as pale-yellow crystals (3.02 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 118-119° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]=1[O:15][CH3:16])[N:4]=[C:3]([CH2:2][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[N:4]=3)[CH2:21][CH2:20]1)[CH:12]=[CH:11]2
Reactant: C1CNCCN1
Reactant: COc1cc2ccc(CCl)nc2c(OC)c1OC
Product: COc1cc2ccc(CN3CCN(Cc4ccc5cc(OC)c(OC)c(OC)c5n4)CC3)nc2c(OC)c1OC

Procedure:
2-Chloromethyl-6,7,8-trimethoxyquinoline (336 mg) and piperazine (54 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8](Br)[N:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1)=[O:4].[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19](B(O)O)=[CH:18][N:17]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:19]2[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=2)[N:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COC(=O)c1cc(-c2cnc(OC)nc2OC)n(C(C)C)c1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step D4) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a yellow solid. tR: 0.97 min (HPLC 3); ESI-MS: tR=0.97 min, [M+H]+ 306 (LC-MS 1); TLC: Rf=0.43 (1:1 EtOAc/heptanes).
Reaction SMILES: CO[Na].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)=[O:6].[CH:21]([C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])=O.C(O)(=O)C>CO.O>[CH2:14]([O:13][C:9]1[CH:8]=[C:7]([C:5](=[O:6])[CH:4]=[CH:21][C:23]2[CH:32]=[CH:31][CH:30]=[C:25]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=2)[CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CO[Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(C=CC(=O)c2cccc(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To CH3ONa (0.45 g, 0.0082 mol) stirring in 20 ml of dry CH3OH at 10° C. was added 3-benzyloxyacetophenone (5.0 g, 0.019 mol) and methyl 3-formylbenzoate (3.12 g, 0.019 mol). A heavy precipitate formed almost immediately, and the mixture was diluted with 20 ml CH3OH, warmed to room temperature and stirred for 18 hours. Glacial acetic acid (3 ml) was added and the mixture poured into 300 ml H2O. Title product was recovered by filtration, air dried and purified by chromatography on silica gel gradiently eluted with 49 to 39:1 toluene:ethyl acetate, 4.97 g of solid; MS 372.2 (M+); 1H-NMR (300 MHz, CDCl3) delta (ppm) 3.95 (s, 3H), 5.14 (s, 2H), 7.2-7.9 (m, 13H), 8.06 (dt, 1H), 8.3 (s, 1H); TLC Rf 0.7 (49:1 CHCl3 :isopropanol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]([CH3:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].NC1C(Cl)=CC(C(N[C@H:23]2[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]2[O:29][CH3:30])=O)=C(OC)C=1.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[OH2:6].[CH3:30][O:29][CH:24]1[CH2:23][CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][C:5]([N:7]([CH3:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH2:25]1
Reactant: CN(C(=O)CCCCl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC1CCCN(CCCC(=O)N(C)c2ccccc2)C1
Product: O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 2.54 parts of 4-chloro-N-methyl-N-phenylbutanamide, 3.14 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 2.45 parts of N,N-diethylethanamine, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide was stirred for 20 hours at 80° C. The reaction mixture was evaporated. The residue was taken up in water and sodium carbonate. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile and a small amount of water. The product was filtered off and dried, yielding 2.05 parts (40.4%) of cis-4-[4-amino-5-chloro-2-methoxybenzoyl)amino]3-methoxy-N-methyl-N-phenyl-1-piperidinebutanamide monohydrate; mp. 97.4° C. (compound 23).
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([O:8]C)=[O:7])[CH2:2][CH2:3][CH3:4].C1(C(CCC)(CCC)C(OC)=O)C=CC=CC=1>>[CH2:1]([C:5]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CCCC)(C(=O)OC)c1ccccc1
Agent: CCCC(CCC)(C(=O)OC)c1ccccc1
Product: CCCCC(CCCC)(C(=O)O)c1ccccc1
Yield: 98 %

Procedure:
The title compound (7.05 g, 98%) was prepared following the procedure of Example 1C, substituting the product of Example 4B for the product of Example 1B. 1H NMR (300 MHz, CDCl3): δ 7.28 (m, 5 H), 2.01 (m, 4 H), 1.28 (m, 4 H), 1.09 (m, 4 H), 0.87 (t, J=7.35 Hz, 6 H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:3]1=O.[CH3:13][O:14][C:15](=[O:18])[CH2:16]Br>>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([C:3]=1[CH2:16][C:15]([O:14][CH3:13])=[O:18])=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=2
Reactant: COC(=O)CBr
Reactant: Cc1ccc2c(c1)CC(C)C2=O
Product: COC(=O)CC1=C(C)Cc2cc(C)ccc21

Procedure:
The above reactions of Example 1C are repeated except that the starting materials are 2,5-dimethylindanone and methylbromoacetate. Using the same reaction conditions and techniques there is obtained methyl 2,6-dimethyl-3-indenylacetate.
Reaction SMILES: COC1C=C2C(=CC=1)C=C(C1C=CC=CC=1N)C=C2.Cl.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:25](O)=O.FC1C=[C:43](C=CC=1OCCN1CCCCC1)[CH2:44][NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]1[CH:61]=[CH:60][C:59]2[C:54](=[CH:55][CH:56]=[C:57]([O:62][CH3:63])[CH:58]=2)[CH:53]=1>>[CH2:44]([N:45]([CH2:25][C:24]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:22]([F:21])[CH:23]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]1[CH:61]=[CH:60][C:59]2[C:54](=[CH:55][CH:56]=[C:57]([O:62][CH3:63])[CH:58]=2)[CH:53]=1)[CH3:43]
Reactant: COc1ccc2cc(-c3ccccc3NCc3ccc(OCCN4CCCCC4)c(F)c3)ccc2c1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: COc1ccc2cc(-c3ccccc3N)ccc2c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1ccccc1-c1ccc2cc(OC)ccc2c1

Procedure:
Synthesized from 2-(6-methoxynaphthalen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxynaphthalen-2-yl)phenyl]amine (362 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxynaphthalen-2-yl)phenyl]amine (310 mg). This compound (308 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (205 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[N:20][NH:21][CH:22]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO.O>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:18]2[CH:19]=[N:20][NH:21][CH:22]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CSc1nccc(Cl)n1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CSc1nccc(-c2cn[nH]c2)n1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
4-Chloro-2-methylsulfanyl-pyrimidine (1.4 g, 8.8 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 10.3 mmol), Na2CO3 (2.8 g, 26.4) and Pd(PPh3)4 (500 mg, 0.43 mmol) were combined in a solvent comprised of toluene/EtOH/H2O (4/4/1, 20 mL). The mixture was degassed by applying a vacuum and backfilling the headspace with argon. The reaction mixture was heated overnight at 100° C. The insoluble portion was filtered and the filtrate was concentrated and purified by silica gel chromatography to provide 2-(methylthio)-4-(1H-pyrazol-4-yl)pyrimidine (1.2 g, 71% yield). 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=6.4 Hz, 1H), 8.24 (s, 1H), 7.23 (s, 1H), 7.05 (d, J=6.4 Hz, 1H), 2.51 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]([O:15][CH3:16])=[O:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:38][C:39]1[CH:40]=[CH:41][C:42]([NH:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[N:43][CH:44]=1>C(Cl)Cl.O>[CH3:38][C:39]1[CH:40]=[CH:41][C:42]([NH:45][CH:46]2[CH2:51][CH2:50][N:49]([CH2:10][C:9]34[CH2:2][CH:3]5[CH2:12][CH:7]([CH2:6][C:5]([C:13]([O:15][CH3:16])=[O:14])([CH2:4]5)[CH2:11]3)[CH2:8]4)[CH2:48][CH2:47]2)=[N:43][CH:44]=1
Reactant: COC(=O)C12CC3CC(CC(CO)(C3)C1)C2
Reactant: Cc1ccc(NC2CCNCC2)nc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C12CC3CC(CC(CN4CCC(Nc5ccc(C)cn5)CC4)(C3)C1)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
After dissolving methyl 3-hydroxymethyltricyclo[3.3.1.1 3,7]decane-1-carboxylate (0.1648 g, 0.735 mmol) and pyridine (0.0829 g, 1.05 mmol) in methylene chloride (5 mL), trifluoromethanesulfonic anhydride (0.185 mL, 1.11 mmol) was added dropwise while cooling on ice and the mixture was stirred for 1 hour. Water (10 mL) was added to the reaction mixture, and after extraction with ethyl acetate (20 mL), the extract was washed with 1N HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL) in that order and dried over anhydrous magnesium sulfate, and then 4-(5-methylpyridin-2-yl)aminopiperidine (0.2995 g, 1.57 mmol) was mixed therewith and the solvent was distilled off under reduced pressure. The obtained yellow oil was heated at 60° C. for 1 hour. It was then subjected to chromatography (50 g Merck Art. 9385, methylene chloride:methanol:ammonia water=97:3:0.2) to obtain the title compound as a white solid (0.2398 g, 0.603 mmole) (82% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([OH:12])[CH:3]=1.[C:13]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)(N1C=CN=C1)=O.[C:25]1(N)[C:30](F)=C(F)C(F)=C(N)[C:26]=1F.Cl.Cl>O1CCCC1.CCOCC>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:22][CH:23]2[CH:25]3[CH2:30][CH2:13][N:20]([CH2:21][CH2:26]3)[CH2:24]2)=[O:8])=[C:4]([OH:12])[CH:3]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Nc1cc(O)c(C(=O)O)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1cc(O)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A solution of 4-amino-5-chloro-2-hydroxybenzoic acid (5.63 g, 30 mmole) in anhydrous tetrahydrofuran (30 ml) under nitrogen is treated with 1,1'-carbonyldiimidazole (5.03 g, 31 mmole), stirred at room temperature for one hour, and degassed by bubbling nitrogen over 20 minutes. A solution of 3-aminoquinuclidine(1) (from 36 mmole of the dihydrochloride) in anhydrous tetrahydrofuran (20 ml) is added, and the mixture is stirred at room temperature for 18 hours and at 50° C. for one hour. The resultant suspension is diluted with ether (50 ml) and filtered, and the solid is washed with ether. Successive trituration from acetonitrile and warm methanol provides 7.95 g (90%) of product as a pale tan solid, mp 300°-302° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[NH:22][C:23]1[C:28]([C:29]([O:31]CC)=[O:30])=[C:27]([CH3:34])[N:26]=[CH:25][N:24]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[NH:22][C:23]1[C:28]([C:29]([OH:31])=[O:30])=[C:27]([CH3:34])[N:26]=[CH:25][N:24]=1
Reactant: CCOC(=O)c1c(C)ncnc1Nc1cc(OCc2c(OC)ccc(F)c2F)c(OC)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Cl)c(Nc2ncnc(C)c2C(=O)O)cc1OCc1c(OC)ccc(F)c1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A solution of ethyl 4-chloro-6-methylpyrimidine-5-carboxylate (0.3 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.49 g) and N,N-diisopropylethylamine (0.26 mL) in acetonitrile (4.5 mL) was stirred at 130° C. in a reaction vessel equipped with a reflux condenser for 1 day. To the reaction mixture was added water (3 mL), and the resulting mixture was stirred at room temperature for 40 minutes. The insoluble material was collected by filtration. The collected material was washed with water and diethyl ether, and dried under reduced pressure to give ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylate (0.71 g). The obtained ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylate (0.2 g) was dissolved in tetrahydrofuran (1.6 mL)−methanol (1.2 mL). To the solution was added 2 mol/L aqueous sodium hydroxide solution (1.2 mL), and the mixture was stirred at 60° C. for 30 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid (3 mL), and the precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylic acid (0.1 g). To this material were added 1,4-dioxane (4.5 mL), triethylamine (0.12 mL) and diphenylphosphoryl azide (0.071 mL), and the mixture was stirred at room temperature for 1 hour, and then heated at reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=9/1) to give the title compound (0.1 g).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=4)[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1cccc(C2CCNCC2)c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)c1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-methoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 30% overall yield. mp 121-123°. FDMS m/e=381 (M+ of free base). α[D]589=−12.69 (c=0.53, methanol).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Yield: 92.3 %

Procedure:
4-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine (135 mg, 0.4 mmol) was dissolved in 5 ml THF and triethylamine was added (112 μL, 0.8 mmol). Trimethyl acetyl chloride (49.3 μL, 0.4 mmol) was added under stirring and the reaction stirred at room temperature overnight. The reaction mixture was concentrated under nitrogen and dissolved in 5 ml methylene chloride and then washed with water. The organic layer was concentrated and evaluated by LCMS. The mixture was purified by MPLC using a Biotage 40s prepacked silica gel cartridge eluting with 3% methanol in methylene chloride. N-{4-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-2,2-dimethyl-propionamide (156 mg) was isolated in 98.2% purity @ 254 nm; LCMS (APCI): 423 [M+H]+