Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:51]([NH:53][CH3:54])=[O:52])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH:31]3[C:39]4[C:34](=[CH:35][C:36](CCCO[Si](C(C)(C)C)(C)C)=[CH:37][CH:38]=4)[CH2:33][CH2:32]3)S(C3C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=3)(=O)=O)[CH:9]=2)=[CH:6][N:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.C(N)(C)C.[CH2:80]1C[O:83][CH2:82][CH2:81]1>>[NH2:1][C:2]1[C:3]([C:51]([NH:53][CH3:54])=[O:52])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([CH2:80][CH2:81][CH2:82][OH:83])[CH:38]=4)[CH2:33][CH2:32]3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: C1CCOC1
Reactant: CNC(=O)c1nc(-c2cccc(CN(C3CCc4cc(CCCO[Si](C)(C)C(C)(C)C)ccc43)S(=O)(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)cnc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(C)N
Solvent: ClCCl
Product: CNC(=O)c1nc(-c2cccc(CNC3CCc4ccc(CCCO)cc43)c2)cnc1N
Reaction time: 0.5 h
Yield: 33 %

Procedure:
3-Amino-6-[3-({[5-(3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-2,3-dihydro-1H-inden-1-yl][(3,5-dinitrophenyl)sulfonyl]amino}methyl)phenyl]-N-methyl pyrazine-2-carboxamide (600 mg, 0.77 mmol) was dissolved in THF and refluxed for an hour in the presence of tetrabutylammonium fluoride in THBF. The reaction mixture was partitioned with water and extracted with ethyl acetate (10 mL×3) and dried over MgSO4. Filteration and concentration under vacuum gave tan oil, which was subjected to the solution of dichloromethane and isopropylamine. After being stirred for 30 min, the solvent was removed in vacuo and purified by flash column chromatography to give the 3-amino-6-[3-({[6-(3-hydroxypropyl)-2,3-dihydro-1H-inden-1-yl]amino}methyl)phenyl]N-methylpyrazine-2-carboxamide (110 mg, 33% yield): 1H NMR (400 MHz, CD3OD): δ 8.59 (s, 1H), 8.06 (bs, 1H), 7.91 (s, 1H), 7.52 (m, 1H), 7.40 (m, 2H), 7.11 (d, 1H), 7.08 (s, 1H), 7.03 (d, 1H), 4.32 (d, 1H), 3.66 (t, 2H), 3.02 (d, 3H), 2.99 (m, 1H), 2.81 (m, 1H), 2.69 (t, 2H), 2.44 (m, 1H), 1.90 (m, 4H), 1.32 (m, 3H), 0.82 (m, 2H); MS (EI) for C25H29N5O2: 432.23 (MH+).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:27][C:28]1[CH:33]=CC=C[CH:29]=1)[C@H:15](OS(C)(=O)=O)/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(OC(N[C@@H](CC(C)C)[C@H](OS(C)(=O)=O)/C=C/C(OC)=O)=O)(C)(C)C>>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:27][CH:28]([CH3:29])[CH3:33])/[CH:15]=[CH:16]/[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH:1]([CH3:3])[CH3:2])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(C)[Mg]Cl
Agent: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Product: COC(=O)[C@@H](/C=C/[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)C

Procedure:
Using the procedure of Example 8 but replacing benzylmagnesium chloride with isopropylmagnesium chloride and replacing the resultant compound of Example 7 with the resultant compound of Example 33 provided the desired compound.
Reaction SMILES: [C:1]([C:9]1[CH:21]=[CH:20][C:12]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])(O)=O.[Na+].CI>CN(C=O)C>[CH3:22][N:13]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]1[CH:20]=[CH:21][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1
Reactant: O=C([O-])O
Reactant: O=C(O)CCCNc1ccc(C(=O)c2ccccc2)cc1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(CCCC(=O)O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1.41 g (0.05 mole) of 4-(4-benzoylanilino)butyric acid are dissolved in 15 ml of DMF, and 0.84 g of NaHCO3 (0.01 mole) and 1.42 g (0.01 mole) of methyl iodide are added, and the mixture is stirred at 80° C. for about 3 h. It is then poured onto ice-water, the mixture is extracted with ethyl acetate, the organic phase is dried with MgSO4, and the solvent is evaporated off in vacuo. The residue is chromatographed on silica gel using n-hexane/ethyl acetate as eluent. The oily product is immediately hydrolyzed with 2 N LiOH. The title compound is obtained and has the melting point 111°-113° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC[C@H](C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC[C@H](C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1-methyl-2-(methyloxy)ethyl]-3-pyridinecarboxamide (Intermediate 13, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1-methyl-2-(methyloxy)ethyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH2:11][NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:18](Cl)([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19]>CO.C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH2:11][N:12]([CH:13]([CH2:14][OH:15])[CH2:16][OH:17])[C:18](=[O:19])[O:20][CH2:21][CH:22]3[C:34]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:28]4[C:23]3=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ncnc2c(CNC(CO)CO)c[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ncnc2c(CN(C(=O)OCC3c4ccccc4-c4ccccc43)C(CO)CO)c[nH]c12
Reaction time: 0.25 h
Yield: 23.6 %

Procedure:
Amine 6 (330 mg, 1.4 mmol) was suspended in methanol (35 mL) and 10% aqueous NaHCO3 (3.5 mL). Fmoc chloride (432 mg, 1.7 mmol) was added and the solution stirred for 15 min. The suspension was concentrated under reduced pressure. Chromatography of the residue on a column of silica gel eluted with 7.5-20% methanol in dichloromethane gave the title compound 7 (150 mg, 0.33 mmol, 48% allowing for recovered starting material). Subsequent elution with 50% methanolic ammonia (3.5M) in dichloromethane returned the starting amine 6 (170 mg, 51%). 7, colourless amorphous solid, ESI-MS+, found 460.1975, calc. for C25H26N5O5 [M+H]+ 460.1985.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH2:18][CH3:19])([CH3:17])[C:13]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:30]1(=[O:36])[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1>>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([C:13]2[C:14]([CH2:18][CH3:19])([CH3:17])[C:15](=[O:16])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:34]4[C:30](=[O:36])[CH2:31][CH2:32][C:33]4=[O:35])[CH2:10][CH2:9]3)[N:12]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: CCC1(C)C(=O)N(C2CCN(C(=O)CCl)CC2)N=C1c1ccc(OC)c(OC)c1
Reactant: O=C1CCC(=O)N1
Product: CCC1(C)C(=O)N(C2CCN(C(=O)CN3C(=O)CCC3=O)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2,4-dihydro-3H-pyrazol-3-one (compound A9) and succinimide as starting compounds.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[C:11]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:38])=[C:24]([NH:26][C:27](=[O:37])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[NH2:36])[CH:25]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)C>C(O)(=O)C>[C:11]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:38])=[C:24]([N:26]2[C:27](=[O:37])[C:28]3[C:29](=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[N:36]=[CH:1]2)[CH:25]=1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3)ccc2Cl)c(N)c1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(=O)n(-c3cc(NC(=O)c4ccccc4)ccc3Cl)cnc2c1

Procedure:
Triethyl orthoformate (0.189 ml) was added to a stirred mixture of N-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide (0.15 g), ethanol (10 ml) and glacial acetic acid (0.022 ml) and the resultant mixture was heated to 70° C. for 16 hours. The mixture was evaporated. The residue was partitioned between methylene chloride and a saturated aqueous solution of sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated and the residue was triturated under a mixture of ethyl acetate and diethyl ether. The material so obtained was further purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound (0.054 g); NMR Spectrum: (DMSOd6) 3.92 (s, 3H), 7.12-7.22 (m, 2H), 7.48-7.6 (m, 3H), 7.68 (d, 1H), 7.88-8.0 (m, 3H), 8.04-8.12 (m, 2H), 8.28 (m, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 406 and 408.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]5[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=5)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60](O)(=[O:62])[CH3:61]>CN(C=O)C>[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]5[CH2:22][CH2:23][N:24]([C:60](=[O:62])[CH3:61])[CH2:25][CH:26]=5)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: CC(=O)O
Reactant: C1=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CC1
Reaction time: 0.5 h

Procedure:
(1H-Indazol-5-yl)-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine hydrochloride (60 mg, 0.137 mmol), HATU (63 mg, 0.164 mmol) and Hunigs base (100 μL, 0.576 mmol) were combined in DMF (4 mL) and stirred for 30 min. Acetic acid (8 μL, 0.168 mmol) was added and the solution was stirred overnight. Another portion of acetic acid (8 μL, 0.168 mmol) was added and the stirred for a further 4 h. The DMF was removed in vacuo and the residue was loaded onto silica. Purification on silica by elution with dichloromethane:methanol (95:5) yielded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.03 & 2.07 (2s, rotamers, 3H), 2.44 & 2.53 (2s, rotamers, 2H), 3.62-3.67 (m, 2H), 4.11 & 4.18 (2s, rotamers, 2H), 6.39 (s, 1H), 6.72 & 6.76 (2s, rotamers, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 8.24 (s, 1H), 8.33 (brs, 1H), 9.35 (brs, 1H), 11.90 (brs, 1H). MS (ES+): m/z 374.5 (100) [MH+].
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=O.C(NC(C)C)(C)C.C([Li])CCC.[O:35]1CC[CH2:37][CH2:36]1>CCCCCC.C(N=CC)(C)(C)C>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:37][CH:36]=[O:35])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: CC=NC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=CC=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1

Procedure:
The compound was prepared according to the procedure described in Example 84. The following reagents were used: 3,3'-bis(trifluoromethyl)benzophenone (31.8 g), diisopropylamine (32.2 mL), 1.6M n-butyl lithium in hexane (144 mL), acetaldehyde N-tert-butylimine (14.75 mL) diethyl chlorophosphonate (16.6 mL) and tetrahydrofurane (200 mL). After the usual work up, the product was purified by HPLC to give 30,8 g of 3,3-bis[3-(trifluoromethyl)phenyl]-2-propenal as an oil.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:25][C:24]([C:22]1[CH:21]=[N:20][CH:19]=[C:18]([C:14]2[CH:15]=[N:16][C:17]3[NH:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:23]=1)([CH3:26])[C:27]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:29]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(C(C)(C)C(=O)O)c3)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)N1CCOCC1)c1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.3 %

Procedure:
To a suspension 6-[5-(1-carboxy-1-methyl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (50 mg, 0.13 mmol) in DMF (1 mL) is added HATU (57 mg, 0.15 mmol), morpholine (11 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.81 mmol). The mixture is stirred at room temperature for 16 h. The reaction mixture is purified by reverse phase HPLC (mobile phase contains 1% TFA) to afford 53 mg of 2-methyl-1-morpholin-4-yl-2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-n2cccc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 100 °C
Yield: 79.2 %

Procedure:
A 2-L three-necked flask equipped with a stirrer, a thermometer, a condenser tube and a nitrogen inlet tube was charged with 134.6 g (0.500 mol) of 2,5-dichloro-4′-fluorobenzophenone, 50.3 g (0.750 mol) of pyrrole, 76.0 g (0.550 mol) of potassium carbonate and 840 ml of dehydrated N,N′-dimethylacetamide. The reaction solution was heated under a nitrogen atmosphere in an oil bath at 100° C. for 3 hours. After thin layer chromatography confirmed that the materials showed no peaks, the reaction liquid was allowed to cool to room temperature. The reaction liquid was slowly added to 3 L of water, and the product was precipitated. The liquid was then filtered. The product obtained by the filtration was dissolved in 2.5 L of toluene. The solution was washed with salt solution using a separating funnel until the water phase became neutral. The organic phase was dried over magnesium sulfate, and the solvent was evaporated with an evaporator. A crude product weighing 133.3 g was obtained. The crude product was subjected to recrystallization using a hexane/ethyl acetate mixed solvent, and the resultant crystal was isolated. As a result, 125.3 g (0.396 mol) of an objective purified product was obtained with a yield of 79.3%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][N:20]4[C:24](=[O:25])[C:23]5=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]5[C:21]4=[O:30])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(c2nsc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.72 g, 0.03 mole) and N-(2-bromoethyl)phthalimide (6.35 g, 0.025 mole) in 200 ml of acetonitrile is heated at reflux for 4 hours. The solids are then removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography over silica gel to provide N-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimide.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](N[C@H]1CCNC1)c1cccc2ccccc12
Reactant: Brc1ncccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H](N[C@H]1CCN(c2ncccn2)C1)c1cccc2ccccc12
Yield: 70.4 %

Procedure:
To a suspension of 156.6 mg of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride in 5 ml of dioxane were added 87.4 mg of 2-bromopyrimidine and 207 mg of diisopropylethylamine, and the mixture was stirred under reflux for 16 hours. The reaction mixture was evaporated, and to the residue were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2→0:1) to obtain 112 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine. (2) In 10 ml of ethyl acetate was dissolved 112 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine, and 1 ml of a solution of 4M hydrochloric acid in ethyl acetate was added to the mixture and the resulting mixture was stirred. The reaction mixture was concentrated under reduced pressure, to the residue was added diethyl ether, precipitates were collected by filtration and washed with ethyl acetate, to obtain 68.3 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine dihydrochloride (the following Table A2, Example 2.010).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].[N+](=[CH2:21])=[N-]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([C:7]1[C:12]([C:13]([O:15][CH3:21])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(Cl)c1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccnc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Chlorobenzoyl)-3-carboxypyridine was dissolved in a solution of 10% methanol and methylene chloride. Diazomethane was added and the solution was stirred for 1 hour at room temperature. The solution was extracted with methylene chloride followed by methylene chloride +1% methanol The desired product was combined from recrystallization (ethyl ether/hexane) and from the filtrate to yield 1.23 g of 2-(3-chlorobenzoyl)-3-methoxycarbonyl-pyridine.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3]O.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[OH-].[Na+]>>[C:8]1([S:14][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Sc1ccccc1
Reactant: N[C@@H](CO)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](CSc1ccccc1)C(=O)O
Temperature: 35 °C
Reaction time: 15 h

Procedure:
To 500 g of an aqueous solution containing 3% of L-serine, 3.1% of thiophenol and 25 ppm of pyridoxal phosphate and having a pH of 10.5 (adjusted with NaOH), the cells were added to a concentration of 0.7% as calculated based on dry cells. The resultant mixture was stirred at 35° C. for 15 hours under a nitrogen gas atmosphere. The molar yield of S-phenyl-L-cysteine so formed was 70% based on the charged L-serine.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(OCC)=O)C.[Si:22]([O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>C1COCC1>[Si:22]([O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1/[CH:32]=[CH:11]/[C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CCOP(=O)(CC(=O)CCCCC(=O)OC)OCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCC(=O)/C=C/c1ccccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.26 g (10.87 mmol) of sodium hydride was added to a solution of 3.20 g (10.87 mmol) of methyl 7-(diethoxyphosphoryl)-6-oxoheptanoate from Ex. XIIb in 53 ml of THF. The mixture was stirred at room temperature for 30 min, a solution of 9.06 mmol of 2-{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde from Ex. XIIa in 20 ml of THF was added and the mixture was stirred at room temperature for 18 h. Water was added, the mixture was extracted with ethyl acetate, the combined organic phases were dried over Na2SO4 and the solvent was removed. The product was purified chromatographically (silica gel, cyclohexane/EA 10:1). This gave 2.51 g (67.8%) of a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C[CH2:11][O:12]CC>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:8][CH3:9])[CH:11]=[O:12]
Reactant: COc1ccccc1F
Reactant: CCOCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)cc1F
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a solution of o-fluoroanisole, 101 g (0.80 mol) in 500 ml dry methylene chloride is added dropwise over 30 minutes a solution of titanium tetrachloride, 182 g (0.96 mol, 1.2 equiv.) and α,α-dichloromethylmethyl ether, 110 g (0.96 mol) in an equal volume of methylene chloride. The temperature is maintained at 10-20° C. with an ice-bath. The mixture is stirred at room temperature for 1 hour longer and then poured over crushed ice-water with stirring. Ether (1) is added, and the mixture stirred under nitrogen until solution occurs. The organic layer is extracted with water (3×), sodium bicarbonate solution (3×) and dried (MgSO4). The solvent is evaporated off at 30° C. to give crude product as an oil. The oil is vacuum distilled through a jacketed Vigreux column when it gives 3-fluoro-4-methoxybenzaldehyde, B.P. 120-121° C., at 10 mm Hg; Rf 0.6 on a silica-gel G plate with methylene chloride.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10](O)[CH:9]=[N:8]2)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O.O>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([Cl:18])[CH:9]=[N:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2nc(O)cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc2nc(Cl)cnc2c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 250 mg (1.236 mmol) of 6-tert-Butyl-quinoxalin-2-ol in 1.07 mL (11.43 mmol) phosphorus oxychloride under nitrogen was heated at 110° C. for 3 h. The solution was cooled to room temperature and added drop wise to water (10-15° C.). Ethyl acetate was added. The aqueous layer was extracted with ethylacetate. The combined organic phases were washed with water, dried over Na2SO4 and concentrated. The crude compound was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 219 mg (80.3%) of the title compound as a green solid. MS(m/e): 220 (M+H+).