Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[C:5]([F:19])=[C:6]([F:18])[C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[C:8]=2[CH:17]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH3:21][O:20][CH:3]([O:2][CH3:1])[C:4]1[C:5]([F:19])=[C:6]([F:18])[C:7]2[O:11][N:10]=[C:9]([C:12]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:14])[C:8]=2[CH:17]=1
Reactant: CC(C)N
Reactant: CCOC(=O)c1noc2c(F)c(F)c(C(OC)OC)cc12
Product: COC(OC)c1cc2c(C(=O)NC(C)C)noc2c(F)c1F

Procedure:
Starting materials: ethyl 5-(dimethoxymethyl)-6,7-difluorobenzo[d]isoxazole-3-carboxylate (Intermediate 206) and isopropyl amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)=[CH:15]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:27]=1)=[CH:15]2
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CNc2cc(-c3cc4cc(F)c(F)cc4[nH]3)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
4-Methoxybenzaldehyde (0.204 g, 1.5 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.405 g, 1.48 mmol) in methylene chloride (125 mL), followed by acetic acid (0.3 g, 1.5 mmol). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.31 g, 1.46 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2SO4. The solvent was evaporated to give a yellow oil. Recrystallization from methanol/water gave the product as off-white crystals (270 mg); mp 173-175° C.
Reaction SMILES: Br[C:2]([C:5]([CH3:7])=[O:6])([CH3:4])[CH3:3].[NH:8]1[CH:12]=[CH:11][CH:10]=[N:9]1>>[CH3:3][C:2]([N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1)([C:5](=[O:6])[CH3:7])[CH3:4]
Reactant: c1cn[nH]c1
Reactant: CC(=O)C(C)(C)Br
Product: CC(=O)C(C)(C)n1cccn1
Yield: 70 %

Procedure:
1 mol of methyl bromoisopropyl ketone is added dropwise at 100° C. to a melt of 4 mols of pyrazole. The reaction mixture is stirred for a further hour. Following customary working up, 2-methyl-2-(pyrazol-1-yl)-butan-3one is obtained in a yield of 70%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:59])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:58])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:28][C:27]=3[C:38]3[CH:43]=[C:42]([C:44](=[O:57])[NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=4)[CH:41]=[CH:40][N:39]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:60]OCCNC>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:60])[C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]([CH3:59])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:58])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:28][C:27]=3[C:38]3[CH:43]=[C:42]([C:44](=[O:57])[NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:55])[F:56])[CH:48]=4)[CH:41]=[CH:40][N:39]=3)[CH:19]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: COCCNC(=O)N1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Reactant: CNCCOC
Product: COCCN(C)C(=O)N1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared according to the procedure described for the synthesis of N-(2-methoxyethyl)-4-(2-(methyl(3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzyl)amino)ethyl)piperazine-1-carboxamide Example 208 substituting 2-methoxy-N-methylethanamine in place of 2-methoxyethanamine. LC-MS (ES, m/z): 829 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.31 (s, 1H), 9.56 (t, J=3.6 Hz, 1H), 8.93 (d, J=6 Hz, 1H), 8.31 (d, J=6 Hz, 2H), 8.04 (s, 1H), 7.94 (d, J=9 Hz, 1H), 7.84-7.86 (m, 1H), 7.56-7.71 (m, 7H), 7.30 (d, J=9 Hz, 1H), 4.63 (d, J=3 Hz, 2H), 4.26 (s, 2H), 3.45 (t, J=6.6 Hz, 2H), 3.23-3.32 (m, 16H), 3.17 (s, 1H), 3.00 (s, 4H), 2.80 (s, 3H), 2.63 (s, 3H), 1.60-1.74 (m, 6H).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.CCOC(C)=O>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([C:5]34[CH2:8][CH2:9][C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(N)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCn1c(=O)c2[nH]c(C34CCC(NS(C)(=O)=O)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
To a solution 100 mg of 8-(4-Amino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 20), (0.28 mmol) in 2 ml of pyridine chilled in an ice/water bath was added 22 μL of methanesulfonyl chloride (0.28 mmol), 30% completion after 24 h at 10° C. Two more aliquots (22 μL and 50 μL) of methanesulfonyl chloride were added to drive the reaction to completion. The reaction mixture was concentrated in vacuo to afford a yellow oil which was taken up in EtOAc (10 ml) and washed twice with sat'd NaHCO3 (5 ml), once with 0.5N HCl and once with brine. The organic layer was dried over NaSO4 and conc'd to an oil. Crystallized from acetonitrile to afford 27 mg (22%) as a white solid (MH+=438.08). The following compounds were prepared in an analogous manner:
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][N:7]([CH2:11][CH:12]([OH:21])[CH2:13][C:14](OCC(C)C)=[O:15])C1C(C)C)(=[O:3])[NH2:2]>CN(C)C=O.O>[OH:21][CH:12]1[CH2:11][N:7]([CH2:8][C:9]([NH:5][CH2:4][C:1]([NH2:2])=[O:3])=[O:10])[C:14](=[O:15])[CH2:13]1
Reactant: CC(C)COC(=O)CC(O)CN1CC(=O)N(CC(N)=O)C1C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CNC(=O)CN1CC(O)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
A solution of 11.8 g (34.3 mol) of 2-methylpropyl 3-carbamoylmethyl-Beta-hydroxy-2-(1-methylethyl)-4-oxo-1-imidazolidinebutanoate in 90 ml of dimethylformamide and 10 ml of water was gently refluxed (external temp. 130° C.) for 24 hours. The solvent was evaporated under reduced pressure. The oily residue was taken up with 40 ml of ethanol and stirred at 0° C. for 30 minutes. The precipitate was collected and crystallized from ethanol/isopropanol 1:1 to give 2.5 g of the title compound as a white powder, m.p. 158°-160° C. Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=197 (M+ --H2O), 180. IR spectrum (oil mull): 3420, 3320, 3220, 1680, 1655 and 1630 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([OH:9])[CH:8]=1)[NH2:5].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C>[CH2:23]([O:22][C:20]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:5][C:4]1[CH:3]=[C:2]([OH:1])[CH:8]=[C:7]([OH:9])[CH:6]=1)=[O:21])[CH3:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc(O)cc(O)c1
Solvent: CCO
Product: CCOC(=O)C(=CNc1cc(O)cc(O)c1)C(=O)OCC
Reaction time: 48 h
Yield: 78.1 %

Procedure:
A mixture of 3,5-dihydroxyaniline (2.0 g), 2-ethoxy-1,1-bis(ethoxycarbonyl)ethene (3.0 g) and ethanol (10 ml) was left to stand at room temperature for 2 days. The resulting solid was filtered off, dissolved in dimethylsulphoxide (20 ml) and then treated with water (100 ml). The resulting solid was washed with water, to give 1,1-bis(ethoxycarbonyl)-2-(3,5-dihydroxyphenylamino)ethene (3.2 g), m.p. 190°-192° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:15](I)[CH3:16]>O1CCCC1>[CH2:15]([N:10]1[CH2:11][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]1=[O:12])[CH3:16]
Reactant: O=C1CC(c2ccccc2)CN1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC(c2ccccc2)CC1=O
Yield: 57 %

Procedure:
A mixture of 4-phenyl-pyrrolidin-2-one (24.2 g; 0.15 mole) and sodium hydride (80% oil suspension) (5.4 g; 0.18 mole) in tetrahydrofuran (150 ml) is refluxed for 2.5 hrs. After cooling, ethyl iodide (29 g; 0.185 mole) is added thereto, and the resulting material is refluxed for another 5 hrs. The solvent is then evaporated off; the residue is taken up into chloroform, washed with water, dried and distilled. B.p. (0.2 mm Hg)=124°-126° C. Yield: 57%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH:13][O:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:13]([O:14][CH3:15])[CH3:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-bromophenyl)acetic acid (4.4 g, 20.56 mmol) in N,N-dimethylformamide (125 ml) was successively added N,O-dimethylhydroxyamine (4.5 g, 46.26 mmol), triethylamine (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.9 g, 46.26 mmol) and 1-hydroxybenzotriazole (6.24 g, 46.26 mmol). The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The residue was purified by flash chromatography on silica gel (50% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 258 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([O:36][CH2:37][C:38]([NH:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1)=[O:39])(=[O:35])[CH3:34]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 mmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, acetoxyacetyl chloride (37 mg, 262 mmol, 4 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (19.6 mg, 57% of theory).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>ClCCl>[Cl:11][C:5]1[C:6]([Cl:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:2][NH:1][C:23](=[O:24])[NH:22][CH2:20][CH3:21]
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(Cl)c1Cl
Solvent: ClCCl
Product: CCNC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 192 mg (0.63 mmol) of the compound from Example 40A in 5.7 ml of dichloromethane was admixed at RT with 100 μl (1.26 mmol) of ethyl isocyanate. The reaction mixture was stirred overnight at RT and then freed from the solvent on a rotary evaporator. The residue was taken up in DMSO and purified by preparative HPLC [Method 20]. The product fraction was freed from the solvents on a rotary evaporator. Drying of the residue in an HV gave 173 mg (73% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16]2.Br[CH2:25][C:26]#[N:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH2:25][C:26]#[N:27])[CH:17]=[CH:16]2
Reactant: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(O)ccc2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(OCC#N)ccc2c1
Reaction time: 1.67 h
Yield: 97.3 %

Procedure:
In a similar manner as described in step 1 of Example 4, the title compound was prepared from 6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.45 g, 1.5 mmol), prepared in the previous step, bromoacetonitrile (0.216 g, 1.8 mmol) and cesium carbonate (2.45 g, 7.52 mmol) with the exception that the reaction was complete after 100 minutes at ambient temperature. The crude material was dissolved in methylene chloride and filtered through silica gel (45 g, 200–300 mesh). The solvent was removed under reduced pressure to give {[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile as an off-white solid (0.494 g, 97%), mp 191.5–192.5° C. Elemental Analysis for C23H18N2O Calc'd: C, 81.63; H, 5.36; N, 8.28. Found: C, 81.06; H, 5.14; N, 8.04.
Reaction SMILES: [OH2:1].[ClH:2].Cl.[CH3:4][N:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[CH:6]1[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8][CH2:7]1.CN(C1C=CC=C(C)C=1)C1CCN(CC2C=CC=CC=2)CC1.Cl.Cl.[H][H]>[Pd].CO>[OH2:1].[ClH:2].[ClH:2].[CH3:4][N:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: [H][H]
Reactant: Cc1cccc(N(C)C2CCN(Cc3ccccc3)CC2)c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cccc(N(C)C2CCNCC2)c1
Yield: 60.9 %

Procedure:
A mixture of 9 parts of N-methyl-N-(3-methylphenyl)-1-(phenylmethyl)-4-piperidinamine dihydrochloride hemihydrate and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo and the filtrate was evaporated. The residue Was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, Yielding 1.5 parts (60.9%) of N-methyl-N-(3-methylphenyl)-4-piperidinamine dihydrochloride monohydrate; mp. 209.1° C. (intermediate 97).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[OH-].[Ca+2:13].[OH-].C(#N)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[Ca+2:13].[CH2:22]([O:21][C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O-:11])=[O:10])[CH2:3][CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:22]([O:21][C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O-:11])=[O:10])[CH2:3][CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)CCC1CCNCC1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C([O-])CCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
3-(4-Piperidyl)propionic acid (20.0 g, 0.12 mol) and calcium hydroxide (14.1 g, 0.19 mol) were suspended in 47 g water and 195 g acetonitrile at 15-25° C. and then cooled to 0-10° C. Benzyl chloroformate (23.9 g, 0.14 mol) was added within 30 minutes and the reaction stirred at 0-5° C. for 2 h. The product precipitated during the reaction and was isolated by filtration to afford the title compound in 95% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:24]C(=O)OCC2C=CC=CC=2)[C:18]([C@@:20]2([CH3:23])[CH2:22][O:21]2)=[O:19])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>CO>[OH:41][C:35]([C:37]([F:40])([F:39])[F:38])=[O:36].[NH2:24][C@H:17]([C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(C[C@H](N)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.17 h

Procedure:
Cbz-protected amine 14 (107 mg, 0.23 mmol) was dissolved in MeOH (5 mL) and to this was added TFA (1.2 eq., 0.27 mmol, 21 μL). Argon was bubbled through the solution for 15 minutes, after which Pd black (10 mg) was added and the flask was charged with hydrogen gas. After 10 minutes, TLC analysis indicated complete conversion of starting material and all solids were removed by filtration over CELITE. Toluene (10 mL) was added and the mixture was concentrated under reduced pressure followed by coevaporation with toluene (2×) in order to remove excess TFA. The purity of the deprotected amine (as TFA salt) was confirmed by LC-MS analysis and the compound was subjected to the next step without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].NO.[OH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]2[C:21]=1[C:20](=O)[CH2:19][CH2:18]2>CO.C(OCC)(=O)C>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]2[C:21]=1[C:20](=[N:2][OH:3])[CH2:19][CH2:18]2
Reactant: NO
Reactant: Cc1ccc(O)c2c1CCC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c2c1CCC2=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
28 Grams of hydroxylamine hydrochloride and 56 g of potassium carbonate were added in 400 ml of methanol, and the mixture was refluxed by hetting for 30 minutes. After cooling the reaction mixture to a room temperature, the supernatant liquor was collected by separation to prepare a methanol solution of hydroxylamine. To this methanol solution of hydroxylamine was added 16.2 g of 7-hydroxy-4-methyl-1-indanone and refluxed by heating for 5 hours under stirring condition. The reaction mixture was concentrated to dryness under a reduced pressure. To the residue thus obtained was added 200 ml of ethyl acetate, then the insoluble matter was removed by filtration. The filtrate was concentrated to dryness under a reduced pressure, and the residue was recrystallized from methanol to obtain 17.6 g of 7-hydroxy-4-methyl-1-indanone oxime in the form of colorless needle-like crystals.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2].[Cl:16]N1C(=O)CCC1=O.O>CN(C=O)C>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C(=O)c1csc(NC=O)n1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-(Formylaminothiazol-4-yl)-2-oxoacetate (9.1 g, 39.87 mmol) (obtained from Aldrich, Milwaukee, Wis.) was slurried in 50 mL of anhydrous DMF. N-Chlorosuccinimide (5.6 g, 41.86 mmol) was added as a solid and the suspension was stirred at room temperature. After 18 hours, the reaction mixture was poured into 500 mL of water. The resulting white precipitate was filtered, washed with water and air dried to afford the title intermediate as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:18])[C@@H:6]([NH2:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:3].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:2]([O:4][C:5](=[O:18])[C@@H:6]([NH:17][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
(S)-Ethyl-2-amino-3-(4-nitrophenyl)propionate hydrochloride (1.23 g, 4.47 mmol) was suspended in dichloromethane (25 mL) and to this suspension was added benzoyl chloride (0.628 g, 4.47 mmol) and triethylamine (1.36 g, 13.4 mmol). The mixture was stirred overnight at room temperature under nitrogen. The crude reaction was washed with 5% HCl, water, brine, dried (Na2SO4), concentrated and purified by flash chromatography (silica gel, 2:1 hexanes:EtOAc) to afford the title compound as a white powder (0.865 g, 57%): MS(ES+) m/e 343 [M+H]; mp 99-101° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([C:18](O)=[O:19])=[C:16]([CH:21]([CH3:23])[CH3:22])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([C:18]([Cl:27])=[O:19])=[C:16]([CH:21]([CH3:23])[CH3:22])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)O)n(-c2ccc(F)cc2)c(=O)c2ccccc12
Reactant: O=S(Cl)Cl
Product: CC(C)c1c(C(=O)Cl)n(-c2ccc(F)cc2)c(=O)c2ccccc12

Procedure:
A mixture of 2-(4-fluorophenyl)-4-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (19.9 g) and thionyl chloride (213 ml) was refluxed for 90 minutes. Excess thionyl chloride was removed in vacuo to give crude 2-(4-fluorophenyl)-4-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carbonyl chloride (21 g) in the form of a grey/green solid, m.p. 113°-115° C. [Elemental analysis: C, 66.2; H, 4.49; N, 4.06; Cl, 10.8%; calculated: C, 66.4; H, 4.40; N, 4.07; Cl, 10.3%].
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[C@@H:14]([O:21][CH3:22])[CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][CH2:24][CH3:25]>>[CH2:24]([C:25]1[N:11]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[C@@H:14]([O:21][CH3:22])[CH2:13]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1)[CH3:23]
Reactant: CO[C@H]1C[C@@H](Nc2c(N)cnc3ccsc23)CC[C@@H]1CC#N
Reactant: CCC
Product: CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)[C@@H](OC)C1

Procedure:
This compound was prepared according to the procedure of Example 34, steps 12, using {(1R,2S,4S)-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-2-methoxycyclohexyl}acetonitrile (racemic) and propane, 1,1,1-triethoxy- as the starting material. LCMS calculated for C19H23N4OS (M+H)+: m/z=355.2. Found: 355.1.