Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][C:28]#[N:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCCl>[CH2:15]([N:22]1[C:26]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:25][CH:24]=[C:23]1[CH2:27][C:28]#[N:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#CCc1cccn1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: N#CCc1ccc(C(=O)c2ccc(Cl)cc2)n1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 8.43 ml. (0.0663 mole) of p-chlorobenzoyl chloride and 8.8 g. (0.0663 mole) of aluminum chloride in 100 ml. of 1,2-dichloroethane is added to a solution of 13.0 g. (0.0663 mole) of 1-benzylpyrrole-2-acetonitrile in 50 ml. of 1,2-dichloroethane at 5° C. over a 5 minute period. The mixture is stirred for 15 minutes, and then heated quickly to reflux for 3 minutes. The reaction mixture is poured into ice-hydrochloric acid and then filtered. The aqueous layer is separated and washed with chloroform. The combined organic solutions are washed successively with N,N-dimethylaminopropylamine solution, dilute hydrochloric acid, and brine and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the oily residue dissolved in benzene-methylcyclohexane and seeded with crystals of 1-benzyl-4-(p-chlorobenzoyl)-pyrrole-2-acetonitrile. After crystallization of the latter substance is complete, the mother liquor is filtered and evaporated and the residue crystallized from methanol. The crystals thus obtained are recrystallized from methanol to give l-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile as a yellow solid, m.p. 104-106° C.
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.C(=O)([O-])O.[Na+].[CH3:15][O:16][CH2:17][CH2:18][OH:19]>>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([O:19][CH2:18][CH2:17][O:16][CH3:15])=[N:4][CH:5]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COCCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Product: COCCOc1ccc(Br)cn1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
1.1 g sodium and 2.5 g 2,5-dibromo-pyridine are added to 50 ml 2-methoxy-ethanol. The reaction mixture is heated to 90° C. and stirred for a further 2.5 hrs, then poured onto 75 ml of a saturated sodiumhydrogen carbonate solution and extracted three times with methylenchloride. The organic phases are combined, dried over sodium sulphate and concentrated and the residue is destilled. 2.2 g 5-Bromo-2-(2-methoxy-ethoxy)-pyridine are obtained., bp. 135° C./0.1 mbar MS (EI): 231 (M).
Reaction SMILES: [NH2:1][C@H](C(O)=O)C.C([O-])=O.[Na+].OP([O-])([O-])=O.[Na+].[Na+].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.[CH2:78]([O:85][C@@H:86]1[C:91](=O)[CH2:90][CH2:89][O:88][CH2:87]1)[C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH2:78]([O:85][C@@H:86]1[C@@H:91]([NH2:1])[CH2:90][CH2:89][O:88][CH2:87]1)[C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1
Reactant: O=C1CCOC[C@@H]1OCc1ccccc1
Reactant: C[C@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: Cl
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Solvent: CCOC(C)=O
Solvent: O
Product: N[C@H]1CCOC[C@@H]1OCc1ccccc1
Reaction time: 15 h

Procedure:
To a solution of L-Alanine (200 g, 2.24 mol), sodium formate (76.0 g, 1.12 mmol), and sodium phosphate dibasic (28.7 g, 202 mmol) in 2.25 L of water adjusted to pH 7.5 was added NAD (2.2 g, 3.21 mmol), pyridoxal-5-phosphate (2.2 g, 8.90 mmol), LDH (0.45 g, 0.22 mol), FDH (4.5 g, 0.20 mol), and TA P1G5 (4.5 g, 0.22 mol). After all the components were completely dissolved, (3S)-3-(benzyloxy)tetrahydro-4H-pyran-4-one (45 g, 0.22 mol) was added and the pH was adjusted to pH 7.25 with 6 N HCl and aged at 30° C. After 15 hours, potassium carbonate (700 g, 5.06 mol) was added slowly, followed by ethyl acetate (2.2 L). The mixture was filtered through a bed of Solka Floc and the cake was washed with ethyl acetate (250 mL). The combined filtrates were separated and the aqueous layer was extracted a second time with ethyl acetate (2 L). The combined organic extracts were concentrated in vacuo to provide crude (3R,4S)-3-(benzyloxy)tetrahydro-2H-pyran-4-amine.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][N:7]([CH2:26][C:27]1[N:28]=[C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]2[CH:39]=1)[C:8]([C:10]1[NH:11][CH:12]=[C:13]([C:15](=[O:25])[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])[CH:14]=1)=[O:9].CC#N.O>CS(O)(=O)=O>[F:22][C:21]1[CH:20]=[C:19]([F:23])[CH:18]=[C:17]([F:24])[C:16]=1[C:15]([C:13]1[C:14]2[CH:2]=[CH:6][N:7]([CH2:26][C:27]3[N:28]=[C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:32]=[CH:31][N:30]4[CH:39]=3)[C:8](=[O:9])[C:10]=2[NH:11][CH:12]=1)=[O:25]
Reactant: O=C(c1c[nH]c(C(=O)N(Cc2cn3ccc(C(F)(F)F)cc3n2)CC2OCCO2)c1)c1c(F)cc(F)cc1F
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: O
Product: O=C(c1c(F)cc(F)cc1F)c1c[nH]c2c(=O)n(Cc3cn4ccc(C(F)(F)F)cc4n3)ccc12
Temperature: 85 °C
Yield: 62.6 %

Procedure:
The product from Step B (744 mg, 1.40 mmol) was dissolved in methanesulfonic acid (6.0 mL) and heated to 85° C. for 50 min. After cooling in an ice-water bath, the reaction mixture was taken up in 2:3 MeCN—H2O (10 mL) and purified by reverse phase HPLC (C-18 column) to give the title compound (430 mg). LC/MS: m/z 491(M+H). 1H-NMR (d6-DMSO, 500 MHz): δ 5.40 (s, 2H), 6.96 (d, 1H), 7.20 (dd, 1H), 7.33 (t, 2H), 7.57 (d, 1H), 7.88 (d, 1H), 8.01 (s, 1H), 8.03 (s, 1H), 8.71 (d, 1H), 13.09 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:22]([O:34][CH3:35])=[CH:23][C:24]2[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=2[CH:33]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:22]([O:34][CH3:35])=[CH:23][C:24]3[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)N(C)C(=O)OCC3)ncc1Cl
Yield: 26 %

Procedure:
In and analogous manner to Example 1503, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as a yellow powder (25 mg, 26%). mp: 235-237° C., MS (ESI+): 483 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.06 (s, 1H), 8.64 (d, J=8 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.53 (d, 2H), 7.46 (t, J=8 Hz, 1H), 7.11 (t, J=7 Hz, 1H), 6.70 (s, 1H), 6.23 (br s, 1H), 4.47 (t, J=6 Hz, 2H), 3.93 (s, 3H), 3.41 (s, 3H), 3.06 (d, J=5 Hz, 3H), 2.85 (t, J=6 Hz, 2H).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:32]=[CH:31][C:19]4[N:20]=[C:21]([NH:23][C@@H:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]5[OH:30])[S:22][C:18]=4[CH:17]=3)[C:11]=2[CH:33]=1)(C)C.C[Si](C#CC1C=CC2N(CC3C=CC4N=C(N[C@@H]5CCCC[C@H]5O)SC=4C=3)C=NC=2C=1)(C)C>>[C:6]([C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:32]=[CH:31][C:19]4[N:20]=[C:21]([NH:23][C@@H:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]5[OH:30])[S:22][C:18]=4[CH:17]=3)[C:11]=2[CH:33]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2c1
Agent: C[Si](C)(C)C#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Product: C#Cc1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2c1

Procedure:
(1R,2R)-2-((6-((6-Ethynyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol was synthesized as a powder (7 mg, 18%) using a procedure analogous to that described in Step 2 of Example 121, substituting (1R,2R)-2-((6-((6-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from the previous step for (1R,2R)-2-((6-((5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol used in Example 121. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.74 (s, 1H), 7.60-7.68 (m, 2H), 7.16-7.34 (m, 3H), 5.48 (s, 2H), 4.80 (d, J=4.0 Hz, 1H), 4.10 (s, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.56-1.67 (m, 2H), 1.11-1.34 (m, 4H); LCMS (ESI) m/z 405 (M+H)+.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH2:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15]([CH3:20])=[CH:14][C:13]=2[O:12]1>>[CH3:20][C:15]1[CH:14]=[C:13]2[O:12][CH2:11][O:19][C:18]2=[CH:17][C:16]=1[CH:4]=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1ccc2c(c1)OCO2
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(cc1C=O)OCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
To DMF (6.5 ml, 83 mmoles) at 0° C. was added phosphorus oxychloride (3.9 ml, 42 mmoles). The solution was stirred 15 minutes at 0° C. followed by the addition of 3,4-(methylenedioxy)toluene (1.0 ml, 8.3 mmoles). The solution was heated to 110° C. upon which it became dark brown. 1.5 hours later the thick dark brown mixture was cooled to ambient temperature then added to ice (100 ml), and extracted with ether (100 ml). The organic layer was dried (MgSO4), filtered and concentrated. Flash chromatography (5% EtOAc/hexanes) provided 0.15 g (11%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15]F.[F-].[Na+]>C(#N)C.ClC(Cl)(Cl)C(F)(F)F>[C:1]1([CH:7]([F:15])[C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Reactant: FF
Agent: [F-]
Agent: [Na+]
Solvent: CC#N
Solvent: FC(F)(F)C(Cl)(Cl)Cl
Product: CCOC(=O)C(=O)C(F)c1ccccc1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
Ethyl 3-phenylpyruvate (10 g; 0.052 mol) is dissolved in a mixture of acetonitrile (60 g) and trichlorotrifluoroethane (410 g), and the resulting solution is cooled to -10° C. Then, fluorine gas (0.067 mol) diluted with nitrogen to 10% concentration is introduced therein over a period of 2.5 hours while stirring vigorously. After addition of sodium fluoride (2 g), the solvent is distilled off under reduced pressure, and the residue is rectified to give ethyl 3-phenyl-3-fluoropyruvate (4.37 g). Boiling point, 90°-95° C./1 mmHg.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 2-benzyloxy-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol (Enantiomer A) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Cl:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.O>CCCCCC.C(OCC)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=2)[OH:18])=[CH:25][CH:26]=1
Reactant: Cn1ccnc1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: Cn1ccnc1C(O)(c1ccccc1)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A solution of 25.5 g (0.08 mol) of 20% butyl lithium in n-hexane in 50 ml. of anhydrous diethyl ether was added at room temperature to a solution of 5 g (0.06 mol) of 1-methylimidazole in 50 ml. of anhydrous diethyl ether. The reaction mixture was stirred for one hour and then a solution of 15.6 g (0.07 mol) of 4-chlorobenzophenone in diethyl ether was added dropwise. The reaction mixture was stirred for 3 hours and it was then poured into a mixture of ice and water. The solid matter was filtered off and crystallised from ethanol. α-(p-Chlorophenyl)-1-methyl-α-phenylimidazole-2-methanol was obtained. Melting point 185°-186° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][O:11][CH2:12][C:13]1([N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[CH3:10][O:11][CH2:12][C:13]1([N:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:18][CH2:17][N:16]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15][CH2:14]1
Reactant: BrCCc1ccccc1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2ccccc2)CC1

Procedure:
A mixture of 3.1 parts of 2-bromoethylbenzene, 4.1 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, 0.1 parts of potassium iodide. 2.4 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours. The reaction mixture is poured onto water and the whole is shaken thoroughly. The organic phase is separated, washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on triturating in n-hexane. The product is filtered off and dried, yielding N-[4-(methoxymethyl)-1-(2-phenylethyl)-4-piperidinyl]-N-phenylpropanamide; mp. 85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:11]2[NH:12][C:13]([C:15]([O:17]C)=[O:16])=[CH:14][C:10]=2[CH2:9][CH2:8]1.[OH-].[Li+].CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:11]2[NH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:10]=2[CH2:9][CH2:8]1
Reactant: COC(=O)c1cc2c([nH]1)C(Cc1cccc(OC)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(CC2CCc3cc(C(=O)O)[nH]c32)c1

Procedure:
The title compound was synthesized from methyl 6-(3-methoxybenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (127 mg, 0.45 mmol) and lithium hydroxide (188 mg, 4.50 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 80 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.10-2.21 (m, 1H) 2.53-2.76 (m, 4H) 2.91-2.99 (m, 1H) 3.34-3.44 (m, 1H) 3.82 (s, 3H) 6.72-6.77 (m, 2H) 6.78-6.86 (m, 2H) 7.24-7.31 (m, 2H) 8.28 (br. s., 1H). LCMS m/e 272 (M+H). Purity>99% (HPLC).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][Si](C(C)(C)C)(C)C)[CH:12]=2)[S:6]1(=[O:26])=[O:25])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[S:6]1(=[O:25])=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C=C(c2cccc(O[Si](C)(C)C(C)(C)C)c2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)N1C(=O)C=C(c2cccc(O)c2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
A solution of 4.08-A (1.39 g, 3.5 mmol) in tetrahydrofuran (14 mL) at 0° C. was treated with tetra-n-butylammonium fluoride (1.1 g, 4.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 30 min and diluted with ethyl acetate (150 mL) and washed with 0.1 N HCl (100 mL) and brine (50 mL). The organic layer was dried with Na2SO4, filtered, and concentrated to give a crude residue which was purified using flash column chromatography (100% hexane to 30% ethyl acetate/hexane) to yield 4.08-B as a white solid (0.95 g, 96%). 1H NMR (500 MHz, CDCl3): δ 7.39 (dd, J=7.8, 7.8 Hz, 1H), 7.34–7.32 (m, 1H), 7.26–7.24 (m, 1H), 7.05–7.02 (m, 1H), 6.63 (s, 1H), 5.3 (br s, 1H), 1.73 (s, 9H); LCMS found for C13H16NO4S (M+H)+: m/z=282.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylate (150 mg, 0.28 mmol) from Example 76 in methanol (3 mL) was added 5N sodium hydroxide (0.170 mL, 0.84 mmol). The reaction was stirred at rt for 20 h and then at 40° C. for 2 h. The reaction was diluted with water, acidified with 2N hydrochloric acid, and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield crude 2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylic acid. HPLC/MS: 520 (M+1), 522 (M+3); Rt=4.61 min.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][N:8]2[C:17]3[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[N:16]=3)[CH:11]=[CH:10][C:9]2=[O:20])C(=O)C2=CC=CC=C12.NN.[ClH:29].C(NN)(=O)C1C(=CC=CC=1)C(NN)=O>C(O)C.O>[ClH:29].[NH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[N:16]=2)[CH:11]=[CH:10][C:9]1=[O:20]
Reactant: Cc1cc(C)c2ccc(=O)n(CCN3C(=O)c4ccccc4C3=O)c2n1
Agent: Cl
Agent: NN
Agent: NNC(=O)c1ccccc1C(=O)NN
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2ccc(=O)n(CCN)c2n1

Procedure:
A mixture of 1-(2-phthalimidoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one (5.2 gm., 0.015 mole) and 95% hydrazine (1.8 ml., 0.053 mole) in absolute ethanol (50 ml.) is refluxed for one hour. The reaction is cooled, water (37.8 ml.) and concentrated hydrochloric acid (37.5 ml.) are added. After refluxing for one half hour, the mixture is cooled in an ice bath and phthalhydrazide (2.85 gm., 0.0125 mole) is filtered off. The filtrate is concentrated and the residue is dissolved in water, made basic with saturated sodium carbonate and extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated. The residue containing the free base of the title compound is dissolved in a minimum amount of methanol and treated with ethereal hydrogen chloride. Recrystallization of the product from isopropanol gives 1-(2-aminoethyl)-5,7-dimethyl-1,8-naphthyridine-2(1H)-one hydrochloride melting at 253.5-254.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](Cl)[N:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2].C(OC(C1C=CN2N=CC=C2N=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)n2nc(-c3ccccc3)cc2n1
Agent: CCOC(=O)c1ccn2nccc2n1
Product: CCOC(=O)c1ccn2nc(-c3ccccc3)cc2n1

Procedure:
This compound was synthesized from 2-phenyl-7-chloro-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester, according to the process for synthesizing the foregoing pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester. mp: 180-181° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[S:9][C:10]([CH2:13][NH:14]C(=O)C)=[CH:11][CH:12]=2)[N:7]=1.S(=O)(=O)(O)O>O>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[S:9][C:10]([CH2:13][NH2:14])=[CH:11][CH:12]=2)[N:7]=1
Reactant: CC(=O)NCc1ccc(-c2csc(N)n2)s1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: NCc1ccc(-c2csc(N)n2)s1
Reaction time: 12 h

Procedure:
To a suspension of 38.2 g of 2-amino-4-(5-acetylaminomethyl-2-thienyl)thiazole hydrochloride in 400 ml of water is added 56 g of concentrated sulfuric acid, and the mixture is stirred for 12 hours on a boiling water bath. The resulting mixture is cooled and the precipitated crystals are collected by filtration. A suspension of the crystals in 1 liter of water is made alkaline with potassium hydroxide and precipitated crystals are collected by filtration to give 28 g of crude crystals. The crude crystals are recrystallized from methanol to give 2-amino-4-(5-aminomethyl-2-thienyl)thiazole, melting at 189° C. with decomposition.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:5][CH2:4]1)[CH3:2].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]2[C:35]3[N:34]=[CH:33][CH:32]=[N:31][C:30]=3[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=2)=[CH:18][N:17]=1.C1C2C(=CC=CC=2)C(B(O)O)=CN=1>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[C:11]([NH:12][C:36]([C:29]3[C:30]4[N:31]=[CH:32][CH:33]=[N:34][C:35]=4[C:26]([C:19]4[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:16]=[N:17][CH:18]=4)=[CH:27][CH:28]=3)=[O:37])[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: O=C(O)c1ccc(-c2cncc3ccccc23)c2nccnc12
Reactant: CCN1CCN(c2cccc(N)c2)CC1
Agent: OB(O)c1cncc2ccccc12
Product: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 3-(4-ethylpiperazin-1-yl)-aniline (Step 2.1) and 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid. The latter compound was synthesized as described in Steps 1.2-1.7 but using 4-isoquinolineboronic acid in Step 1.4. Title compound: ESI-MS: 489.2 [M+H]+; tR=11.28 min (System 2).
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:18][CH:19]([CH3:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH:19]([CH3:23])[C:20]([NH:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][OH:10])=[O:21]
Reactant: CC(Cl)C(=O)Cl
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)C(=O)N[C@@H](CO)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of (R)-2-phenylglycinol (1.00 g, 7.3 mmol) and triethylamine (1.02 mL, 7.3 mmol) in CH2Cl2 (50 mL) at 0° C. was slowly added 2-chloropropionyl chloride (0.72 mL, 7.3 mmol). After 20 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=228 (M+1).