Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([S:31][CH2:32][C:33]3[N:34]=[C:35]([C:38]4[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=4)[S:36][CH:37]=3)[N:26]=[C:25]([N:45]3[CH2:48][CH2:47][CH2:46]3)[C:24]=2[C:49]#[N:50])=[CH:19][CH:18]=1)=[O:12])[CH3:10])=O)(C)(C)C.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54]>ClCCl>[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].[NH2:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([S:31][CH2:32][C:33]3[N:34]=[C:35]([C:38]4[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=4)[S:36][CH:37]=3)[N:26]=[C:25]([N:45]3[CH2:46][CH2:47][CH2:48]3)[C:24]=2[C:49]#[N:50])=[CH:19][CH:18]=1)=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
39 mg (0.053 mmol) of 2-{4-(2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyanopyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-alaninate (Example 13A) were initially charged in 1.5 ml dichloromethane. 0.5 ml (6.49 mmol) of trifluoroacetic acid was added, and the reaction solution was then stirred at RT for 1.5 h. The reaction solution was concentrated by evaporation and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 40 mg (100% of theory) of the target compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].C(N(CC)CC)C.[CH3:16][N:17]([C@@H:27]1[C@H:32]([CH3:33])[CH2:31][CH2:30][NH:29][CH2:28]1)[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1>C1(C)C=CC=CC=1>[CH3:33][C@@H:32]1[CH2:31][CH2:30][N:29]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:28][C@@H:27]1[N:17]([CH3:16])[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Reactant: CCOC(=O)CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
Ethyl 2-cyanoacetate (140 mg, 1.23 mmol, 6.00 equiv.) and triethylamine (40 mg, 0.39 mmol, 2.00 equiv.) were added to a solution of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 12 (50 mg, 0.19 mmol, 1.00 equiv.) in toluene (10 mL). The resulting solution was stirred at about 110° C. for about 16 hours and then was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol (50:1)) to give the title product as a light yellow solid (33 mg; yield=52%). 1H NMR (300 MHz, CD3OD) δ: 8.10 (s, 1H), 7.10 (d, J=4.0 Hz, 1H), 6.65 (d, J=4.0 Hz, 1H), 5.00-5.10 (m, 1H), 3.80-4.00 (m, 2H), 3.55-3.75 (m, 1H), 3.40-3.55 (m, 1H), 3.30-3.40 (m, 5H), 2.40-2.55 (m, 1H), 1.82-2.00 (m, 1H), 1.60-1.80 (m, 1H), 1.05-1.20 (m, 3H). LC-MS: m/z=313 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)=[CH:21][CH:20]=2)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)(O)=[O:2].CN(C)C=O.S(Cl)([Cl:42])=O>>[Cl:42][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)=[CH:21][CH:20]=2)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(c2ccc(Oc3cccc([N+](=O)[O-])c3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(c2ccc(Oc3cccc([N+](=O)[O-])c3)cc2)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
146 g (0.3 mol) of 2-(4-carboxyphenyl)-2-[4-(3-nitrophenoxy)phenyl]hexafluoropropane were suspended in 714 g of thionyl chloride, 1 cm3 of dimethylformamide was added, and the mixture was refluxed till evolution of gas was no longer observed. The thionyl chloride was removed by distillation, and the residue was recrystallized from acetonitrile.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[F:22])[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([NH2:36])[CH:33]=[N:34][CH:35]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:36][C:32]3[CH:33]=[N:34][CH:35]=[C:30]([N:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)[CH:31]=3)=[C:3]([CH3:23])[C:4]([C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=3[F:22])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methylquinoline (26.0 mg, 0.078 mmol) and 5-morpholinopyridin-3-amine in toluene to give 7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.58 (1H, dd, J=6.2, 2.8 Hz), 8.39 (1H, ddd, J=9.1, 4.4, 2.9 Hz), 8.11 (1H, br. s.), 8.03 (1H, dd, J=9.4, 5.9 Hz), 7.78 (2H, dd, J=9.8, 2.5 Hz), 7.64 (1H, br. s.), 7.29-7.42 (2H, m), 6.44 (1H, t, J=2.2 Hz), 3.77-3.87 (4H, m), 3.04-3.19 (4H, m), 2.19 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=478.1 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].[C:9]([OH:28])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][N:2]([CH2:6][CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][O:5][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CN(CCO)CCO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCN(C)CCOC(=O)CCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound A-5 (348 mg, 54.0%) was obtained in the same manner as that in Reference Example 2, by using N-methyldiethanolamine (Tokyo Chemical Industry Co., Ltd.; 119 mg, 1.00 mmol) and linoleic acid (Aldrich; 617 mg, 2.20 mmol).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:13]([O:15][C:16](=[O:29])[C@@H:17]([O:26][CH2:27][CH3:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH3:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[CH2:13]([O:15][C:16](=[O:29])[C@@H:17]([O:26][CH2:27][CH3:28])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:2]/[CH:3]=[CH:4]/[C:5]#[C:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:23][CH:24]=1)[CH3:14]
Reactant: ClC/C=C/C#Cc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccccc2)cc1)OCC

Procedure:
To a solution of (E)-(5-chloro-pent-3-en-1-ynyl)-benzene (177 mg, 1.0 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (238 mg, 1.0 mmol) in acetone (15 mL) was added potassium carbonate (700 mg, 5.0 mmol) and potassium iodide (17 mg, 0.1 mmol). The mixture was heated to reflux over night with stirring. Water was added and the product extracted with tert-butyl methyl ether (×3) The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo, to give the title compound as a crude product.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[C:30]([O:34][C:35](=[O:44])[NH:36][CH:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:44])[NH:36][CH:37]1[CH2:38][CH2:39][CH:40]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:41][CH2:42]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NC1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:39])=[C:16]([NH:18][C:19]2[N:23]([CH3:24])[C:22]3[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:30])=[CH:28][C:21]=3[N:20]=2)[CH:17]=1>CC#N.C(Cl)Cl>[Cl:39][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][NH:10][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[CH:17][C:16]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:30])=[CH:28][C:21]=2[N:20]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)NCC3CCCCC3)ccc21
Solvent: CC#N
Solvent: ClCCl
Product: Cn1c(Nc2cc(CNS(=O)(=O)c3cccs3)ccc2Cl)nc2cc(C(=O)NCC3CCCCC3)ccc21

Procedure:
Thiophene-2-sulfonyl chloride (64 mg, 0.35 mmol) in MeCN (1 mL) was added to a mixture of 2-(5-aminomethyl-2-chlorophenylamino)-N-cyclohexylmethyl-1-methylbenzimidazole-5-carboxamide (150 mg, 0.35 mmol), TEA (150 L, 1.1 mmol) and MeCN (2 mL). After 12 h at rt the mixture was diluted with DCM and washed with NH3 (aq, sat) and brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give the title compound. Yield: 36 mg (18%). 200 MHz 1H-NMR (DMSO-d6, ppm) 8.50-8.36 (2H, m) 8.35-8.22 (1H, m) 7.94-7.82 (3H, m) 7.69-7.57 (2H, m) 7.42 (1H, d, J=8.2 Hz) 7.37 (1H, d, J=8.2 Hz) 7.18-7.11 (1H, m) 7.04-6.95 (1H, m) 4.09-3.96 (2H, m) 3.71 (3H, s) 3.14-3.00 (2H, m) 1.77-1.47 (7H, m) 1.29-1.07 (4H, m). MS m/z: 572 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:14](O)[CH3:15]>>[Br:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:14][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Br)o1
Temperature: 25 °C

Procedure:
To a stirred suspension of 8.43 g (44.14 mmol) of 5-bromo-2-furoic acid in 100 ml absolute ethanol was added 4 ml of thionyl chloride. This mixture was stirred at reflux for 3 hours and at room temperature for 18 hours. The solvent was removed in vacuo, the residual oil treated with 100 ml water and extracted with 3×75 ml ether. The combined ether extracts were washed with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was removed in vacuo and the residue kugelrohr distilled (60° C.; 0.4 mm) to give the captioned compound as a colorless oil.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:11][O:12]/[N:13]=[C:14](\[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26]Br)/[C:15]([O:17][CH3:18])=[O:16].O>CN(C=O)C>[CH3:11][O:12]/[N:13]=[C:14](\[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8])/[C:15]([O:17][CH3:18])=[O:16]
Reactant: CO/N=C(/C(=O)OC)c1c(C)cccc1CBr
Reactant: Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/N=C(/C(=O)OC)c1c(C)cccc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
o-Cresol (5.9 g, 0.542 mol) was added to a suspension solution of sodium hydride (95%, 2 g, 0.813 mol) in DMF (100 mL) at 0 ° C., the reaction mixture was stirred for 1 hour at room temperature. This above reaction solution was added dropwise to a solution of methyl E-2-bromomethyl-6-methylphenylglyoxylate O-methyl oxime (16.2 g, 0.542 mol) in DMF (100 mL) for 30 min at 0 ° C. After was stirred for 1 hour at room temperature, the reaction mixture was added water (200 mL) and extracted with ether (100 mL) three times. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude product which was used in the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])=[CH:11][C:10]=1[CH:21]1[CH2:30][C:29]([CH3:32])([CH3:31])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=2)[NH:22]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])=[CH:11][C:10]=1[CH:21]1[CH2:30][C:29]([CH3:31])([CH3:32])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[CH:27]=2)[NH:22]1
Reactant: CC1(C)CC(c2cc(N3CCOC3=O)ccc2Cl)Nc2ccc(C(=O)O)cc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cc(N3CCOC3=O)ccc2Cl)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.9 %

Procedure:
To a suspension of 60% sodium hydride (70 mg, 1.75 mmol) in N,N-dimethylformamide (3 mL) was added methanesulfonamide (166 mg, 1.75 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A26. A solution of 2-[2-chloro-5-(2-oxo-oxazolidin-3-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.25 mmol) and 1,1′-carbonyldiimidazole (81 mg, 0.5 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B26. Solution B26 was added to Solution A26 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[2-chloro-5-(2-oxo-oxazolidin-3-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (13 mg, 11%) as a white solid: MS (ESI) M+1=478.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1.S(Cl)([Cl:18])=O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2ncccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: ClCc1ccc(Oc2ncccn2)cc1

Procedure:
A stirred solution of 4.0 grams (0.02 mole) of (4-pyrimidin-2-yloxyphenyl)methanol (known compound) and seven drops of pyridine in 35 mL of methylene chloride was cooled in an ice-water bath and a solution of 2.0 mL (0.027 mole) of thionyl chloride was added dropwise. Upon completion of addition the reaction mixture was stirred at about 10° C. to 20° C. during a three-hour period. After this time, the reaction mixture was poured into a cold aqueous solution of sodium bicarbonate. The mixture was then stirred for 30 minutes and the organic layer was separated. The aqueous layer was extracted with one 50 mL portion of methylene chloride. The extract was combined with the organic layer, and the combination was passed through silicone-coated filter paper to remove traces of water. The filtrate was concentrated under reduced pressure, yielding grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=O)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:17])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19]
Reactant: Cc1sc2nc3ccc(C(N)=O)cn3c(=O)c2c1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1sc2nc3ccc(C#N)cn3c(=O)c2c1C
Yield: 94.2 %

Procedure:
From 1.0 g (0.0037 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carboxamide (Example 26), 50 ml of phosphorus oxychloride and 50 ml of chloroform and refluxing on a steam bath for eighteen hours, following the procedure of Example 27, there is obtained 0.89 g of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 306°-307° C. after recrystallization from glacial acetic acid.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:7]1[N:6]=[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[C:4]2[C:31](=[O:34])[NH:32][CH2:33][C:3]=2[C:2]=1[F:1]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)NC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)c1
Yield: 63.7 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(7-fluoro-3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (40.0 mg, 0.085 mmol) and TFA (2 mL, 26.0 mmol) in DCM (1 mL) was stirred at RT for 1 h. The mixture was concentrated and the resulting residue was purified by preparative HPLC to give the title compound as a white solid (20 mg, 63.5%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36-1.97 (m, 8H), 2.30 (s, 3H), 3.70 (br s, 1H), 4.27 (br s, 1H), 4.33-4.46 (m, 2H), 6.73 (d, J=6.35 Hz, 1H), 6.79 (d, J=7.32 Hz, 1H), 7.17 (t, J=7.57 Hz, 1H), 7.43 (d, J=7.81 Hz, 1H), 7.46 (s, 1H), 7.76 (br s, 2H), 8.29 (s, 1H), 8.79 (s, 1H). [M+H] calc'd for C20H24FN5O, 370. found, 370.
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][N:19]=2)[CH:12]=1)=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[CH3:25][O:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:26])=[NH:8])[CH:16]=[CH:15][C:14]=2[CH3:17])[CH:23]=1
Reactant: COc1ccnc(-c2cc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc2C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccnc(-c2cc(NC(=N)N)ccc2C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methoxypyridin-2-yl)-4-methylphenyl)guanidine (0.2 g) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (50 ml), and the precipitate was collected by filtration and dried under reduced pressure to give (3-(4-methoxypyridin-2-yl)-4-methylphenyl)-guanidine dihydrochloride (137 mg).
Reaction SMILES: [N+](=[CH:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[N-].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH3:13]>O1CCOCC1>[O:11]=[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][O:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:12][CH3:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23]
Reactant: CCOc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCC(=O)C=[N+]=[N-]
Solvent: C1COCCO1
Product: CCCCCCC(=O)COS(=O)(=O)c1ccc(OCC)cc1
Yield: 59 %

Procedure:
A 1.0 g quantity of 1-diazo-2-octanone is dissolved in 30 ml of dioxane, and 2.0 g of p-ethyoxybenzenesulfonic acid is slowly added to the solution at room temperature. The mixture is stirred until no nitrogen is evolved. The reaction mixture is distilled in a vacuum to remove the solvent, and the residue is extracted with 50 ml of ether, washed with water and dried over anhydrous sodium sulfate. The dried product is distilled in a vacuum to remove the solvent and obtain an oily product, which is purified by column chromatography (silica gel, developer solvent chloroform), affording 1.26 g of 2-oxooctyl-p-ethoxybenzene sulfonate (Compound 46), m.p. 38° to 39° C. Yield 59.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.[NH3:26]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:21]([C:22]([NH2:26])=[O:24])=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: N
Reactant: COC(=O)c1cccc2nc(-c3ccc(C4CCCN4)cc3F)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCN4)cc3F)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 18 %

Procedure:
Methyl 2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate (200 mg, 1.40 mmol) was added to ammonia in methanol (10 mL) and the mixture was stirred at room temperature for 3 days. The mixture was concentrated, and then purified by prep-HPLC to obtain 2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide as a white solid (34.6 mg, yield 18%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.50-1.55 (m, 1H), 1.74-1.79 (m, 2H), 2.18-2.23 (m, 1H), 2.95-3.02 (m, 2H), 4.19-4.23 (m, 1H), 7.42-7.51 (m, 3H), 7.74-7.80 (br s, 1H), 7.80-7.82 (d, J=6.8 Hz, 2H), 7.96-7.98 (dd, J1=7.6 Hz, J2=0.8 Hz, 1H), 8.22 (t, J=8.4 Hz, 1H); LC-MS (ESI) m/z: 326 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:9]3([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:9]3([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1)(=[O:28])=[O:27]
Reactant: CN1CCC2(CC1)CC(=O)c1cc(N)ccc1O2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCC2(CC1)CC(=O)c1cc(NS(C)(=O)=O)ccc1O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 419 %

Procedure:
3,4-Dihydro-6-amino-1'-methyl-spiro[2H-1-benzopyran-2,4'-piperidin]-4-one (5.6 g, 0.0027 mol) was stirred in methylene chloride (50 ml) and pyridine (16 ml) at room temperature under a nitrogen atmosphere as methanesulfonyl chloride (2.7 ml, 0.035 mol) was added dropwise over several minutes. Some gum separated so additional pyridine (25 ml) was added. The mixture was stirred at ambient temperature for 16 hours. The methylene chloride and pyridine were removed in vacuo and the residue was taken up in saturated NaHCO3 (150 ml) and methylene chloride (150 ml). The methylene chloride layer was separated and the aqueous phase was again extracted with methylene chloride. The combined extracts were washed with sodium bicarbonate, dried filtered and concentrated in vacuo. The residual mixture was chzomatographed on silica gel (500 g) using 15% methanol/chloroform to yield 3.67 g (50%) of product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-])=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([Cl:18])[N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2ccc(Br)cc2c1Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc2ccc(Br)cc2c(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7-Bromo-1-chloroisoquinoline 2-oxide (1.43 g, 5.56 mmol) and POCl3 (20 mL) were heated at reflux for 2 h. The reaction mixture was cooled and carefully poured onto a mixture of ice/water (500 g), stirred for 1 h and the pH adjusted to 10.0 with 10M NaOH. The mixture was extracted with chloroform (2×100 mL) and the chloroform extracts washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (1.40 g). LRMS (M+H)+=276.0.