Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9][C:8]=1[CH3:17])([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li+].CC([N-]C(C)C)C.[C:35]([O:39][C:40](=[O:58])[NH:41][C@@H:42]([C:52](=[O:57])N(OC)C)[CH2:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[F:51])([CH3:38])([CH3:37])[CH3:36].OS([O-])(=O)=O.[Na+]>C1COCC1.O>[C:35]([O:39][C:40](=[O:58])[NH:41][C@H:42]([CH2:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[F:51])[C:52](=[O:57])[CH2:17][C:8]1[C:7]([C:6](=[O:18])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:11]=[C:10]([C:13]([F:14])([F:15])[F:16])[N:9]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CON(C)C(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)NC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C(F)(F)F)nc1CC(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C
Temperature: -68 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-tert-butyl-2-methyl-6-trifluoromethyl-nicotinamide (2.3 g, 8.7 mmol) and TMEDA (2.7 mL, 17 mmol) in 130 mL of THF at −68° C. is slowly added LDA (2M, 8.7 mL, 17.4 mmol). The reaction temperature is maintained at −68° C., then warmed to −20° C. and is then immediately re-cooled to −68° C. To the reaction is added a solution of [(R)-2-(2,5-difluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (1 g, 2.9 mmol) in 20 mL of THF over a period of 10 minutes. The reaction is allowed to stir an additional 20 min after which the reaction is poured into 150 mL of a chilled 3% (w/v) solution of NaHSO4 in water. The solution is adjusted to pH7 by addition of pH7 buffer and the product is extracted into dichloromethane. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the resultant residue by silica gel flash column chromatography provides the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.COC1C=CC(C2C=CC3C(=CC=CC=3)N=2)=CC=1>CN(C)C=O.COCCOC>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: COc1ccc(O)cc1
Agent: COc1ccc(-c2ccc3ccccc3n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc3ccccc3n2)cc1
Temperature: 5 °C

Procedure:
To a stirred suspension of 32 g. sodium hydride (52% suspension in mineral oil) in 475 ml. dimethylformamide and 475 ml. 1,2-dimethoxyethane was added, portionwise during about fifteen minutes, 59.5 g. 4-methoxyphenol followed by, after five minutes, a solution of 95.5 g. 2-chloroquinoline in 130 ml. dimethyl formamide in one portion and the resulting mixture was heated under reflux for sixteen hours, cooled to 5° C., poured into 4000 ml. ice-water and extracted with ether. The ether extract was washed with ice cold 2% aqueous sodium hydroxide solution, water and saturated salt solution, dried and evaporated to dryness under reduced pressure. The resulting crystals were recrystallized from benzene-hexane to give 104 g. 2-(4-methoxyphenyl)quinoline; m.p. 96.5°-98° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Nc1ccc(O)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(NS(C)(=O)=O)cc1
Yield: 22.2 %

Procedure:
A solution of 22.63 g (0.25 mol) of acryloyl chloride in 250 ml of methylene chloride was added over a period of 35 minutes to a mixture of 46.81 g (0.25 mol) of N-(4-hydroxyphenyl)methanesulfonamide, 25.30 g (0.25 mol) of triethylamine and 750 ml of methylene chloride at 0° C. The resultant solution was stirred at reduced temperature for 2.17 hours, washed three times with water and dried over magnesium sulfate. Concentration of the solution in vacuo gave a solid which after two recrystallizations from benzene and drying gave 13.4 g (22.2 percent yield) of N-(4-acryloyloxyphenyl)methanesulfonamide; m.p.=136.5° to 139.5° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([NH:5][C:6](=[O:8])[CH3:7])[CH3:4].[CH2:9](I)[CH3:10].[OH-].[Na+]>>[CH3:1][O:2][CH:3]([N:5]([CH2:9][CH3:10])[C:6](=[O:8])[CH3:7])[CH3:4]
Reactant: CCI
Reactant: COC(C)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CCN(C(C)=O)C(C)OC
Yield: 51 %

Procedure:
58.5 g (0.5 mole) of N-α-methoxyethyl-acetamide and 84.2 g (0.55 mole) of ethyl iodide are simultaneously added dropwise to 300 ml of 50% strength sodium hydroxide solution at 10° C. Two hours after the addition has ended, the phases are separated in a separating funnel, the aqueous portion is extracted with hexane and, after stripping off the solvent, the residue is distilled in vacuo. 37 g (51% of theory) of N-α-methoxyethyl-N-etyl-acetamide of boiling point16 83°-85° C. are obtained.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:18][C:19]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OC)c(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(CSc2ccc(OCC(=O)O)c3c2CCC3)cc1OCc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 78C. mp 150-151° C.; IR (KBr) cm−1: 3046, 1722, 1515, 1328, 1232, 1106; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.71 (d, 2H, J=8.1 Hz), 7.58 (d, 2H, J=8.1 Hz), 7.03 (d, 1H, J=8.5 Hz), 6.70-6.86 (m, 3H), 6.57 (d, 1H, J=8.5 Hz), 5.01 (s, 2H), 4.61 (s, 2H), 3.89 (s, 2H), 3.69 (s, 3H), 2.75 (t, 2H, J=7.3 Hz), 2.62 (t, 2H, J=7.3 Hz), 1.87 (pentet, 2H); MS m/z 517 (M−1). Anal. Calc'd for C27H25F3O5S: C, 62.54; H, 4.86. found: C, 62.54; H, 4.71.
Reaction SMILES: [CH:1]([N:4]([CH:32]([CH3:34])[CH3:33])[C:5](=[O:31])[CH:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=NC1C=C(C)C(O)=C(C)C=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]>C(O)C>[CH:32]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:31])[CH:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:34])[CH3:33]
Reactant: Cc1cc(N=Nc2ccccc2C(=CC(=O)N(C(C)C)C(C)C)c2ccccc2)cc(C)c1O
Solvent: CCO
Product: CC(C)N(C(=O)C=C(c1ccccc1)c1ccccc1N)C(C)C

Procedure:
N,N-Diisopropyl-3-[2-(3,5-dimethyl-4-hydroxyphenylazo)phenyl]-3-phenylpropenamide (2.58 g, 5.68 mmol) was treated as described in Example 28.3. The crude residue gave crystals from aqueous ethanol. Yield 1.23g (67%).
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25](Cl)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Cl)cc1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCc2ccccc2)cc1

Procedure:
A sample of 10.0 g. of 4-(hexadecylamino)hydrocinnamoyl chloride hydrochloride is treated with 9.5 g. of 4-dimethylaminopyridine and 2.5 g. of benzyl alcohol in 80 ml. of methylene chloride and the solution is heated to reflux for 4 hours. The reaction solution is then cooled, washed twice with water and dried over magnesium sulfate. The methylene chloride solution is passed through a pad of alumina. The filtrate is concentrated and the residue recrystallized from chloroform-hexane to yield benzyl 4-(hexadecylamino)hydrocinnamate.
Reaction SMILES: ClC1C=C([N:8]2N=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)C=CC=1.[NH2:19][C:20]1[C:21]([Cl:26])=[N:22][CH:23]=[CH:24][CH:25]=1.N1C=CC=CC=1C=O>>[Cl:26][C:21]1[C:20]([N:19]2[N:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:11]2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Nc1cccnc1Cl
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: Clc1ncccc1-n1nnc(-c2ccccn2)n1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-amino-2-chloropyridine (38.6 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(2-chloro-3-pyridyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=O)[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[CH3:29])/[N:7]([CH2:31][C@H:32]2[CH2:36][CH2:35][CH2:34][O:33]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[CH3:29])=[S:46])/[N:7]([CH2:31][C@H:32]2[CH2:36][CH2:35][CH2:34][O:33]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCC[C@H]1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1ccc(C(F)(F)F)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 95 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of Example 24 (300 mg, 0.571 mmol) in toluene (6 mL) at ambient temperature was added Lawesson's Reagent (231 mg, 0.571 mmol). This mixture was warmed to 95° C. and allowed to stir for 4 hours. The mixture was then cooled to ambient temperature, concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL) and washed with NaHCO3 solution. The organics were combined, dried, concentrated, and the residue was purified by Analogix® Intelliflash280™ (SiO2, 0-10% (7 M ammonia in methanol) in CH2Cl2 over 25 min) to obtain the title compound in 87% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (s, 9 H) 1.47-1.63 (m, 4 H) 1.73-1.89 (m, 4 H) 2.10 (q, J=8.59 Hz, 1 H) 2.19 (s, 3 H) 2.38-2.47 (m, 1 H) 2.81-2.90 (m, 1 H) 3.59-3.67 (m, 1 H) 3.71-3.81 (m, 1 H) 3.96 (ddd, J=14.67, 9.41, 5.76 Hz, 2 H) 4.27-4.34 (m, 3 H) 7.23 (d, J=8.82 Hz, 1 H) 7.55-7.59 (m, 2 H) 7.63 (dd, J=8.82, 2.03 Hz, 1 H); MS (DCI/NH3) m/z 542 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:9]=2)=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][CH2:39][CH:40]1[CH2:41][CH2:42][N:43]([C:12]([C:11]2[C:10]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=3)=[N:9][C:8]([O:7][C:6]3[CH:29]=[CH:30][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[CH:16][CH:15]=2)=[O:13])[CH2:44][CH2:45]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(OC(F)(F)F)cc2)CC1
Yield: 66.5 %

Procedure:
6-(4-Cyano phenoxy)-2-(4-trifluoromethoxy phenoxy)nicotinic acid (0.15 g, 0.36 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.082 g, 0.36 mmol) were coupled using the procedure of Example 5(c) to afford 0.15 g of the required product. Percentage purity (LCMS): 43.23%.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[Cl:7].C([N-]C(C)C)(C)C.[Li+].CN([CH:19]=[O:20])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:6]=[C:5]([CH:19]=[O:20])[S:4][C:3]=1[Cl:7]
Reactant: Clc1sccc1Br
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cc(Br)c(Cl)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a −78° C. solution of 3-bromo-2-chloro-thiophene (10.03 g, 50.79 mmol) in THF (anhydrous, 100 mL) was added lithium diisopropyl amide solution (Aldrich, 2.0M in heptane/THF/ethylbenzene, 38.1 mL, 76.20 mmol) dropwise over 45 minutes under argon. The reaction mixture was stirred for one hour at −78° C., treated with DMF (Aldrich, anhydrous, 19.7 mL, 254.40 mmol), stirred for 15 minutes at −78° C., warmed to room temperature, and stirred for 45 minutes. Aqueous citric acid was added and the reaction mixture was stirred for 5 minutes. The mixture was diluted with ethyl acetate and was washed with saturated NaHCO3, water, and brine. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (silica gel, 1-3% ethyl acetate/hexanes) to afford the title compound as a yellow solid (10.63 g, 92.8% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:9]=1[C:10](O)=[O:11].Cl>O1CCCC1.O.O1CCCC1>[Cl:7][C:8]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1cc(O)ccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(O)ccc1Cl
Temperature: 0 °C

Procedure:
Lithium aluminium hydride (1M in diethyl ether, 25 mL, 25 mmol) was added to an ice-cooled solution of 2-chloro-5-hydroxy-benzoic acid (4 g, 23.2 mmol) in tetrahydrofuran (200 mL) and the mixture was heated under reflux for 6 hours. The mixture was then diluted with a mixture of water/tetrahydrofuran, acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The organic solution was dried over sodium sulphate and concentrated in vacuo to afford the title compound in quantitative yield, 4.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[CH:8]=2)[N:3]=1
Reactant: C1=COCCC1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1ccc2cc(OC3CCCCO3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloroquinolin-6-ol (36 g, 0.20 mol) was dissolved in dichloromethane (500 ml) and tetrahydrofuran (500 ml). 3,4-dihydro-2H-pyran (74 ml, 0.81 mol) and p-toluenesulfonic acid (0.49 g, 0.005 mol) were added to the mixture in ice cooling water bath, followed by stirring at room temperature overnight. A 10% sodium hydroxide aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The result was dried over potassium carbonate and subjected to filtration, and then the filtrate was concentrated under reduced pressure. The crude crystal thus obtained was recrystallized from ethanol to afford the title compound as a colorless granular compound (47 g, yield 89%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:14][O:15][C:16]([C:18]1[S:27][C:21]2[N:22]=[CH:23][N:24]=[C:25](Cl)[C:20]=2[C:19]=1[CH3:28])=[O:17].Cl>O1CCOCC1>[CH3:14][O:15][C:16]([C:18]1[S:27][C:21]2[N:22]=[CH:23][N:24]=[C:25]([NH:13][C:12]3[C:7]([O:6][C@@H:3]4[CH2:4][CH2:5][O:1][CH2:2]4)=[N:8][CH:9]=[CH:10][CH:11]=3)[C:20]=2[C:19]=1[CH3:28])=[O:17]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1cccnc1O[C@@H]1CCOC1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@@H]3CCOC3)c2c1C
Temperature: 100 °C
Reaction time: 36 h

Procedure:
A mixture of 166 mg (0.92 mmol) 2-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-ylamine, 364 mg (1.5 mmol) 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 39 μl hydrochloric acid (4M in dioxane) and 30 ml dioxane was stirred at 100° C. for 1.5 days. The reaction mixture was concentrated and used for the next synthesis step without further purification.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:23]1([CH2:22][CH2:21][CH2:20][O:16][C:13]2[CH:14]=[CH:15][C:10]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[N:2]3)=[CH:11][CH:12]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Oc1ccc(-n2ncc3ccccc32)cc1
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)cnn2-c1ccc(OCCCN2CCCC2)cc1
Temperature: 70 °C
Yield: 15.6 %

Procedure:
4-Indazol-1-yl-phenol (0.07 mmol) was dissolved in N,N′dimethylformamide (0.5 mL), and sodium hydride (3 mg, 60% dispersion in mineral oil, 0.085 mmol), 1-(3-chloropropyl)pyrrolidine (10 mg, 0.07 mmol) and a catalytic amount of sodium iodide were added. The reaction was heated at 70° C. for 2.5 hours. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic extracts were dried over MgSO4, concentrated, and purified by semi-prep LC-MS to give 3.5 mg of the desired product. LC-MS (C20H23N3O calculated 321) m/z 322 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(C#N)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Mg]I.CC[O:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:20](=[O:19])[CH3:21])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Agent: C[Mg]I
Product: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (238 g) in ether (500 ml) was added at reflux temperature under nitrogen over 40 minutes to stirred ethereal methylmagnesium iodide solution (3M; 701 ml). After the addition was complete, the mixture was stirred at reflux temperature for 3 hours and at ambient temperature for 60 hours. The resulting solid was collected by filtration, washed well with ether, and added in portions to a stirred mixture of crushed ice (1 l) and concentrated hydrochloric acid (1 l). The resulting mixture was stirred at 95° C. for 1 hour then cooled to ambient temperature. The product was extracted into dichloromethane (3×250 ml), and the combined extracts were washed with water (3×200 ml), dried (MgSO4), and the solvent was removed in vacuo. The residue was distilled to give 1-[1-(4-chlorophenyl)cyclobutyl]ethanone as a brown oil (198.1 g), b.p. 95-100° C. at 0.3 mbar.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]#[N:8])[CH:4]=[N:3][CH:2]=1.[NH2:9][OH:10]>CO>[OH:10][N:9]=[C:7]([C:5]1[CH:6]=[N:1][CH:2]=[N:3][CH:4]=1)[NH2:8]
Reactant: N#Cc1cncnc1
Reactant: NO
Solvent: CO
Product: NC(=NO)c1cncnc1

Procedure:
A solution of the product of Example 79B (5.47 g, 52 mmol) and aqueous hydroxylamine (Aldrich, 50%, 2.3 mL, 78 mmol) in methanol (50 mL) was stirred at 65° C. for 1 hour and then concentrated under reduced pressure to remove the volatiles. The residue was triturated with EtOAc (30 mL). The precipitates were collected by filtration and dried to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 6.14 (s, 2 H), 9.03 (s, 2 H), 9.18 (s, 1 H), 10.06 (s, 1 H) ppm; MS (DCI/NH3) m/z 139 (M+H)+, 156 (M+NH4)+.
Reaction SMILES: [F:1][C:2]([F:14])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:3]([F:6])([F:5])[F:4].N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>O>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2]([F:14])([F:1])[C:3]([F:5])([F:4])[F:6])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCC(F)(F)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCC(F)(F)C(F)(F)F)cc1
Yield: 73.3 %

Procedure:
Into a reaction vessel, 5.00 g (22.7 mmol) of 6-(perfluoroethyl)hexanol (1) and 6.3 ml of pyridine were placed, and 5.21 g (27.3 mmol) of p-toluene-sulfonyl chloride was added little by little thereto under stirring and cooling with ice. After the addition, the system was stirred for 6 hours. The reaction product was poured into iced water, acidified by addition of 6 ml of hydrochloric acid and then extracted with chloroform. The organic layer was washed with salt water and dried with sodium sulfate, followed by solidification by removal of the solvent under a reduced pressure. The residue was purified by silica gel column chromatography with eluents of hexane/toluene=2/1, toluene, and toluene/ethyl acetate=5/1, successively, having increasing polarity, thereby obtaining 6.23 g (yield=73.3%) of 6-(perfluoroethyl)hexyl p-toluenesulfonate (2).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
4-Acetamidocinnamic acid (80 mg) was suspended in methanol (5 ml) and 10% palladium on carbon (15 mg) was added thereto. The mixture was stirred under hydrogen atmosphere at 25° C. for 3 hours. Catalyst was removed and the solution was concentrated to give 3-(4-acetamidophenyl)propionic acid (69 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[C:10]([I:13])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[Cl:22][C:23]1[C:24]([CH3:45])=[C:25]([C:34]2[CH:35]=[CH:36][C:37]([C:40]([N:42]([CH3:44])[CH3:43])=[O:41])=[N:38][CH:39]=2)[C:26]([O:32][CH3:33])=[C:27]([CH:29](Cl)[CH3:30])[CH:28]=1>CN(C=O)C.CO>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[C:10]([I:13])=[CH:9][N:8]([CH:29]([C:27]3[C:26]([O:32][CH3:33])=[C:25]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([N:42]([CH3:43])[CH3:44])=[O:41])=[N:38][CH:39]=4)[C:24]([CH3:45])=[C:23]([Cl:22])[CH:28]=3)[CH3:30])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: Nc1ncnc2[nH]cc(I)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1c(C(C)n2cc(I)c(=O)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
To a mixture of 4-amino-6-iodopyrido[2,3-d]pyrimidin-5(8H)-one (255 mg, 0.885 mmol), cesium carbonate (0.43 g, 1.3 mmol) and potassium iodide (14.7 mg, 0.0885 mmol) in DMF (9.4 mL) was added 5-{3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (325 mg, 0.885 mmol) (from example 25 step 1) and the mixture was stirred at 140° C. for 1 h. The mixture was diluted with methanol and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired compound (221 mg, 40%). LCMS calculated for C25H25ClIN6O3 (M+H)+: m/z=619.1; Found: 619.0.