Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:9][O:8]2)[CH:2]=1.[NH2:10][C@H:11]([CH3:31])[CH2:12][C:13]1[C:21]2[C:16](=[C:17]([O:22][CH2:23][C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1>O.C(O)C>[CH2:29]([N:26]([CH2:27][CH3:28])[C:24](=[O:25])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:12][C@H:11]([NH:10][CH2:9][C@H:7]([OH:8])[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:31])[CH3:30]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N)c[nH]c12
Reactant: c1cncc([C@@H]2CO2)c1
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Yield: 20.6 %

Procedure:
A solution of (R)-(pyridin-3-yl)oxirane (97 mg, 0.80 mmol) and (R)-2-[3-(2-aminopropyl)-1H-indol-7-yloxy]-N,N-diethylacetamide (243 mg, 0.80 mmol) in water (0.8 mL) and ethanol (8 mL) is refluxed for 5 hours. After concentrated, the resulting residue is purified by preparative TLC (SiO2, 20×20 cm, 0.5 mm, iPrOH/saturated ammonia solution in chloroform=1/10) to give the desired N,N-diethyl-2-{3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}-acetamide (70 mg, yield: 21%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:10]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([O:13][Si:14]([CH:15]([CH3:16])[CH3:17])([CH:18]([CH3:19])[CH3:20])[CH:21]([CH3:22])[CH3:23])[CH2:11][OH:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Si](O[C@@H](CO)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Solvent: CO
Product: CC(C)[Si](O[C@@H](CO)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Yield: 67 %

Procedure:
The monosilylated diol of Step 2 was hydrogenated with 5% Rh-C at 60 psi and 60° C. in MeOH (135 mL). The mixture was filtered and the filtrate evaporated. The residue was purified by chromatography, eluting with (15% EtOAc in hexane) to give the title alcohol (8.70 g, 67% yield, mp 61-63° C.). The 1H, 13C, and APT NMR spectral data were consistent with the proposed product.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[O:27])=[CH:21][CH:20]=2)[CH:15]=[CH:14][N:13]=1)=[O:10])=[O:5])C.[OH-].[Na+].CO.Cl>CN(C)C=O>[C:4]([CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[O:27])=[CH:21][CH:20]=2)[CH:15]=[CH:14][N:13]=1)=[O:10])([OH:5])=[O:3]
Reactant: CCOC(=O)CCCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)CCCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1

Procedure:
N-{4-[2-(4-Ethoxycarbonylbutyryl)aminopyridin-4-yl]oxyphenyl}-N′-(4-fluorophenyl)urea (22 mg), 2N aqueous sodium hydroxide (1 ml), methanol (2 ml) and dimethylformamide (1 ml) were stirred together at 80° C. for 20 minutes. After returning the mixture to room temperature, 0.4 ml of 5N aqueous hydrochloric acid was added and the precipitated solid was filtered out to obtain 16 mg of the target substance as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.[OH-].[Ca+2].[OH-].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>O1CCOCC1>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)[C:4]([CH3:8])=[N:3]1
Reactant: Cc1cc(=O)n(C)[nH]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nn(C)c(O)c1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
In 22 ml. of dry dioxane is dissolved 2.24 g. of 1,3-dimethyl-5-pyrazolone and then 2.96 g. of calcium hydroxide is added thereto. 3.71 g. of p-nitrobenzoyl chloride is added dropwise thereto while stirring at room temperature. After completion of the dropwise addition, the mixture is heated under reflux for 1 hour. After completion of the reaction, the reaction mixture is allowed to cool and then 40 ml. of a 2N hydrochloric acid solution is added thereto. Crystalline substances thus separated are recovered by filtration and washed with water to give 4.38 g. of crude crystals. This product is recrystallized from methanol to give 3.62 g. of the desired product as pale yellow columns having a melting point of 234°-235° C. Yield 69.3%
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([O:27]CC)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.C(O)CCC.CC([O-])(C)C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc12
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Temperature: 100 °C
Yield: 92.3 %

Procedure:
Ethyl 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a19; 52.73 g; 131.4 mmol) is dissolved in tert. BuOH (500.0 mL) and water (5.0 mL). After addition of commercially available KOtBu (73.70 g; 656.8 mmol) the reaction mixture is stirred at 100° C. over night and cooled to ambient temperature. Water (1500 mL) is added and pH is adjusted to 6.0 by careful addition of 2M aqueous citric acid. The precipitated product is filtered washed with several portions of water and dried under reduced pressure to yield 45.3 g of the title compound as off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc2[nH]nc(Br)c2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
To a suspension of ethyl 3-bromo-1H-indazole-5-carboxylate (1032 g, 0.04 mol) in 160 mL of THF was added NaH (2.8 g, 0.068 mol) portion wise at 5-10 C under ice/water bath. The solution was stirred for 15 minutes further until no more bubling. Tritylchloride (14 g, 0.05 mol) was added in several portions. After the addition, the cooling bath was removed and the orange suspension was stirred at room temperature for overnight. The reaction mixture was poured slowly into 100 mL of saturated NH4Cl with stirring and 100 mL EtOAc. The layers were separated and the aqueous phase extracted with Ethyl acetate (2 Lx2). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4, filter and concentrated. The solid was triturated with hexane (100 mL), filtered and washed with hexane and dried under vacuum to give 20 gram product as light yellow solid.
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([C:21]#[N:22])[C:15]=2[N:14]=[C:13]1[CH3:29].OO>O.C1COCC1>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:19]=[C:20]([C:21]([NH2:22])=[O:1])[C:15]=2[N:14]=[C:13]1[CH3:29]
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 50 °C
Yield: 51.1 %

Procedure:
A solution of KOH (78 mg, 1.4 mmol) in water (10 mL) was added dropwise to solution of 1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carbonitrile (280 mg, 0.7 mmol) and 30% H2O2 (3 mL) in THF (10 mL) at rt. The mixture was heated at 50° C. for 2 h. When TLC showed no starting material left, the pH of the mixture was acidified to pH ca. 5 and extracted with EtOAc (50 mL×3). The organic layer was washed with brine, dried over MgSO4, concentrated. The resulting residue was purified by silica gel chromatography eluted with EtOAc to give the product (150 mg, 51%), as a white solid. 1H NMR (300 Mhz, DMSO-d6) δ ppm 2.44 (s, 3H), 3.11 (t, 4H, J=4.8 Hz), 3.71 (t, 4H, J=4.8 Hz), 5.60 (s, 2H), 6.31 (d, 1H, J=8.1 Hz), 7.16 (br s, 2H), 7.25 (t, 1H, J=8.1 Hz), 7.35 (d, 1H, J=1.8 Hz), 7.41 (d, 1H, J=1.8 Hz), 7.60 (d, 1H, J=8.1 Hz); LC-MS: m/e=419 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](Cl)=[N:7][OH:8])=[CH:4][CH:3]=1.[CH3:12][CH2:13][O:14][C:15](/[CH:17]=[C:18](/N1CCCC1)\[CH3:19])=[O:16].C(N(CC)CC)C>C(O)C>[CH2:13]([O:14][C:15]([C:17]1[C:6]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:7][O:8][C:18]=1[CH3:19])=[O:16])[CH3:12]
Reactant: CCOC(=O)/C=C(\C)N1CCCC1
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Yield: 69.8 %

Procedure:
To a suspension of 4-chloro-N-hydroxy-benzimidoyl chloride (1.11 g, 5.88 mmol) in dry ethanol (9 ml) was added a solution of ethyl (E)-3-(1-pyrrolidino)crotonate (1.08 g, 5.88 mmol) and triethylamine (492 μl, 3.53 mmol) in dry ethanol (9 ml) over a period of twenty minutes at room temperature. The suspension was stirred for eighteen hours before the mixture was concentrated and the residue partitioned between ethyl acetate and water. The organic layer was washed with 0.5 N HCl and brine, before it was dried and concentrated in vacuo. The residue was purified by flash column chromatography with a gradient of ethyl acetate and hexanes on silica gel (40 g) to give the title compound as a white solid (1.09 g): 1H NMR (CDCl3, 200 MHz): δ=7.57 (m, 2H), 7.42 (m, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.74 (s, 3H), 1.27 (t, J=7.0 Hz, 3H); MS: (+) m/z 266.31 (M+1).
Reaction SMILES: II.[CH2:3](I)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO[CH2:14][CH2:15][O:16]C>>[CH2:3]([C:15]1([OH:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:14]1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COCCOC
Reactant: ICCc1ccccc1
Agent: II
Product: OC1(CCc2ccccc2)CCCCC1
Yield: 96 %

Procedure:
Since TmI2(DME)x exhibits such high reactivity at room temperature, its viability at reduced temperature is examined. In these reactions, TmI2(DME)x is added as a DME solution by syringe using a saturated stock solution generated in situ from Tm and I2. Phenethyl iodide reacts smoothly at −22° C. in 10 minutes to form phenethylcyclohexanol in 96% yield (entry f). The reaction of phenethyl bromide with cyclohexanone at 0° C. produces a 96% yield of phenethylcyclohexanol in 20 minutes (entry g), while reaction at −22° C. gave a 94% yield in 60 minutes (entry h). Phenethyl chloride reacts at 0° C. to give a 90% yield after 1 hour (entry j). This variation of reaction time as a function of temperature could be used to control regiochemistry in sequenced reactions.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25](SC)=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]=[CH:41][CH:40]=[CH:39]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:57][NH2:58]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25]([NH:58][CH3:57])=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]=[CH:41][CH:40]=[CH:39]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc4ncccc4c3)c(F)cc1C)C2
Reactant: CN
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc4ncccc4c3)c(F)cc1C)C2

Procedure:
Using a procedure analogous to Example A2, the sulfide was oxidized with mCPBA to the sulfone and then treated with methylamine to provide 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea. 1H NMR (400 MHz, DMSO-d6): δ 8.95 (m, 2H), 8.48 (m, 1H); 8.15 (m, 1H), 8.04 (d, J=8 Hz, 1H), 7.92 (m, 2H), 7.60 (dd, J=8, Hz, 1H), 7.17 (d, J=12 Hz, 1H), 7.02 (m, 1H), 6.46 (s, 1H), 4.53 (d, J=14 Hz, 1H), 4.33 (d, J=14 Hz, 1H), 3.25 brs, 3H), 2.78 (d, J=5 Hz, 3H), 2.04 (s, 3H), 1.28 (s, 9H); MS (ESI) m/z 609.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)=[C:4]([F:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:14]([C:13]4[CH:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=5[F:19])[NH:9][C:10](=[O:18])[NH:11][C:12]=4[CH3:17])=[O:16])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3cc(F)cc(F)c3)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cc(F)cc(F)c4)c3c2)C(c2ccc(Cl)cc2F)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(4-Chloro-2-fluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3,5-difluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=527 [M+H]+.
Reaction SMILES: CN(C=O)C.O.[Na].[CH3:8][CH:9]([SH:12])[CH2:10][CH3:11].[NH2:13][C:14]1[N:22]=[C:21](Cl)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cl-].[Na+].O>[NH2:13][C:14]1[N:22]=[C:21]([S:12][CH:9]([CH2:10][CH3:11])[CH3:8])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCC(C)S
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Sc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 35.2 %

Procedure:
To DMF suspension (10 ml) containing sodium hydrate (300 mg, 7.5 mmol, 60%in mineral oil) were added 2-butanethiol (1 ml, 11 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (85 mg, yield 35%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:18]C=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: On1nnc2ccccc21
Reactant: Nc1nc(Cl)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a solution of 2-amino-6-chloronicotinic acid (1.0 g, 5.79 mmol), HOBT (932 mg, 6.95 mmol) and EDCI (2.22 g, 11.6 mmol) in 15 mL of DMF was added triethylamine (5.86 g, 57.9 mmol) and NH4Cl (1.55 g, 28.9 mmol). Then the mixture was stirred at room temperature for 16 h. The solution was concentrated in vacuo to remove DMF and the residue was suspended in saturated NaHCO3 Finally the 2-amino-6-chloronicotinamide (800 mg, yield: 81%) was obtained by filtration without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 7.95 (d, J=8.4 Hz, 1H), 7.62 (s, 2H), 7.39 (s, 2H), 6.59 (d, J=8.4 Hz, 1H). MS (M+H)+: 172/174.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:24]1[C:29]([CH3:30])=[CH:28][C:27](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:26][C:25]=1[CH3:38].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.CCCCP(CCCC)CCCC>C1COCC1>[CH3:38][C:25]1[CH:26]=[C:27](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:28]=[C:29]([CH3:30])[C:24]=1[O:20][CH:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[N:14]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCOC(=O)/C=C/c1cc(C)c(O)c(C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1c(C)cc(/C=C/C(=O)OCC)cc1C)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A stirred solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (62 mg, 0.20 mmol) and ethyl (2E)-3-(4-hydroxy-3,5-dimethylphenyl)-2-propenoate (79 mg, 0.36 mmol) in THF (4 mL) at 0° C. under nitrogen was added ADDP (101 mg, 0.40 mmol) followed by tri-N-butylphosphine (0.100 mL, 0.40 mmol). The resulting mixture was then allowed to warm slowly to ambient temperature overnight. After 66 h the solvent was removed under vacuum (Genevac) and the resulting solid partitioned between DCM (5 mL) and water (5 mL), the layers separated and the aqueous re-extracted with DCM (5 mL). The combined organic layer was then reduced under vacuum and purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 20:1 to 1:1) to give the title compound (35 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1.CO.[OH-].[Na+].Cl>O>[NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Compound 39b (1.0 g) was added to methanol (10 mL), and 4M aqueous sodium hydroxide (650 μL) and water (400 μL) were further added thereto, followed by stirring at room temperature for 2 hours. After completion of reaction, 6N aqueous hydrochloric acid was added to the reaction mixture, to thereby adjust the pH to 3, and the precipitate was filtrated, whereby compound 39c was yielded (862 mg, yield: 90%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]([O:17]C(Cl)=O)(Cl)Cl>O1CCCC1>[C:4]1([CH2:3][C@H:2]2[C:10](=[O:12])[O:11][C:14](=[O:17])[NH:1]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: C1CCOC1
Product: O=C1N[C@@H](Cc2ccccc2)C(=O)O1

Procedure:
A mixture of 8.9 g of L-phenylalanine, 4.8 ml of trichloromethylchloroformate (Diphosgene), 70 ml of dry tetrahydrofuran and 0.135 g of activated carbon is heated in an oil bath at 55° C. for 2 hours, until the L-phenylalanine is in solution. The reaction is filtered through diatomaceous earth. The filtrate is concentrated in vacuo, treated with diethyl ether and hexane, and the resulting crystals are collected to give 1.04 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(=O)([O-])O.[Na+].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>O.C(Cl)Cl>[C:19]1([O:18][C:16](=[O:17])[NH:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1cccc(O)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxybenzylamine (200 mg, 1.62 mmol) and Sodium hydrogen carbonate (273 mg, 3.25 mmol) suspended in water/DCM (4 ml, 1:1) is treated with phenyl chloroformate (0.204 ml, 1.62 mmol). After stirring at RT overnight, the reaction mixture is diluted with more DCM/water and the organic phase is separated. The organic portion is concentrated in vacuo to afford the titled compound. (MH+ 244)
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Temperature: 0 °C

Procedure:
To a solution of 5 (1 g) in chloroform (70 mL) was added N-bromosuccinimide (0.82 g) and azobis(isobutyronitrile) (0.010 g). A light source was directed onto the flask and the mixture was refluxed for 18 h. The solution was cooled to 0° C., a precipitate was filtered, and flitrate was concentrated in vacuo to obtain the crude product. Purification on silica gel with hexane/ethyl acetate 9/1 afforded the product as a solid. NMR (300 MHz, CDC3) δ 8.10 (1H, d, J=9 Hz), 7.95 (1H,d, J=9 Hz), 7.54 (1H,t, J=9 Hz), 5.14 (2H, s), 3.99 (3H, s).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10](Cl)=[O:11]>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:11]
Reactant: CC(C)CN
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: CC(C)CNC(=O)c1ccc(F)c(Cl)c1
Reaction time: 2 h

Procedure:
Isobutyl amine (2 molar equivalent) was added to a solution of 3-chloro-4-fluorobenzoyl chloride (1 g) in DCM (10 ml) and stirred for 2 h. The reaction was diluted with DCM, washed with water, dried (MgSO4) and evaporated under reduced pressure to give a white solid (1.2 g).
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[N:5][CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2].CN(C=O)C.O=S(Cl)[Cl:22]>>[Cl:22][C:4]1[C:3]([C:1]#[N:2])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cnc(O)c(C#N)c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c(C#N)c1
Temperature: 25 °C

Procedure:
To a solution of 222 mg (1.16 mmol) of ethyl 5-cyano-6-hydroxynicotinate (from Step A) in 5 mL of SOCl2 was added 500 μL of DMF. After refluxing overnight, the mixture was cooled to rt and concentrated. The residue was dissolved in EtOAc (20 mL) and washed with brine (10 mL), saturated NaHCO3 (10 mL), and brine (10 mL), dried over Na2SO4, and concentrated. Chromatography on a Biotage 40M cartridge using 1:9 v/v EtOAc/hexanes gave 145 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.44 (d, J=7.1, 3H), 4.46 (q, J=7.1, 2H), 8.58 (d, J=2.1, 1H), 9.15 (d, J=2.1, 1H).