Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH3:25])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:27](=[O:29])[CH3:28]>>[C:27]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH3:25])[C:19]=1[OH:18])(=[O:29])[CH3:28]
Reactant: N#Cc1ccc(Sc2cccc(CO)c2)nc1
Reactant: CC(=O)c1ccc(O)c(C)c1O
Product: CC(=O)c1ccc(OCc2cccc(Sc3ccc(C#N)cn3)c2)c(C)c1O
Yield: 127.6 %

Procedure:
Using the method of Preparation 166 using 6-(3-(hydroxymethyl)phenylthio) nicotinonitrile (1.46 g, 6.02 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (1.00 g, 6.02 mmol) affords the title compound (3.00 g). MS (APCI-neg) m/z (rel intensity): 389 (M−H, 100%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Cn1cc(-c2cccc3cnc(Cl)cc23)cn1
Reactant: COc1ccc(N)c(OC)c1
Product: COc1ccc(Nc2cc3c(-c4cnn(C)c4)cccc3cn2)c(OC)c1
Reaction time: 1.5 h
Yield: 27 %

Procedure:
The title compound was prepared according to Method 3 (Example 27) using 3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline (Preparation 7) and 2,4-dimethoxyaniline at 80° C. for 1.5 hours followed by 100° C. for 1.5 hours. The reaction mixture was concentrated onto silica gel in vacuo and purified by silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane to afford the title compound (22 mg, 27%).
Reaction SMILES: [OH-].[Na+].CN(C=O)C.[CH2:8]([SH:10])[CH3:9].Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1>O>[Br:18][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([S:10][CH2:8][CH3:9])[CH:17]=1
Reactant: Brc1cncc(Br)c1
Reactant: CCS
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
Under a nitrogen atmosphere, NaOH (1.25 g, 31.3 mmol) was added to anhydrous DMF (40 mL). Ethanethiol (2.60 mL, 2.20 g, 35.5 mmol) was then added by syringe and the mixture was stirred for 6 h at 25° C. while the NaOH dissolved. The solution was cooled to 0° C., and 3,5-dibromopyridine (5.92 g, 25.0 mmol) was added. After stirring for 15 min at 0° C. and 45 min at 25° C., the mixture was poured into water (250 mL) and extracted with ether (2×100 mL). Drying (Na2SO4) and evaporation of the ether, followed by vacuum distillation of the crude product gave 4.39 g (80.6% yield) of colorless oil, bp 91-95° C. at 0.30 mm Hg.
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O-:29])(=O)=[O:27])=[CH:22][CH:21]=1>CN(C)C=O>[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:3])(=[O:29])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of thionyl chloride (8.0 mL) and 2 drops of N,N-dimethylformamide stirring under nitrogen at 0° C. is added the title B compound, 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonic acid sodium salt (1.42 g, 3.8 mmol) in one portion. The resulting suspension is stirred at 0° C. for 10 minutes. The ice bath is removed and the suspension is stirred at room temperature for 1.5 hours. Three more drops of N,N-dimethyl-formamide is added, after which a clear solution results upon stirring for an additional hour. The solution is concentrated under vacuo to a solid residue. The residue is partitioned between water (20 mL) and ethyl acetate (20 mL). The organic layer is separated and washed successively with water (3×20 mL), 0.1N aqueous sodium hydroxide (3×20 mL) and brine (20 mL). The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo to give an oil which slowly solidifies to give 0.48 g of 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride: [M+1]+=363.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:42][CH3:43])=[C:6]([C@@:8]2([F:41])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:22][C:23](=[O:39])[CH2:24][CH2:25][O:26][P:27]([O:34]C(C)(C)C)([O:29]C(C)(C)C)=[O:28])[C:9]2=[O:40])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:42][CH3:43])=[C:6]([C@@:8]2([F:41])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:22][C:23](=[O:39])[CH2:24][CH2:25][O:26][P:27]([OH:34])([OH:29])=[O:28])[C:9]2=[O:40])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)CCOP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)CCOP(=O)(O)O)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.7 %

Procedure:
To a 25 mL flask containing (S)-3-(di-tert-butoxy-phosphoryloxy)-propionic acid 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indol-1-ylmethyl ester ((S)-XVII, n=1) (0.144 g, 0.22 mmol) was added 2 mL anhydrous dichloromethane, and trifluoroacetic acid (0.075 g, 0.66 mmol). The reaction was allowed to stir at room temperature for 4 hours. The dichloromethane was evaporated in vacuo, and the crude foam was purified by reverse phase chromatography (C18 2:1CH3CN:H2O) producing the title compound (0.070 g, 59%) as a white powder. 1H NMR (CDCl3 400 MHz): δ=7.70 (s, 1H), 7.36 (s, 1H), 7.32-7.27 (m, 3H), 7.20 (d, 1H, J=6 Hz), 6.73 (d, 1H, J=8 Hz), 5.91 (d, 1H, J=11.2 Hz), 5.73 (d, 1H, J=11.2 Hz), 4.27 (m, 2H), 3.44 (s, 3H), 2.75 (m, 2H); 31P NMR (CDCl3 162 MHz) δ=1.15; 19F NMR (CDCl3 376 MHz) δ=−63.2, −159.4; LRMS [M−H]−539.89, [M+NH4]+564.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][CH3:25])O1>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][CH3:25])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CSc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccccc1-c1cnc(Cl)nc1Cl
Temperature: 70 °C
Yield: 71.9 %

Procedure:
A solution of 2,4-dichloro-5-iodopyrimidine (50.15 g, 182 mmol), 4,4,5,5-tetramethyl-2-(2-(methylthio)phenyl)-1,3,2-dioxaborolane (47.9 g, 192 mmol) in THF (1368 ml) and water (456 ml) was degassed with nitrogen. Pd(PPh3)4 (10.54 g, 9.12 mmol) was added and degassing continued for several minutes. The mixture was then heated to reflux at 70° C. overnight. After 24 hrs the reaction was cooled to room temperature, the aqueous layer was removed, and the organic layer was washed with brine. The aqueous layer was extracted once with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography in 10-15% DCM 1-2% EtOAc/heptanes (v/v/v). The product was further purified by dissolving in EtOH and precipitating with heptanes, yielding 35.5 g (72% yield) of 2,4-dichloro-5-(2-(methylthio)phenyl)pyrimidine as white solids.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH:44]1CC[S:46](=[O:50])(=[O:49])[CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH:14]3[CH2:44][CH2:45][S:46](=[O:50])(=[O:49])[CH2:15]3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S1(=O)CCC(Br)C1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(C3CCS(=O)(=O)C3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromo-tetrahydro-thiophene 1,1-dioxide and isolated as white solid. MS (m/e): 401.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Cl-].[NH4+]>C1COCC1>[CH:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=[CH:11][C:2]=1[B:17]([OH:22])[OH:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2c(c1)CCCC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)CCCC2
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To 6.60 g of 6-bromo-1,2,3,4-tetrahydronaphthalene in THF (60 ml) cooled on a dry ice-acetone bath, 25 ml of n-butyllithium (1.60 M/hexane solution) was added dropwise over 30 minutes in an argon stream, and after the dropwise addition, the reaction mixture was stirred for 1 hour under the same conditions. Then, 6.47 g of triisopropyl borate was added dropwise over 20 minutes, and after the dropwise addition, the reaction mixture was allowed to react for 3.5 hours. The reaction mixture was poured into ice-cold water and brought to almost neutral (pH 8) with ammonium chloride and then extracted with ethyl acetate (400 ml×1, 100 ml×2), and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol/chloroform=1/30), and the resulting solid was washed with a small amount of cold hexane to obtain 5.11 g of the desired product (yield 93%).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[C:32]1([S:38]([O:24][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:25])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OS(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
The compound of step 2 of example 15 (200 mg, 0.586 mmol) was dissolved in ACN (3 ml), potassium carbonate (243 mg, 1.7 mmol) and benzenesulfonyl chloride (155 mg, 0.88 mmol) were added, and the mixture was stirred for 30 min. The mixture was partitioned between EA and saturated sodium chloride solution, the aqueous phase extracted with EA, and the combined organic extracts were dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was dissolved in dioxane (0.8 ml), lithium hydroxide (0.8 ml of a 1 N aqueous solution) was added, and the mixture was stirred at room temperature for 2.5 h. The mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase extracted with EA, and the combined organic extracts were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to give 115 mg of the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Cl.[NH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:5]([NH:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][CH:12]=1)(=[O:7])[CH3:6]
Reactant: N#Cc1cccc(CN)n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Acetic anhydride (1.29 ml) was added dropwise to a mixture of 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (2.10 g) in pyridine (21 ml). The solution was stirred for four hours at ambient temperature and evaporated in vacuo. The residue was mixed with aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo to give 6-(acetylaminomethyl)-2-pyridinecarbonitrile (1.72 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[F:9][C:10]([F:15])([F:14])[CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][C:10]([F:15])([F:14])[F:9])=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: OCCC(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)CCOc1ccc(Br)nc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1.00 g (5.75 mmol) 2-bromo-5-hydroxypyridine, 0.66 g (5.75 mmol) 3,3,3-trifluoro-1-propanol and 1.51 g (5.75 mmol) triphenylphosphine are added to 50 mL THF. Then 1.32 g (5.75 mmol) di-tert-butyl azodicarboxylate are added and the reaction mixture is stirred at 60° C. for 3 h. The solvent is removed in vacuo and the crude product is purified by column chromatography (silica gel, PE/EtOAc).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH3:18])[CH:12]=[CH:13][C:14]=1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:20][C:21]1[S:22][CH2:23][CH2:24][N:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:19])[N:11]([CH3:18])[CH:12]=[CH:13][C:14]=1[C:15]([SH:22]1[CH2:23][CH2:24][NH:25][C:21]1=[S:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc(C(=O)O)c(OCc2ccccc2)c1=O
Reactant: SC1=NCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1ccc(C(=O)[SH]2CCNC2=S)c(OCc2ccccc2)c1=O
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 3-benzyloxy-4-carboxy-1-methyl-2(1H)-pyridinone (1.05 g, 4 mmol), 2-mercaptothiazoline (0.50 g, 4.2 mmol) and a catalytic amount of 4-dimethylaminopyridine (DMAP) in dry methylene chloride (50 mL), N,N'-dicyclohexylcarbodiimide (DCC) (0.86 g, 4.2 mmol) is added. Alter stirring for 4 hours, the dicyclohexylurea (DCU) solids are removed by filtration, the yellow filtrate is rotary evaporated to give a yellow solid. Crystallization from isopropanol-methylene chloride gives the title compound (1.16 g, 80.4%) as bright yellow crystalline plates, m.p. 149°-150° C. 1H NMR (250 MHz, CDCl3) δ2.867 (t, 2H, J=7.32), 3.594 (s, 3H), 4.313 (t, 2H, J=7.33), 5.301 (s, 2H), 6.107 (d, 1H, J=6.99), 7.126 (d, 1H, J=7.00), 7.31-7.45 (m, 5H). Anal for C17H16N2O3S2Calcd. (found): C, 56.64 (56.36); H, 4.47 (4.47); N, 7.73 (7.73); S, 17.78 (17.41).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:13])[N:8]([CH3:14])[C:7]2=[O:15].C([Sn](CCCC)(CCCC)[C:21]([O:23]CC)=[CH2:22])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:13])[N:8]([CH3:14])[C:7]2=[O:15])(=[O:23])[CH3:22]
Reactant: CSc1nc2c(Br)cccc2c(=O)n1C
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1nc2c(C(C)=O)cccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.5 %

Procedure:
A solution of 8-bromo-3-methyl-2-(methylthio)quinazolin-4(3H)-one (500 mg, 1.753 mmol), tributyl(1-ethoxyvinyl)stannane (Synthonix, Wake Forest, N.C.; 0.652 mL, 1.929 mmol), and Pd(PPh3)4 (81 mg, 0.070 mmol) in toluene (9.0 mL) was stirred under argon at 100° C. for 19 h, then at 110° C. for 1 d. The reaction was cooled to 25° C. and concentrated onto silica gel. Chromatographic purification (silica gel, 0-50% EtOAc/Hexanes) furnished 8-acetyl-3-methyl-2-(methylthio)quinazolin-4(3H)-one (128.7 mg, 0.518 mmol, 30% yield) as a white solid: m/z (ESI, +ve) 249.2 (M+H)+. 8-(1-ethoxyvinyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one (35.5 mg, 0.128 mmol, 7% yield) as a colorless oil: m/z (ESI, +ve) 277.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CN1CCCC(O)C1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCCC(Oc2nc(N)nc(-c3ccco3)c2C#N)C1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 3-hydroxy-1-methylpiperidine and DBU in DME. ES-MS m/e (%): 300 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([N+:14]([O-:16])=[O:15])=[C:4](Cl)[N:3]=1.[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1N1CCOCC1
Reactant: Nc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(Nc2cccnc2)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
A mixture of 4-(2,6-dichloro-5-nitro-4-pyrimidinyl)morpholine (U.S. Pat. Appl. Publ. No. 2009/0181963, the disclosure of which is incorporated herein by reference in its entirety) (1.89 g, 3.6 mmol) and 3-aminopyridine (0.68 g, 7.2 mmol) in THF at −70° C. was treated with 7.2 mL of LiHMDS (1M solution in THF, 2 eq.) and the mixture was stirred at that temperature for 1.5 hrs, and then allowed to warm to room temperature. The solvent was removed and the crude product was extracted with 0.5 M HCl. After filtration, the aqueous solution was made basic with sat. Na2CO3, to give a precipitate, which was collected by filtration, and dried, to give 1.12 g (52% yield) of 2-chloro-6-(4-morpholinyl)-5-nitro-N-(3-pyridinyl)-4-pyrimidinamine: mp (aq. MeOH)>310° C.; 1H NMR (CDCl3) δ 10.19 (br s, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.45 (dd, J=4.8, 1.4 Hz, 1H), 8.12 (ddd, J=8.3, 2.6, 1.5 Hz, 1H), 7.35 (dd, J=8.4, 4.8 Hz, 1H), 3.81 (m, 4H), 3.61 (m, 4H).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>CN(C)C=O.CO.[Cu]>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(C)nc2)cc1

Procedure:
7.4 g of a potassium salt of 5-hydroxy-2-methylpyridine, 8.5 g of p-bromotoluene and 500 mg of a copper powder were suspended in 25 ml of dimethylformamide, and the mixture was allowed to react in a nitrogen gas stream at 130° C. for 14 hours under stirring. The reaction mixture was diluted with 70 ml of methanol and filtered. The filtrate was immediately concentrated, and to the residue was added 150 ml of chloroform. The mixture was washed with 100 ml of a 0.01 N aqueous sodium hydroxide solution, whereby the unreacted 5-hydroxy-2-methylpyridine shifted to the aqueous layer. The chloroform layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 8.9 g of oily 5-(p-methylphenoxy)-2-methylpyridine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.O.N1(O)C2C=CC=CC=2N=N1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C>[N:36]1([C:7](=[O:9])[CH2:6][O:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:12]=[CH:11][CH:10]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: O=C(O)COc1cccc(O)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1cccc(O)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-hydroxyphenoxy)acetic acid (246 mg) in DMF (10 mL) were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (336 mg), 1H-benzotriazol-1-ol hydrate (268 mg) and morpholine (153 μL) at room temperature, followed by overnight stirring at room temperature. The solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0-95/5) to obtain 3-(2-(morpholin-4-yl)-2-oxoethoxy)phenol (305 mg).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH2:13][C@@H:11]([OH:12])[CH2:10][C@@H:6]1[C:7]([OH:9])=[O:8].[CH3:14]O>>[OH:12][C@@H:11]1[CH2:13][NH:5][C@@H:6]([C:7]([O:9][CH3:14])=[O:8])[CH2:10]1
Reactant: O=C(O)[C@H]1C[C@H](O)CN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1C[C@H](O)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.83 ml, 11.4 mmol) is added dropwise into a suspension of H-D-Hyp-OH (1.0 g, 7.6 mmol) in methanol (25 ml) at 0° C. The mix is stirred at room temperature for 1 hr, then 65° C. for another 1 hr. Solvent is evaporated to dryness. Compound 18 is obtained as a white crystal and used for the next step.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:11]([NH2:34])[C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[C:14]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35](Cl)(=[O:37])[CH3:36].C(N(CC)CC)C>ClCCl>[CH:1]1([NH:7][C:8]([C:10]2[CH:11]([NH:34][C:35](=[O:37])[CH3:36])[C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[C:14]([O:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[CH:13]=3)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)Cl
Reactant: NC1C(C(=O)NC2CCCCC2)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1C(C(=O)NC2CCCCC2)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 19.9 %

Procedure:
1-Amino-6-(2-morpholine-4-yl-ethoxy)-3-phenyl-1H-indene-2-carboxylic acid cyclohexylamide (14 mg, 0.03 mmol) prepared in Example 22 was dissolved in dichloromethane (10 mL), acetyl chloride (24 mg, 0.3 mmol) and triethylamine (30 mg, 0.3 mmol) were added thereto in order at 0° C., and stirred for 24 hrs at RT. The resulting mixture washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 3 mg of the titled compound (yield: 20%).