Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1OCC(C[O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])[C:12]=2[CH3:29])CO1.[Na:30].COC1OCC(COC2C=CN=C(CS(C3NC4C=CC=CC=4N=3)=O)C=2C)CO1.[CH3:60][C:61]1([CH3:68])[O:66][CH2:65][CH:64](O)[CH2:63][O:62]1>>[Na:30].[CH3:60][C:61]1([CH3:68])[O:66][CH2:65][CH:64]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)=[O:19])[C:12]=2[CH3:29])[CH2:63][O:62]1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: CC1(C)OCC(O)CO1
Agent: [Na]
Product: Cc1c(OC2COC(C)(C)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 18 %

Procedure:
The same procedure as in the steps (6d), (6e), and (6f) of Example 6 was repeated using 2,2-dimethyl-1,3-dioxan-5-ol obtained in the step (9a) to obtain the title compound (530 mg, total yield: 18%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][C@H:39]([CH3:43])[CH2:38]1)=[O:36]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH2:41][CH2:42][N:37]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:38][C@H:39]5[CH3:43])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COCC(=O)N1CCN[C@H](C)C1
Product: COCC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)[C@H](C)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-2-(R)-methyl-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-Methoxy-1-(3-(R)-methyl-piperazin-1-yl)-ethanone following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([NH:16][CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[N:24]=[CH:23]1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH:17]1([N:16]([CH:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:13]=2)[CH3:15])[C:27]([C:25]2[N:24]=[CH:23][N:22]([CH3:21])[CH:26]=2)=[O:28])[CH2:20][CH2:19][CH2:18]1
Reactant: CC(NC1CCC1)c1ccnc(-c2ccc(F)cc2)c1
Reactant: Cn1cnc(C(=O)Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(c1ccnc(-c2ccc(F)cc2)c1)N(C(=O)c1cn(C)cn1)C1CCC1
Yield: 85.7 %

Procedure:
A solution of N-{1-[2-(4-fluorophenyl)pyridin-4-yl]ethyl}cyclobutaneamine (100 mg), 1-methyl-1H-imidazole-4-carbonyl chloride (110 mg) and triethylamine (100 mg) in chloroform (5 mL) was stirred at room temperature overnight. Water was added thereto, followed by extraction with chloroform, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=75:25-0:100) to afford the title compound (120 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[CH:16]=[C:15]([CH3:18])[S:14][C:13]=3[NH:12][C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH2:4][C@@H:3]1[CH2:23][OH:24].[CH3:25]OC[C@@H]1NCCN(C2C3C=C(C)SC=3NC3C=CC=CC=3N=2)C1>>[CH3:25][O:24][CH2:23][C@@H:3]1[N:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[CH:16]=[C:15]([CH3:18])[S:14][C:13]=3[NH:12][C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH2:4]1
Reactant: COC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CO)C1
Product: COC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1C

Procedure:
Using a similar method to (R)-[1-methyl-4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-methanol, using (R)-10-(3-methoxymethyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (800 mg) affords the title compound as a yellow solid (758 mg): mp 76-80° C.; 1H NMR (CDCl3) δ 2.31 (s, 3H), 2.42-2.27 (m, 2H), 2.39 (s, 3H), 2.84 (dt, 1H), 2.99 (dd, 1H), 3.14 (ddd, 1H), 3.36 (s, 3H), 3.46 (dd, 1H), 3.54 (dd, 1H), 3.91 (d, 1H), 4.02 (d, 1H), 4.96 (s, 1H), 6.30 (d, 1H), 6.60 (dd, 1H), 6.87 (dt, 1H), 6.96 (dt, 1H), 7.04 (dd, 1H); MS (APCI) m/z (rel intensity) 357.2 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[S:24][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH3:25]N(C=O)C.[H-].[Na+].CI>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH3:25])[C:9]([C:11]1[S:24][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CN(C)C=O
Reactant: O=C(Nc1ccncc1Cl)c1cc2c(s1)-c1ccccc1OCC2
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Following Example 17, 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonylchloride and 4-amino-3-chloropyridine were reacted to give N-(3-chloropyridin-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide. To a solution of N-(3-chloropyridin-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.340 g, 0.953 mmol) in DMF (5 mL, 60 mmol) was added sodium hydride (0.0381 g, 0.953 mmol). The reaction mixture was stirred at room temperature for about 10 min. followed by the addition of methyl iodide (65.25 uL, 1.048 mmol) and stirred at room temperature for another 1 hr. An aliquot was analyzed by LC/MS showing clean conversion to desired product. The reaction mix was diluted with EtOAc and washed with water/saline, dried (Na2SO4) then concentrated to a residue which was analyzed by LC/MS and 1H NMR. The crude product was taken into DMF at about 100 mg/mL, but was not totally soluble. Soluble material was purified by preparative RP-HPLC to give 184 (yield 30% of theoretical). MS: (ESI+) 372.2
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]#[N:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>CN1C(=O)CCC1.O>[C:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:17]([C:2]1[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:18][CH2:19][CH2:20]2)#[N:28]
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: N#Cc1ccc2c(c1)CCCN2
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc(C#N)ccc43)nc2c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.26 mmol) in NMP (0.5 mL) was added 1,2,3,4-tetrahydroquinoline-6-carbonitrile (597 mg, 3.77 mmol) with stirring for 1 h at 150° C. in an oil bath. The resulting solution was diluted with water (100 mL) and the solids were collected by filtration to afford methyl 3-(6-cyano-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (200 mg, 44%).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].COC1C=CC(O)=CC=1.[C:33]([O:37]CC1OC1)(=[O:36])[CH:34]=[CH2:35].[Al]>P([O-])([O-])([O-])=O>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:33]([O-:37])(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)OCC1CO1
Agent: COc1ccc(O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: C=CC(=O)[O-]

Procedure:
Four batches of sucrose acrylate monomers were prepared. For each batch, 10 g of sucrose, 1.9 g of TAB (99%), and a small amount of p-methoxyphenol, which was used as a polymerization inhibitor, were dissolved in 20 ml phosphate buffered aqueous solution (pH 7.2, 0.05 M) in a 200 ml Erlenmeyer flask equipped with magnetic stirrer. The TAB was used as a phase transfer catalyst. Glycidyl acrylate (GA) (Lancaster Synthesis, Inc.; Windham, N.H.) was added to each batch to make sucrose:GA ratios of 1:4, 1:1.5, 1:1:5, and 1:8. The reaction was performed at room temperature with continuous stirring and the flasks were covered with aluminum foil to avoid the light.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:14]2[N:18]([CH2:19][CH2:20][CH2:21]O)[C:17](=[O:23])[CH2:16][S:15]2)[CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])([CH3:3])[CH3:2].S(Cl)([Cl:26])=O>ClCCl>[CH:1]([C:4]1[CH:5]=[C:6]([CH:14]2[N:18]([CH2:19][CH2:20][CH2:21][Cl:26])[C:17](=[O:23])[CH2:16][S:15]2)[CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C2SCC(=O)N2CCCO)cc(C(C)C)c1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1cc(C2SCC(=O)N2CCCCl)cc(C(C)C)c1O
Yield: 60.2 %

Procedure:
To a dichloromethane (50 ml) solution of the 2-(3,5-diisopropyl-4-hydroxyphenyl)-3-(3-hydroxypropyl)-1,3-thiazolidin-4-one (1.97 g) obtained in Reference Example 1 was added thionyl chloride (1.04 g) under a nitrogen atmosphere, then the mixture was refluxed for 1 hour. The solvent was evaporated under reduced pressure, and to the residue were added brine and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane) to afford 1.25 g (60%) of the title compound as pale yellow crystals. mp 105-106° C. NMR (CDCl3, 60 MHz) δ: 1.23 (12H, d, J=6.6 Hz), 1.5-2.1 (2H, m), 2.6-3.8 (6H, m), 3.67 (2H, brs), 5.20 (1H, s), 5.50 (1H, brs), 6.88 (2H, s)
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH:21]=[C:7]1[C:6](=[O:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1=[O:1])[CH3:20]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CC(=O)CC(=O)C1
Solvent: Cc1ccccc1
Product: CN(C)C=C1C(=O)CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
To a solution of 122 (12.39 g, 58.11 mmol) in toluene (120 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (11.62 mL, 87.16 mmol) and the reaction was heated to 80° C. for 30 min then at 50° C. for 1 h. The reaction was concentrated to afford 16.5 g (105%) of crude tert-butyl 4-((dimethylamino)methylene)-3,5-dioxopiperidine-1-carboxylate (124) which was used without additional purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.CN(C=O)C.Br[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
Potassium carbonate (152 g, 1.1 mol) and 4-bromophenol (95.2 g, 550 mmol) were added to a DMF (500 mL) solution of methyl 2-bromomethylbenzoate (115 g, 500 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and thereafter the solvents were distilled off under a reduced pressure. The residue was purified by column chromatography (hexane-toluene=1:1), to give 139 g (86%) of the captioned compound in the form of a colorless oily product.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1)=[O:2].Cl[CH2:13][C:14](=[O:16])[CH3:15].C(N(C(C)C)CC)(C)C>C(O)C>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:13]([C:14](=[O:16])[CH3:15])=[CH:8][C:7]=2[CH:10]=1)=[O:2]
Reactant: O=Cc1ccc(O)c(C=O)c1
Reactant: CC(=O)CCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc2cc(C=O)ccc2o1
Reaction time: 5 h

Procedure:
About 5.0 g (1.0 equivalent) of 5-formylsalicylaldehyde was dissolved in about 15 ml of ethanol, and about 3.25 g (about 1.05 equivalents) of monochloroacetone was added thereto. Then, about 8.7 ml (about 1.50 equivalents) of diisopropylethylamine was added thereto at room temperature. The mixture was heated while being stirred for about 5 hours, and maintaining the reaction temperature at about 60° C. to 70° C. After confirming the completion of the reaction by TLC, the mixture was allowed to cool down. The produced solid matter was separated by filtering, and washed with ethanol. Then, the solid matter was recrystallized from ethanol so as to obtain about 5.8 g of the target 5-formyl-2-acetylbenzo[b]furan in the form of white crystal (yield: about 92.6%).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:22])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:22]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(OCC(C)C)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)COc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 1.5 h
Yield: 48 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 90 minutes while stirring through a solution, cooled to -70°, of 5.1 g of (RS)-2-(2-buten-1-yl)-6-isobutoxy-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.16 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 170 ml of dichoromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 2.3 g (48%) of (RS)-2-(2-oxoethyl)-6-isobutoxy-1-indanone were obtained as a red-brown oil.
Reaction SMILES: [OH:1][C@:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:30])[C:3]([N:5]1[CH2:29][CH2:28][CH2:27][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH:19]C(OC(C)(C)C)=O)=[O:8])=[O:4]>CCOC(C)=O>[OH:1][C@:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:30])[C:3]([N:5]1[CH2:29][CH2:28][CH2:27][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH2:19])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@@](C)(O)c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN)c1ccccc1
Temperature: 0 °C

Procedure:
1-((2S)-2-Hydroxy-2-phenyl-propanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide from the previous step (0.125 g, 0.24 mmol) was dissolved in EtOAc (10 mL) and cooled with stirring to 0° C. Into this solution was bubbled in HCl gas for 5 min. The resulting solution was stirred at 0° C. for 30 min, then concentrated in vacuo. The solid which had formed was triturated with Et2O and collected by filtration and washed with several portions of ether. The hydrochloride salt of the title compound was obtained as a white solid after drying overnight under high vacuum (HPLC RT=2.66 min, method A; LC-MS m/z=416.1; 1H NMR, 400 MHz, CD3OD, 7.54 ppm (s, 1H), 7.42 ppm (m, 4H), 7.34 ppm (m, 2H), 7.26 ppm (m, 1H), 4.54 ppm (d, 1H), 4.4 ppm (d, 1H), 4.3 ppm (m, 2H), 3.6 ppm (m, 1H), 3.24 ppm (m, 1H), 2.08 ppm (m, 1H), 1.8 ppm (m, 1H), 1.7 ppm (m, 1H), 1.6 ppm (s, 3H), 1.5 ppm (m, 1H)).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[N:6][C:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:8][CH:9]=1)([O-])=O.ClC1N=C(N[C@@H](C2C=CC=CC=2)C)C([N+]([O-])=O)=CC=1.N1C2C(=C(B(O)O)C=CC=2)C=CC=1.[C:61](=O)([O-])[O-:62].[K+].[K+]>CN(C=O)C.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>[C:23]1([C@H:21]([N:20]2[C:5]3=[N:6][C:7]([C:10]4[CH:19]=[CH:18][CH:17]=[C:16]5[C:11]=4[CH:12]=[CH:13][CH:14]=[N:15]5)=[CH:8][CH:9]=[C:4]3[NH:1][C:61]2=[O:62])[CH3:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H](Nc1nc(-c2cccc3ncccc23)ccc1[N+](=O)[O-])c1ccccc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[C@@H](Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccccc1
Agent: OB(O)c1cccc2ncccc12
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2ccc(-c3cccc4ncccc34)nc21
Temperature: 85 °C
Yield: 74 %

Procedure:
(R)-3-Nitro-N-(1-phenylethyl)-6-(quinolin-5-yl)pyridin-2-amine. To a solution of (R)-6-chloro-3-nitro-N-(1-phenylethyl)pyridin-2-amine (1.12 g, 4.03 mmol) and quinolin-5-ylboronic acid (0.91 g, 5.24 mmol) in DMF (75 mL) was added potassium carbonate (2.23 g, 16.1 mmol) in water (25 mL). The reaction solution was purged with a stream of nitrogen followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.466 g, 0.403 mmol). After heating at 85° C. for 2 h, the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography to afford the title compound (1.1 g, 74% yield). MS (ESI) m/z 371.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)=[S:10])[CH:7]=1
Reactant: Nc1cc[nH]n1
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: Cc1ccc(Cl)cc1NC(=S)Nc1cc[nH]n1
Yield: 66 %

Procedure:
Prepared using Method A from 5.5 g (30.1 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 2.5 g (30.1 mmol) of 3-amino-1H-pyrazole to give 5.3 g of tite compound as a white solid (66% yield, m.p. 221-222° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][C:8]([CH3:22])=[C:9]([CH2:13][C:14]3[O:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[C:10]=2[CH3:12])[O:5][CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][O:49][C:50]1[C:55]([NH2:56])=[C:54]([O:57][CH3:58])[N:53]=[C:52]([NH:59][CH2:60][CH2:61][CH2:62][N:63]2[CH2:68][CH2:67][O:66][CH2:65][CH2:64]2)[N:51]=1>CN(C=O)C>[CH3:58][O:57][C:54]1[C:55]([NH:56][C:19]([C:17]2[O:18][C:14]([CH2:13][C:9]3[C:10]([CH3:12])=[C:11]4[C:6](=[CH:7][C:8]=3[CH3:22])[O:5][CH2:4][CH2:3][C:2]4([CH3:1])[CH3:23])=[CH:15][CH:16]=2)=[O:21])=[C:50]([O:49][CH3:48])[N:51]=[C:52]([NH:59][CH2:60][CH2:61][CH2:62][N:63]2[CH2:68][CH2:67][O:66][CH2:65][CH2:64]2)[N:53]=1
Reactant: COc1nc(NCCCN2CCOCC2)nc(OC)c1N
Reactant: Cc1cc2c(c(C)c1Cc1ccc(C(=O)O)o1)C(C)(C)CCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc(NCCCN2CCOCC2)nc(OC)c1NC(=O)c1ccc(Cc2c(C)cc3c(c2C)C(C)(C)CCO3)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.4 %

Procedure:
In a 50-mL round-bottom flask, 5-[(4,4,5,7-tetramethyl-3,4-dihydro-2H-chromen-6-yl)methyl]-2-furoic acid (114.53 mg, 0.364 mmol) and HATU (152.36 mg, 0.400 mmol) were dissolved in DMF (2 mL). To this solution 4,6-dimethoxy-N2-(3-morpholin-4-ylpropyl)pyrimidine-2,5-diamine (209) (108.32 364 mmol) and triethylamine,(91.98 mg, 0.911 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solution was filtered through a PTFE (polytetrafluoroethylene) membrane micro filter. The crude mixture was purified by HPLC C18 column, eluted with aceonitrile/water/0.1% ACOH (30% ACN-70% CAN over 30 min) to yield N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[(4,4,5,7-tetramethyl-3,4-dihydro-2H-chromen-6-yl)methyl]-2-furamide (I1) (15.9 mg, 7% yield). 1H NMR (CDCl3) δ 1.31(s, 6H), 1.80(m, 4H, J=6.80, 6.42, 6.04 Hz), 2.15(s, 3H), 2.23(s, 3H), 2.49(m, 6H), 2.63(t, 2H, J=6.80 Hz), 3.49(q, 2H, J=6.04, 5.67 Hz), 3.75(t, 4H, J=4.53 Hz), 3.87(s, 6H), 3.98(s, 2H), 5.74(s, 1H), 5.80(d, 1H, J=3.02 Hz), 6.56(s, 1H), 7.01 (d, 1H, J=3.02 Hz), 7.05(s, 1H). (M+1) 594.2.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[CH:11]=O)=[CH:6][CH:5]=1.Cl.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17]>O1CCCC1>[CH2:20]([O:19][C:16](=[O:18])/[CH:17]=[CH:11]/[C:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)([CH3:14])[CH3:13])[CH3:21]
Reactant: CCOC(C)=O
Reactant: CC(C)(C=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of triethyl phosphonoacetate (4.58 ml) in tetrahydrofuran (30 ml) was added portionwise sodium hydride (1.00 g, 60% dispersion in oil). The mixture was stirred for 1 hour at room temperature and then a solution of 2-(4-fluoro-phenyl)-2-methyl-propionaldehyde (3.46 g) in tetrahydrofuran (10 ml) was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 day. The mixture was then acidified by addition of 1 M aq. hydrochloric acid and taken up in ethyl acetate. The mixture was washed sequentially with water and with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc gradient) to yield a colourless oil, (4.14 g, 84%); MS (ISP): 237.3 ([M+H]+).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.N1C=C[CH:13]=[CH:12][C:11]=1[C:16]1C=CC=CN=1.C([Li])CCC.CC(CC)C(Cl)=O.Cl>O1CCCC1>[CH3:16][CH:11]([CH2:12][CH3:13])[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: c1ccc(-c2ccccn2)nc1
Agent: CCC(C)C(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(C)CC
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of monoethyl malonate (49.5 mL, 0.42 mol) and a few milligrams of 2,2′-bipyridyl in tetrahydrofuran at −70° C. was added 2.5 M n-butyl lithium in hexanes (0.34 L, 0.84 mol) dropwise over approximately 1.5 hours. Then 2-methylbutyryl chloride (26 mL, 0.21 mol) was added dropwise. The mixture was allowed to warm to ambient temperature and was then poured into 1 N hydrochloric acid. The mixture was extracted three times with ether and the combined organic layers were dried over magnesium sulfate and concentrated. The resulting oil was purified by vacuum distillation (boiling range 75-85° C.) to afford ethyl 4-methyl-3-oxohexanoate (36.4 g, 100%). 1H-NMR (400 MHz, DMSO-d6) δ 4.06 (q, J=7 Hz, 2H), 3.60 (s, 2H), 2.57-2.49 (m, 1H), 1.64-1.53 (m, 1H), 1.36-1.26 (m, 1H), 1.15 (t, J=7 Hz, 3H), 0.97 (d, J=7 Hz, 3H), 0.78 (t, J=7 Hz, 3H).