Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([OH:27])=O)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:53]([N:56]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=1)[CH2:57][CH2:58][CH3:59])[CH2:54][CH3:55]>CN(C=O)C>[CH2:53]([N:56]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([NH:67][C:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([CH2:14][N:7]([CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)[CH2:8][C:9]3[NH:13][CH:12]=[CH:11][N:10]=3)=[CH:16][CH:17]=2)=[O:27])=[CH:63][CH:62]=1)[CH2:57][CH2:58][CH3:59])[CH2:54][CH3:55]
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)c2ccccc12
Reactant: CCCN(CCC)Cc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (130 mg) obtained in Example 36-4 was dissolved in DMF (3.0 ml) and then added with DCC (60.0 mg) and HOBt (40.0 mg), followed by stirring at room temperature for 2 hours. The compound (50.0 mg) obtained in Example 19-2 was added to the solution at room temperature, and the whole was stirred overnight. After completion of the reaction, insoluble matter was removed from the solution through a G4 glass filter and the solvent was distilled off. The residue was dissolved in chloroform and then washed with 1 mol/l hydrochloric acid. The organic layer was added with hydrochloric acid to separate the solution into layers. Then, the aqueous layer was added with a sodium hydroxide aqueous solution to adjust it to pH 12. The aqueous layer was subjected to extraction with chloroform, and the organic layer was dried with anhydrous sodium sulfate. Then, the solvent was distilled off. Subsequently, the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (17.4 mg) of the subject compound as a white foamed compound.
Reaction SMILES: COC1C=C(CNCCCNCCCCNCCCNCC2C=CC(O)=C(OC)C=2)C=CC=1O.OCC[CH:38]1[N:43]2[C:44]3[C:49]([CH2:50][CH2:51][CH:42]2[CH2:41][CH2:40][CH2:39]1)=[C:48]([OH:52])[CH:47]=[C:46]([O:53][CH:54]([CH2:56][CH2:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH3:55])[CH:45]=3.C(N(CC)CC)C.[C:72]([O:75][C:76](=[O:78])[CH3:77])(=O)[CH3:73]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:76]([O:75][C:72]1[CH:47]=[C:46]([O:53][CH:54]([CH2:56][CH2:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH3:55])[CH:45]=[C:44]2[C:73]=1[CH:50]([CH2:49][CH2:48][OH:52])[CH2:51][CH:42]1[CH2:41][CH2:40][CH2:39][CH2:38][N:43]12)(=[O:78])[CH3:77]
Reactant: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1C(CCO)CCCC1CC2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cc(OC(C)CCCc2ccccc2)cc2c1C(CCO)CC1CCCCN21
Temperature: 25 °C

Procedure:
A solution of 4.09 g. (0.01 mole) dl-6-(2-hydroxyethyl)-7-hydroxy-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline in 60 ml. methylene chloride containing 1.01 g. (0.01 mole) triethylamine is cooled to 0° C. while stirring in a nitrogen atmosphere. To this is added a solution of 1.22 g. (0.01 mole) 4-dimethylaminopyridine in 5 ml. of methylene chloride followed by 1.02 g. (0.01 mole) acetic anhydride. After stirring at 0°-5° C. for one hour, the mixture is allowed to warm to room temperature, extracted with methylene chloride and the extracts washed with sodium bicarbonate. After drying over anhydrous magnesium sulfate and evaporation of solvent, the desired product is obtained. It can be purified by column chromatography on silica gel if desired.
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][C:57]=1[CH2:66][NH2:67]>CN(C)C=O>[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]([F:63])([F:64])[F:65])=[CH:58][C:57]=1[CH2:66][NH:67][C:8](=[O:10])[C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:11][CH3:12]
Reactant: CC[C@H](C(=O)O)c1ccccc1
Reactant: NCc1cc(C(F)(F)F)ccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C(=O)NCc1cc(C(F)(F)F)ccc1F)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of (S)-2-phenylbutanoic acid (1-d, 50 mg, 0.30 mmol, Sigma-Aldrich, Milwaukee, Wis.) and diisopropylethylamine (98 uL, 0.60 mmol) in N,N-dimethylformamide (1 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 158 mg, 0.30 mmol). After 15 min, (2-fluoro-5-(trifluoromethyl)phenyl)methanamine (1-g, 60 mg, 0.30 mmol, Synthesis, Inc., Wyndham, N.H.) was added. The reaction mixture was stirred for 3 h, partitioned between dichioromethane and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with 0.5N—HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was concentrated in vacuo to give the desired product (1-1); HRMS (M+1)=340.129; 1H NMR (500 MHz, CDCl3) δ7.49 (bs, 1H), 7.41 (d, 1H, J=6.5 Hz), 7.34-7.26 (m, 5H), 7.10 (t, 1H, J=9.0 Hz), 5.77 (bs, 1H), 4.47 (d, 1H, J=3.0 Hz), 3.30 (t, 2H, J=7.5 Hz), 2.22 (m, 1H), 1.82 (m, 1H), 0.89 (t, 3H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[Si:21]([O:9][CH2:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=[C:2]([Cl:1])[N:7]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: COc1cc(Cl)nc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)nc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of 6-chloro-2-hydroxymethyl-4-methoxypyridine (1.85 g), which was prepared by a method mentioned in Tokkaihei 10-59942 (JP1998-59942A), and imidazole (0.87 g) in N,N-dimethylformamide (30 mL) was added tert-butyldimethylchlorosilane (1.77 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=85/15) to give 2-(tert-butyldimethylsilyloxy)methyl-6-chloro-4-methoxypyridine (2.83 g). To a solution of N,N-diisopropylamine (0.54 mL) in tetrahydrofuran (20 mL) was added n-butyllithium (2.77 mol/L n-hexane solution, 1.25 mL) at −78° C., and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added a solution of 2-(tert-butyldimethylsilyloxy)methyl-6-chloro-4-methoxypyridine (1 g) in tetrahydrofuran (5 mL), and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added N,N-dimethylformamide (0.32 mL), and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was stirred at room temperature for 5 minutes. The mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/1) to give 6-(tert-butyldimethylsilyloxy)methyl-2-chloro-4-methoxy-3-formylpyridine (0.28 g). The title compound was prepared in a similar manner to that described in Reference Example 15 using 6-(tert-butyldimethylsilyloxy)methyl-2-chloro-4-methoxy-3-formylpyridine instead of 2,6-dibromo-3-formylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:13])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[OH:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[CH2:26]([O:13][C:10]1[C:11]([F:12])=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[OH:19])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cnc2c(O)c(F)c(F)cc2c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(OCc3ccccc3)c(F)c(F)cc2c1O
Reaction time: 11 h

Procedure:
To a stirred solution of ethyl 6,7-difluoro-4,8-dihydroxy-3-quinolinecarboxylate (300 mg) in dry dimethylformamide (6 ml), was added anhydrous potassium carbonate (308 mg) and then benzyl chloride (145 μl). The mixture was stirred at 55°-65° C. for 11 hours. The reaction mixture was diluted with water (30 ml) and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (7 g) using acetone/chloroform (1:20) as an eluent to give 113 mg of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate, mp 200°-201° C.; MS m/z 359 (M+), after recrystallization from methanol.
Reaction SMILES: Cl.[C:2]([C:6]1[C:7]2[CH2:8][C:9]([CH3:22])([CH3:21])[NH:10][C:11]=2[C:12]([CH3:20])=[C:13]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][C:14]=12)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])O.[Na+].C(N(CC)CC)C.[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>C1COCC1>[C:2]([C:6]1[C:7]2[CH2:8][C:9]([CH3:22])([CH3:21])[N:10]([C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([F:35])=[CH:37][CH:38]=3)[C:11]=2[C:12]([CH3:20])=[C:13]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][C:14]=12)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c2c(c(C(C)(C)C)c3c1NC(C)(C)C3)OC(C)(C)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c2c(c(C(C)(C)C)c3c1N(C(=O)c1ccc(F)cc1)C(C)(C)C3)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
8-tert-Butyl-3, 5, 6, 7-tetrahydro-2,2,4,6,6-pentamethyl-2H-furo[2,3-f]indole hydrochloride (715.8 mg, 2.21 mmol) was suspended in THF (20 ml). To the mixture was added a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and stirred for 1 hour at room temperature. After extracting with isopropyl ether followed by drying over magnesium sulfate, the solvent was removed under reduced pressure. The residue was dissolved in THF (20 ml). To the solution were added triethylamine (0.35 ml, 2.51 mmol) and p-fluorobenzoyl chloride (371.8 mg, 2.34 mmol) and stirred at room temperature for 5 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1) to obtain 417 mg of the title compound as an amorphous powder.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17](B3OC(C)(C)C(C)(C)O3)[C:16]=2[CH2:15][NH:14]1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH:15]=[N:14][N:13]4[CH3:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN1NCc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Reactant: Clc1nc2c(Br)cccn2n1
Product: Cn1ncc2c(-c3cccn4nc(Cl)nc34)cccc21

Procedure:
2-Chloro-8-(1-methyl-1H-indazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 1-methyl-2H-indazole-4-boronic acid pinacol ester in a manner analogous to Example 2c (0.36 g, 59%). MS=284 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=2[F:26])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=1[F:26]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc([N+](=O)[O-])cc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2c(F)cc([N+](=O)[O-])cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
6.0 g of 5-(4-chlorophenyl)-4-(2,6-difluoro-4-nitrophenyl)-6-methyl-2H-pyridazin-3-one and 30 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 6.15 g of 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-nitrophenyl)-6-methylpyridazine (hereinafter, referred to as compound (ix) of the present invention).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1[C:28](C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1CCC(N)CC1)(C)C>C(O)(=O)C>[CH:24]([CH:4]1[CH2:5][CH2:6][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:3]1)([CH3:28])[CH3:25]
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: CC(C)C1CCC(N)CC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CC(C)C1CCC(n2cnc3c(-c4ccccc4)csc3c2=O)CC1
Yield: 58.4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 4-isopropylcyclohexylamine (0.148 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 88.5 mg (0.25 mmol, 58.4% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([NH2:17])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH3:32][CH2:31][O:30][C:28]([N:15]1[C:16]([NH2:17])=[C:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][C:11]2=[N:14]1)=[O:29]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(N)c2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1nc2c(c1N)CN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 94.1 g of 3-amino-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester in 1.7 L of THF were added 135 mL of N,N-diisopropylethylamine. A solution of 37.6 mL of ethyl chloroformate in 300 mL of THF was added dropwise at 0° C. during 75 min. The mixture was stirred at 0° C. for 30 min. then evaporated under vacuum. The residue was taken-up with 1 L of water and extracted with ethyl acetate. The combined organic extracts were washed with 500 mL brine, dried over sodium sulfate, and evaporated to dryness. The crude mixture of isomers was purified by silica gel flash-chromatography, using a starting 87:13 mixture of dichloromethane-ethyl acetate as eluant, and increasing gradually the percentage of ethyl acetate up to 50%. The fractions containing the same isomer were evaporated to give 61.6 g of 3-amino-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=3)[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH-:25].[Na+].OO>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:24])=[O:25])[CH:18]=3)[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#Cc1cc(-c2nc(-c3cccc(O)c3)nc3ccsc23)ccn1
Agent: OO
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cc(-c2nc(-c3cccc(O)c3)nc3ccsc23)ccn1
Reaction time: 8 h

Procedure:
A mixture of 4-[2-(3-hydroxy-phenyl)-thieno[3,2-d]pyrimidin-4-yl]-pyridine-2-carbonitrile, (48 mg), sodium hydroxide (1M, 0.3 mL) and aqueous hydrogen peroxide (30%, 0.1 mL) was stirred in methanol (3 mL) at room temperature. After stirring overnight, the reaction mixture was concentrated in vacuo, neutralised with HCl (2M), and diluted with water, yielding a precipitate. This was collected by filtration and purified using flash chromatography to yield the title compound (29 mg).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[OH:16])=[O:5])C.[CH3:17][C:18]([NH2:22])([C:20]#[CH:21])[CH3:19]>CCO>[CH3:17][C:18]([NH:22][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[OH:16])=[O:5])([CH3:19])[C:20]#[CH:21]
Reactant: C#CC(C)(C)N
Reactant: CCOC(=O)c1c(O)c2sccc2[nH]c1=O
Solvent: CCO
Product: C#CC(C)(C)NC(=O)c1c(O)c2sccc2[nH]c1=O

Procedure:
3.1 g (13 mmol) of 6-ethoxycarbonyl-7-hydroxy-thieno[3,2-b]pyridin-5(4H)-one and 1.3 g (1.2 eq.) of 1,1-dimethylpropargylamine in 80 ml of EtOH were stirred for 8 hours at 150° C. in an autoclave. The solvent was removed under reduced pressure and the solid residue was stirred with diethyl ether. The solid was filtered off and purified chromatographically (silica gel, methylene chloride/methanol =8/1).
Reaction SMILES: [C:1]([Si:5]([CH3:35])([CH3:34])[O:6][CH:7]1[CH2:23][N:11]2[C:12](=[O:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=[C:10]2[N:9]([C:24]2[CH:29]=[CH:28][N:27]=[C:26](S(C)(=O)=O)[N:25]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:36]1([C@@H:42]([NH2:44])[CH3:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCOCC1.CCOC(C)=O>[C:1]([Si:5]([CH3:35])([CH3:34])[O:6][CH:7]1[CH2:23][N:11]2[C:12](=[O:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=[C:10]2[N:9]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:44][CH:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH3:43])[N:25]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2ccnc(S(C)(=O)=O)n2)c2nc(-c3ccccc3)cc(=O)n2C1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(N2CC(O[Si](C)(C)C(C)(C)C)Cn3c2nc(-c2ccccc2)cc3=O)n1)c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 7-(tert-butyl-dimethyl-silanyloxy)-9-(2-methanesulfonyl-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one, prepared from last step (0.6 mmol) and (S)-1-phenylethylamine (1.0 mL, 7.8 mmol) in dioxane (6 mL) was heated at 110° C. for 17 h. The brown solution was cooled to room temperature and was diluted with EtOAc (10 ML). The mixture was washed with H2O (2×), dried (Na2SO4), and concentrated to oil. Purification on silica (0-1% 2N NH3-MeOH in DCM) provided the product as a white solid. M+1: 555.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[H-].[Na+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:24]([O:28][C:29](=[O:32])[CH2:30][O:17][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:18]([F:19])([F:20])[F:21])[CH:6]=2)[CH2:12][CH2:13]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=[N+]([O-])c1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
In a 250 ml round-bottomed flask under nitrogen, a solution of 4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (10 g, 33 mmol) in 150 ml of THF was cooled using an external ice bath. Sodium hydride (3.65 g, 152 mmol, 3 eq) was then added and the mixture was stirred at ˜0° C. for 30 minutes before adding the tert-butyl-2-bromoacetate (9.6 g, 49.2 mmol, 1.5 eq). The solution was allowed to warm to room temperature while stirring overnight. The reaction was then diluted using 500 ml of ice-water. The mixture was then extracted with 3×200 ml of ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 10% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to provide 5 g (36%) of the desired ester as a yellow oil. Repeating this reaction on a larger scale yielded 51% of the desired product.
Reaction SMILES: [C:1]([CH2:14][C:15]([CH2:18][C:19]([CH2:22][CH2:23]I)([F:21])[F:20])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].CNC=[O:28].O>CCOCC>[C:10]([C:7]([C:4]([C:1]([CH2:14][C:15]([CH2:18][C:19]([CH2:22][CH2:23][OH:28])([F:21])[F:20])([F:17])[F:16])([F:3])[F:2])([F:6])[F:5])([F:9])[F:8])([F:13])([F:12])[F:11]
Reactant: FC(F)(CCI)CC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CNC=O
Solvent: CCOCC
Solvent: O
Product: OCCC(F)(F)CC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
Ethylene (56 g) was introduced to an autoclave charged with C4F9(CH2CF2)2I (714 g) and d-(+)-limonene (3.2 g), and the reactor heated at 240° C. for 12 hours. The product was isolated by vacuum distillation to provide C4F9(CH2CF2)2CH2CH2I. A mixture of C4F9(CH2CF2)2CH2CH2I (10 g, 0.02 mol) and N-methylformamide (8.9 mL, 0.15 mol) was heated to 150° C. for 26 hours. The mixture was cooled to 100° C., followed by the addition of water to separate the crude ester. Ethyl alcohol (3 mL) and p-toluene sulfonic acid (0.09 g) were added and the mixture stirred at 70° C. for 0.25 hours. Ethyl formate and ethyl alcohol were removed by distillation to give a crude product. The crude product was dissolved in ether, washed with 10 wt % aqueous sodium sulfite, water and brine, in turn, and dried over magnesium sulfate. Distillation provided the alcohol product, CF3(CF2)3(CH2CF2)2CH2CH2OH, (6.5 g, 83% yield): bp 94-95° C. a 2 mm Hg (266 Pascals).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[C:23]([C:29](O)=[O:30])=[N:22]2)=[CH:16][C:15]=1[CH3:32].C(N=C=NC(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:7][O:8][C:29]([C:23]2[C:24](=[O:28])[NH:25][C:26](=[O:27])[N:21]([C:17]3[CH:18]=[C:19]([CH3:20])[C:14]([O:13][C:12]4[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:10]([Br:9])[CH:11]=4)=[C:15]([CH3:32])[CH:16]=3)[N:22]=2)=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2C)cc1Br
Reactant: OCC1CCCCC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)OCC4CCCCC4)c(=O)[nH]c3=O)cc2C)cc1Br
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of cyclohexylmethanol (9 μmol) in DMF were added sequentially solutions of 2-[4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (5 μmol), diisopropylcarbodiimide (10 umol) and 4-dimethylaminopyridine (10 μmol). The resulting solution was shaken at 50° C. for 18 h. HPLC and LCMS shows the starting material to be consumed and the desired product present. MS Calc.: 557.1; Found: 556.1 (M−1).