Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][C:10]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[N:22])[CH:17]=3)[C:11]=2[N:12]=1.BrNC(=O)CCC(N)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][C:10]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[N:22])[CH:17]=3)[C:11]=2[N:12]=1
Reactant: CC1(C)COC(=O)N1c1nc2c(s1)CCc1cc(C#N)ccc1-2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: NC(=O)CCC(=O)NBr
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)COC(=O)N1c1nc2c(ccc3cc(C#N)ccc32)s1
Yield: 54.1 %

Procedure:
2-(4,4-Dimethyl-2-oxo-1,3-oxazolidin-3-yl)-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile (0.65 g, 2.0 mmol), prepared in step 5 of Example 111, N-bromosuccinamide (0.39 g, 2.2 mmol) and a catalytic amount of 2,2′-azobis(2-methylproprionitrile) were stirred in carbontetrachloride (68 mL) at reflux for 4 h. The reaction was diluted with ethyl acetate and washed with 10% sodium thiosulfate. The layers were separated and the organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 0.64 g of crude product. Purification of the crude product on silica gel using a stepwise gradient of 6:1 to 1:1 hexane:ethyl acetate as the eluent gave 0.35 g of product that contained an impurity. Recrystallization from ethyl acetate afforded the title compound (0.02 g, 3%), mp>230° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+:11].CC(C)=O.[C:16](Cl)(=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O>[C:16]([NH:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5])(=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[Na+:11].[Na+:11]
Reactant: CCCCCCCCCCCCCCC(=O)Cl
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a one L three-necked flask were placed 31.9 g (0.24 mol) of L-aspartic acid and an aqueous solution of 19.2 g (0.48 mol) of sodium hydroxide in 150 mL of water under stirring. After the L-aspartic acid was dissolved, 120 mL of acetone was added to the mixture in the flask. Then, to the resultant reaction liquid which had been cooled to 0° C. were added dropwise over a period of 30 minutes, 52.2 g (0.2 mol) of pentadecanoyl chloride and an aqueous solution of 0.2N sodium hydroxide in 30 mL of water simultaneously therewith, while maintaining the reaction temperature at 0 to 5° C. and pH at 11 to 12. Thereafter, by gradually raising the temperature of the reaction liquid to room temperature (25° C) under stirring over a period of 2 hours, a solution of disodium pentadecanoyl-L-aspartate was obtained. To the resultant solution was added 140 mL of 5N hydrochloric acid to lower the pH of the solution to 1. The crystal thus precipitated was separated from the solution by means of vacuum filtration, washed with water and dried under reduced pressure. The resultant crystal was washed with 500 mL of hexane, dried and recrystallized from a mixed solvent of ethanol/water (1:1 v/v). As a result 39.8 g (0.11 mol) of N-pentadecanoyl-L-aspartic acid was obtained in a yield of 55.6% based on the fed pentadecanoyl chloride. The physical properties of the objective N-pentadecanoyl-L-aspartic acid were as follows.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[C:13]1([CH2:19][CH2:20]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O.C(N(CC)CC)C>[C:13]1([CH2:19][CH2:20][N:9]2[CH2:8][CH2:7][C:6]3([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]3)[CH2:11][CH2:10]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1COC2(CCNCC2)CN1
Reactant: BrCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COC2(CCN(CCc3ccccc3)CC2)CN1

Procedure:
A solution of 3.0 g of 1-oxa-4,9-diazaspiro[5.5]undecan-3-one and 5 ml of phenylethyl bromide in 60 ml of dimethylformamide and 10 ml of triethylamine was heated at 70° C. for 3 hours. The mixture was poured into water, extracted with methylene chloride and the extract was washed with water and evaporated. Crystallization of the residue from ethyl acetate gave 1.2 g of 9-(2-phenylethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, m.p. 140°-141° C. The HCl salt of 9-(2-phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one was prepared by dissolving the free base in methanolic HCl and precipitating with ether, m.p. 247°-250° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:12](NNC1C=CC(NC(NC2C=CC=CC=2)=O)=CC=1)=[O:13]>>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][NH:11][CH:12]=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=CNNc1ccc(NC(=O)Nc2ccccc2)cc1
Reactant: NNc1cccc([N+](=O)[O-])c1
Product: O=CNNc1cccc([N+](=O)[O-])c1

Procedure:
By reacting 3-nitrophenylhydrazine as in the same manner as in (1) above, 430 g of 2-(3-nitrophenyl)-1-formylhydrazine was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([I:13])[CH:7]=1)[CH3:2].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][C:17]([CH3:19])=O>C1C=CC=CC=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH2:22]([O:21][C:15](=[O:20])[CH:16]=[C:17]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[CH:7][C:8]=1[I:13])[CH3:19])[CH3:23]
Reactant: CCOC(=O)Cc1ccc(N)c(I)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C=C(C)Nc1ccc(CC(=O)OCC)cc1I
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of (4-amino-3-iodo-phenyl)acetic acid ethyl ester (9.85 g, 32.3 mmol), ethyl acetoacetate (4.2 g, 32.3 mmol), and toluenesulfonic acid monohydrate (0.3 g, 1.6 mmol) in benzene (150 mL) is refluxed under Dean-Stark conditions overnight. The solution is then cooled to room temperature and washed with sodium bicarbonate (NaHCO3) (2×50 mL) and concentrated in vacuo to give the desired product (12.5 g, 93%). The product is used without further purification in Step 3. MS: 418 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IN1C(=O)CC[C:26]1=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Temperature: 65 °C
Yield: 121.9 %

Procedure:
A mixture of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.83 g, 15.6 mmol) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) in anhydrous acetonitrile (55 mL) was heated at 65° C. for 4 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractions were collected according to ES MS (M+H 436) and washed with Na2SO3 to remove the color impurities. The fractions were concentrated under reduced pressure and dried in vacuo to afford the desired product (6.15 g, 90%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 7.73 (d, 1H, J=7.6 Hz), 7.36 (m, 6H), 7.08 (m, 3H), 6.39 (d, 1H, J=8.0 Hz), 5.28 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z 436.0196 (M+H calculated for C19H16NO2FI requires 436.0210). Step 2. Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-methylpyridin-2(1H)-one
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[Br:21]C1C=CC(/C=C/[N+]([O-])=O)=CC=1>>[Br:21][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Reactant: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(Br)cc1
Yield: 27 %

Procedure:
This compound was synthesized using the same methodology described in Intermediate C, using the commercially available (E)-1-bromo-4-(2-nitrovinyl)benzene as starting material. Yield: 27%.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][Si](C)(C)C)[CH:7]=1)([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[CH:13])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cccc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccc(C(=O)OC(C)C)c1
Reaction time: 0.08 h
Yield: 76.2 %

Procedure:
A solution of 3-trimethylsilanylethynyl-benzoic acid isopropyl ester (Intermediate 136, 0.6 g, 2.3 mmol) in anhydrous tetrahydrofuran (3 mL) was treated with a 1M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (4.6 mL, 4.6 mmol) and the resulting reaction mixture was stirred in an ice bath for 5 min. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil that was purified by flash column chromatography using 5%-30% ethyl acetate in hexane as the eluent to afford the title compound as a solid (0.33 g, 76%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:39])([C:37]#[CH:38])[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31].N(CC)CC>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(CC)CC>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:38]#[C:37][C:29]([CH3:28])([CH3:39])[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: C#CC(C)(C)C(=O)OCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CCN(CC)CC
Product: CCCCOC(=O)C(C)(C)C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Yield: 17.6 %

Procedure:
A microwave vial was charged with (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.12 mmol), butyl 2,2-dimethylbut-3-ynoate (40 mg, 0.23 mmol), CuI (2.2 mg, 0.012 mmol), PdCl2(PPh3)2 (5 mg, 0.008 mmol), Et3N (2 mL) and Et2NH (0.2 mL). The mixture was sparged with N2 for 10 min and heated at 100 C for 2 h. The mixture was concentrated, redissolved in EtOAc (90 mL), washed with 5% aq HCl (20 mL) and brine (20 mL), and dried over Na2SO4. Removal of the solvent left an oil (75 mg) which was purified by prep HPLC to afford butyl 4-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2,2-dimethylbut-3-ynoate (11 mg, 19%). LC-MS Method 1 tR=2.13 min, m/z=520, 462.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Na]N1C2C(=CC=CC=2)C=C1.[CH3:22][Si:23](Cl)([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH3:22][Si:23]([CH3:28])([C:24]([CH3:27])([CH3:26])[CH3:25])[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]n1ccc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1ccc2ccccc21
Yield: 79 %

Procedure:
1-(dimethyl-t-butylsilyl)indole is prepared by treatment of indole with sodium hydride in THF at temperature followed by the reaction of 1-sodioindole with dimethyl-t-butylsilyl chloride in THF according to the procedure described in D. Dhanak, C. B. Reese J. Chem. Soc., Perkin Trans. 1 1986, 2181-2186. The yield is 79%. The physical and spectral characteristics are described in this article.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 125 °C
Yield: 39.7 %

Procedure:
A stirred mixture of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (90 mg, 0.260 mmol) from Step 4 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (120 mg, 1.03 mmol), and DIEA (133 mg, 1.03 mmol) in anhydrous DMA (3 mL) was heated at 125° C. for 15 h. After the reaction mixture had cooled to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (41 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.42 (s, 1H), 8.08 (dd, J=2.4, 9.4 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.17-7.33 (m, 2H), 5.48 (s, 2H), 4.76 (br s, 1H), 3.45-3.55 (m, 2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.10-1.33 (m, 4H). LCMS (ESI) m/z 398 (M+H)+.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])[CH3:2].[Na].O>CC(CC(C)C)O.C1(C)C=CC=CC=1>[CH2:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(=Cc1ccc(C)cc1)C(=O)O
Agent: [Na]
Solvent: CC(C)CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(Cc1ccc(C)cc1)C(=O)O

Procedure:
A suspension of 91 g of α-ethyl-4-methyl-cinnamic acid in 1.5 liters of methyl-isobutyl-carbinol is added dropwise within one hour to 100 g of sodium in 250 cc of toluene at 130° while stirring well. After a further hour, sodium is no longer present and the mixture is cooled and 500 cc of water are carefully added thereto. The aqueous phase is separated and the methyl-isobutyl-carbinol phase is again extracted twice with water. The entire aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The ether extract is washed with water, dried over sodium sulphate and evaporated. The crude α-ethyl-4-methyl-dihydrocinnamic acid is obtained as an oil and may be purified by chromatography.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(CC)CC.[Cl-].[CH2:33]([O:35][C:36](=[O:48])[CH:37]([OH:47])[CH:38]([NH3+:46])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:34].[N:49]1[N:50]([C:58]2[N:66]=[CH:65][CH:64]=[CH:63][C:59]=2[C:60](O)=[O:61])[CH:51]=[C:52]2[C:57]=1[CH:56]=[CH:55][CH:54]=[CH:53]2>ClCCl>[N:49]1[N:50]([C:58]2[N:66]=[CH:65][CH:64]=[CH:63][C:59]=2[C:60]([NH:46][CH:38]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]([OH:47])[C:36]([O:35][CH2:33][CH3:34])=[O:48])=[O:61])[CH:51]=[C:52]2[C:57]=1[CH:56]=[CH:55][CH:54]=[CH:53]2
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Reactant: O=C(O)c1cccnc1-n1cc2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Reaction time: 0.08 h
Yield: 56.5 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (1.748 g, 4.60 mmol) and Et3N (1 ml, 7.17 mmol) were successively added to a suspension of 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride (1.303 g, 5.02 mmol) and 2-(2H-indazol-2-yl)nicotinic acid (1 g, 4.18 mmol) in dichloromethane (75 ml) at 5° C., and the mixture was stirred for 5 minutes. A pH of 10 was adjusted by adding Et3N (750 μl, 5.41 mmol), stirring was continued for 1 hour at 5° C. and then overnight at room temperature. The reaction mixture was then concentrated under reduced pressure and poured into 100 ml of water. The precipitate formed was filtered off with suction and dried in vacuo to give 1.05 g of the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.O>N1C=CC=CC=1>[C:18]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: O=C(CC1CCCCC1)c1ccc(O)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(CC1CCCCC1)c1ccc(OC(=O)c2cccnc2)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
11 g (50 mmol) of p-cyclohexylacetylphenol and 9.6 g (54 mmol) of nicotinic acid chloride hydrochloride was mixed with 160 ml of dry pyridine and stirred for 8 hours at 40° C. Subsequently, water (66 ml) was added drop by drop until the solution was turbid. The solution was placed in the ice bath, the precipitate sucked off, freed from pyridine by washing with water and dried.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[CH:8][C:7]=1[CH2:15][OH:16].C(N(CC)CC)C>ClCCl>[N:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[CH:8][C:7]=1[CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: OCc1cc2ccccn2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc2ccccn2n1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (0.149 g, 0.13 mmol) in dichloromethane (2 mL) was added to a solution of pyrazolo[1,5-a]pyridin-2-yl-methanol (0.148 g, 0.1 mmol) and triethylamine (0.303 g, 0.3 mmol) in dichloromethane (3 mL) at −10° C. under N2. After the addition was complete, the mixture was stirred at −10° C. for 1 h. Ice water (10 mL) was added, and the organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum to give methanesulfonic acid pyrazolo[1,5-a]pyridin-2-ylmethyl ester as a yellow oil, which was used for the next step without further purification. A solution of this material (0.22 g, 0.1 mmol) in dry dichloromethane (2 mL) was added to a solution of 1-methyl-4-phenyl-1,3-dihydro-imidazole-2-thione (0.190 g, 0.1 mmol) and DIPEA (0.303 g, 0.3 mmol) in dry DMF (3 mL) at −10° C. under N2. The mixture was stirred at 0° C. for 2 hours, and was then concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (50 mg, 15%). LC-MS: m/z=321.1 (MH+), tR=2.16 min, method F.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1.C(Cl)[Cl:27]>>[Cl:27][C:7]1[CH:2]=[C:3]([Cl:9])[N:4]=[C:5]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][C@@H:20]2[CH3:19])[N:6]=1
Reactant: C[C@H]1COCCN1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of trichloropyrimidine (5.04 g, 27.3 mol) in DCM (50 mL) cooled to 0° C. was added DIPEA (4.79 mL, 27.3 mol), followed by 3-(S)-methylmorpholine (3.11 g, 30.5 mol) dropwise. The reaction mixture was allowed to warm to RT and stirred for 3 h wherupon it was diluted with DCM, washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (5-10% EtOAc in petroleum ether (40-60)) to yield the two isomers.
Reaction SMILES: [OH:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[H][H]>C(O)C.[Pd]>[NH2:13][C:12]1[C:2]([OH:1])=[C:3]([CH:9]=[CH:10][CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CN(C)C(=O)c1cccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)c1cccc(N)c1O
Yield: 101 %

Procedure:
A solution of 33.5 g of 2-hydroxy-N,N-dimethyl-3-nitrobenzamide in 600 ml of ethanol were added to a suspension of 3.35 g of Pd/C 10% in 70 ml of ethanol. The reaction medium was stirred under 2 bar of hydrogen overnight. TLC and HPLC control (t=0.66 M+181). The reaction medium was filtered through celite and the filtrate was evaporated. 29 g of 3-amino-2-hydroxy-N,N-dimethylbenzamide were obtained in the form of an oily brown solid. Yield=100%.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[NH:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17]([CH2:21][CH:22]([CH3:26])[C:23](Cl)=[O:24])([O:19][CH3:20])=[O:18]>C(=S)=S>[C:17]([CH2:21][CH:22]([CH3:26])[C:23]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:12])[NH:3][CH:2]2[CH3:1])=[O:24])([O:19][CH3:20])=[O:18]
Reactant: CC1NC(=O)Nc2ccccc21
Reactant: COC(=O)CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CC(C)C(=O)c1ccc2c(c1)C(C)NC(=O)N2
Temperature: 25 °C

Procedure:
3,4-Dihydro-4-methyl-2(1H)-quinazolinone (3.9 g) is added to a stirred suspension of anhydrous aluminum chloride (16.5 g) in carbon disulfide (120 ml) under nitrogen. 3-Carbomethoxy-2-methyl-propionyl chloride (4 g) is added dropwise to the stirred suspension, which is refluxed for about 17 hours and cooled to RT. The liquid phase is decanted and the residue is treated with ice/H2O (150 ml) and extracted with methylene chloride. The organic extract is dried, filtered, and concentrated in vacuo, affording the desired crude product as an oil, which is used in the next step without further purification.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]1(O)[CH2:23][CH2:22][CH2:21][CH2:20]1.C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]1[CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: OC1(c2ccncc2Br)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Brc1cnccc1C1=CCCC1
Temperature: 120 °C
Yield: 72.6 %

Procedure:
PTSA (819 mg, 4.315 mmol) was added portionwise to a stirred mixture of 1-(3-bromo-pyridin-4-yl)-cyclopentanol (I-34a: 520 mg, 2.15 mmol) in 25 mL of toluene. The resulting mixture was heated to reflux at 120° C. for 4 hours. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was concentrated, basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated to afford the crude product. Purification by column chromatography on silica gel (8% ethyl acetate in hexane) afforded 350 mg of the product (73% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([Cl:12])=[C:4]([NH2:13])[N:3]=1.Cl[CH2:15][C:16](=O)[CH2:17][CH2:18][CH3:19].[I-].[Na+]>>[NH2:13][C:4]1[N:3]2[CH:15]=[C:16]([CH2:17][CH2:18][CH3:19])[N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Cl:12]
Reactant: CCCC(=O)CCl
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Agent: [I-]
Agent: [Na+]
Product: CCCc1cn2c(N)c(Cl)cc(C(=O)OC)c2n1

Procedure:
The title compounds were prepared according to the procedure described in the step 2 EXAMPLE 1 (METHOD B) using methyl 2,6-diamino-5-chloro-3-pyridinecarboxylate (EXAMPLE 1, METHOD B, Step 1), 1-chloropentane-2-one (Synthesis, 1987, 2, 188-190) and sodium iodide.