Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:24][CH3:25])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:24][CH3:25])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CO[C@@H](Cc1ccc(CCCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared as follows: (2S)-3-{4-[5-(Biphenyl-4-yloxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionic acid from Example 21 (0.08 mmol) was dissolved in methanol (10 mL). Palladium 10% on activated carbon (0.004 g, 0.004 mmol) was added and the solution saturated with hydrogen (1 Atm) and stirred for 5 hours. The mixture was filtered through a pad of celite and concentrated under vacuum. The residue was purified by column chromatography. MS (ES) for C27H30O4 [M−H]−: 417.3.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]I.[OH-].[K+]>CO>[CH3:12][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CI
Reactant: O=C(O)c1cc(S)cc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1cc(Cl)cc(C(=O)O)c1
Yield: 70 %

Procedure:
In a manner similar to procedure of Example 14, 3-mercapto-5-chlorobenzoic acid is contacted with methyl iodide in methanol containing potassium hydroxide as the base to yield the desired product in 70% yield, m.p. 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH:13]([CH3:21])[C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:19][CH2:18][CH2:17][CH:16]2[C:15](=[CH:24][N:25]([CH3:26])[CH3:27])[C:14](=[O:20])[CH:13]3[CH3:21])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CC1C(=O)C(=CN(C)C)C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-2-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (500 mg, 1.52 mmol) in DMF (1 mL) was added N,N-dimethylformamide dimethyl acetal (1 mL). The resulting mixture was heated to 110° C. for 2 h after which the reaction mixture was concentrated under reduced pressure to give the desired product as a brown oil. This crude product was directly taken to the next reaction without any further purification. Retention time (min)=2.2 min, Method [1], MS (ESI) 356 (M−NMe2+OH+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:24](=[O:59])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:31](=[O:50])[NH:32][CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:38]([O:40]C)=[O:39])=[N:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1.O>[C:13]([O:12][C:11]([NH:10][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:24](=[O:59])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:31](=[O:50])[NH:32][CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]([NH:42][C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[C:38]([OH:40])=[O:39])=[N:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])([CH3:14])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@H](CCCCNC(=O)[C@H](CCCCNC(=O)[C@H](CCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of methyl ester 48 (1.40 g, 1.32 mmol) in MeOH/THF/H2O (45 mL/45 mL/15 mL) was charged with NaOH (265 mg, 6.61 mmol) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the pH of the solution was adjusted to 5 with aqueous 1 N HCl. The suspension was partitioned between CH2Cl2 (50 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL) The combined organic extracts were dried over Na2SO4 and concentrated to afford compound 49 (1.20 g, 87%) as a white solid, which was used directly in the next step: 1H NMR (400 MHz, CD3OD) δ 4.06-3.89 (m, 3H), 3.35 (t, J=7.6 Hz, 2H), 3.25-3.11 (m, 4H), 1.86-1.66 (m, 3H), 1.64-1.55 (m, 5H), 1.54-1.30 (m, 10H), 1.52 (s, 9H), 1.46 (s, 9H), 1.43 (s, 27H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:30][C:27]3[CH:28]=[N:29][C:24]([N:21]4[CH2:20][CH2:19][O:18][CH2:23][CH2:22]4)=[CH:25][CH:26]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCOCC4)nc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 73-1 (40 mg, 0.18 mmol), 6-morpholinopyridin-3-amine (40 mg, 0.22 mmol) and HATU (80 mg, 0.21 mmol) in 2 mL DMF was added DIEA (104 μL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give the title compound 73 as white solid. MS m/z 389.19 (M+1); 1H NMR 400 MHz (DMSO-d6) δ11.30 (s, 1H), 8.82 (d, 1H, J=6.4 Hz), 8.57 (d, 1H, J=2.4 Hz), 8.35 (m, 1H), 8.24 (dd, 1H, J1=6.4 Hz, J2=1.6 Hz), 8.19 (dd, 1H, J1=10.0 Hz, J2=2.8 Hz), 8.02 (m, 2H), 7.63 (m, 2H), 7.42 (d, 2H, J=9.6 Hz), 3.87 (s, 2H), 3.75 (m, 4H), 3.66 (m, 4H), 2.80 (s, 3H).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([N:27]([CH3:39])[C:28](=[O:38])[CH2:29][CH2:30]2)[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)[CH3:18])=[O:15])[CH3:2].I([O-])(=O)(=O)=[O:41].[Na+].I([O-])(=O)(=O)=O>CC(C)=O.O>[CH2:1]([S:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([N:27]([CH3:39])[C:28](=[O:38])[CH2:29][CH2:30]2)[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)[CH3:18])=[O:15])=[O:41])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCSCCCCCCCCCCC(=O)OC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCS(=O)CCCCCCCCCCC(=O)OC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a stirred solution of 20-(11-(ethylthio)undecanoyloxy)-4-methyl-5α-4-azapregnan-3-one (0.056 g, 0.1 mM) in acetone (5 mL) at room temperature was added a solution of sodium periodate (0.033 mg, 0.154mM) in water (3 drops). After prolonged stirring with additional portions of the periodate added (0.046 g total) over 3 days, the solvents were removed in vacuo, and the residue extracted with methylene chloride. The methylene chloride was removed in vacuo, and the resulting residue was flash chromatographed on silica gel (30% acetone/methylene chloride eluant) to give the title compound as a glaze. MS M+ calculated for C34H59NO4S, mw=577.90; observed m/e 577.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
(S)-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (10 g, 0.05 mol) was taken into anhydrous pyridine (51 mL). The reaction was cooled to 0° C. and p-toluenesulfonyl chloride (10.42 g, 0.055 mol) in anhydrous pyridine (25 mL) was added dropwise over 10 min. The reaction ran at 0° C. for 2 h. and then allowed to warm to room temperature overnight. The mixture was concentrated to dryness and the residue was taken into ethyl acetate (200 mL) and washed with 0.5N HCl (50 mL). The ethyl acetate was then washed with aqueous sodium bicarbonate (100 mL), brine, dried over sodium sulfate and concentrated to dryness to obtain the title product (17.55 g, 0.049 mol, 99% yield); MS; m/z 355, found 356 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 1.28 (s, 9H), 1.72 (s, 3H), 1.90 (s, 1H), 2.42 (s, 3H), 3.14-3.23 (m, 2H), 3.84 (s, 1H), 3.97-4.06 (m, 2H), 7.49 (d, J=8.0, 2H), 7.78 (d, J=8.0, 2H).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42]C1C=NC=CC=1)[CH2:4][CH2:3]2.Br[C:50]1[S:51][CH:52]=[CH:53][N:54]=1.C(O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:50]1[S:51][CH:52]=[CH:53][N:54]=1)[CH2:4][CH2:3]2
Reactant: Brc1nccs1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccnc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3nccs3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-bromothiazole (0.015 g, 0.091 mmol) was used in place of 3-bromopyridine. The product was isolated after reverse phase preparative HPLC purification using Prep HPLC Method 7 as a beige solid (12.8 mg, 18% yield) bis TFA salt. LCMS: m/e 656.4 (M+H)+, 2.38 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.91 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 7.08 (d, J=3.7 Hz, 1H), 6.68 (d, J=4.0 Hz, 1H), 5.28 (d, J=4.6 Hz, 1H), 4.86 (s, 1H), 4.74 (br. s., 1H), 3.69 (dd, J=9.9, 5.3 Hz, 1H), 3.43-3.36 (m, 1H), 2.13 (dd, J=17.2, 6.3 Hz, 1H), 2.05 (d, J=15.0 Hz, 1H), 2.01-1.79 (m, 6H), 1.73 (s, 4H), 1.70-1.46 (m, 8H), 1.46-1.27 (m, 6H), 1.27-1.22 (m, 2H), 1.22-1.10 (m, 2H), 1.07 (s, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1.[N+:18]([O-])([OH:20])=[O:19]>O>[Cl:6][C:7]1[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[C:10]([OH:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 78 %

Procedure:
224.5 g of sulphuric acid (50% w/w) was dissolved in 300 ml of water and cooled to 25° C. while stirring under a mild nitrogen purge. 185.1 g (1 mole) of N-(5-chloro-2-hydroxyphenyl) acetamide prepared according to Example 1a was added to the diluted sulphuric acid and mixed intensively. 4 ml of nitric acid 65% w/w was added to the foam formed on top of the reaction mixture at low stirring speed. The stirring speed was increased and 75 ml of nitric acid 65% w/w was added in 45 minutes, while maintaining the temperature between 23 and 26° C. The mixture was stirred vigorously for an additional 1 hour at 23-26° C. Then the mixture was cooled to 0-5° C. and vigorously stirred at this temperature for 1 hour. The solid was filtered off quickly, washed three times with 300 ml of cold water, sucked for at least 30 minutes and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. The crude product was suspended in 2000 ml 96% ethanol, heated till reflux and refluxed under stirring for about 15 minutes until a clear solution was obtained. The solution was cooled to 25-30° C. in about 1 hour, while stirring slowly, further cooled to 0-5° C. and stirred at this temperature for an additional hour. The solid was filtered off, washed twice with 250 ml of cold 96% ethanol, and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 78%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][O-:13].[Na+]>CO.O>[C:8]([C:7]1[C:2]([O:13][CH3:12])=[N:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH3:10])#[N:9]
Reactant: C[O-]
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C)cc(C)c1C#N
Temperature: 60 °C
Yield: 64.6 %

Procedure:
A solution of 2-chloro-3-cyano-4,6-dimethylpyridine (4.60 g, 27.7 mmol) in methanol (30 mL) is added to a stirred solution of sodium methoxide (2.09 g, 38.78 mmol) in methanol (20 mL) and the reaction mixture is heated at 60° C. for 4 hr. After cooling, the reaction is diluted with water (150 mL) and the solids are collected by filtration, washed with water and dried to yield 3-cyano-4,6-dimethyl-2-methoxypyridine (2.90 g, 65%) as an off-white solid containing the same impurity as the starting material. LC/MS: MS m/e=163 (M+H); RT 3.29 min; 1H NMR (CDCl3, δ ppm) 6.69, (1H, s), 4.00 (3H, s), 2.43 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([O:20]CC)=[O:19])[C:9]2=[O:23])[O:4][N:3]=1.O.[OH-].[Li+]>C(O)C.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([OH:20])=[O:19])[C:9]2=[O:23])[O:4][N:3]=1
Reactant: CCOC(=O)c1nc2ccccc2n(Cc2cc(C)no2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Cn2c(=O)c(C(=O)O)nc3ccccc32)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
3.0 g (9.58 mmol) of ethyl 1-[(3-methylisoxazol-5-yl)methyl]-2-oxo-1,2-dihydroquinoxaline-3-carboxylate and 0.46 g (11.5 mmol) of lithium hydroxide monohydrate were dissolved in a solvent mixture of ethanol (30 mL) and water (30 mL), and the solution was stirred for 2 hours at room temperature. The reaction solution was concentrated to a half the original volume, and water was added to the residue. The mixture was acidified using 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated, to obtain 2.3 g (yield: 84%) of 1-[(3-methylisoxazol-5-yl)methyl]-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Cl)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([O:15][C:4]3[C:5]([C:9]4[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1cc(O)c(-c2cccnc2)nc1C
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCc1ccccc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
5,6-Dimethyl-3-hydroxy-[2,3′]bipyridine (400 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.80 g), and 4-dimethylaminopyridine (732 mg) were suspended in o-dichlorobenzene (8 ml), and the suspension was stirred at 140° C. for 6 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (811 mg, yield 88%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]1[CH:26]=[CH:25][N:24]2[N:27]=[CH:28][C:29]([C:30]([N:32]3[CH:37]4[CH2:38][CH2:39][CH:33]3[CH2:34][N:35](C(OC(C)(C)C)=O)[CH2:36]4)=[O:31])=[C:23]2[CH:22]=1>C(Cl)Cl.CCOC(C)=O>[CH:33]12[N:32]([C:30]([C:29]3[CH:28]=[N:27][N:24]4[CH:25]=[CH:26][C:21]([N:17]5[CH2:18][CH2:19][CH2:20][C@@H:16]5[C:10]5[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=5[F:8])=[CH:22][C:23]=34)=[O:31])[CH:37]([CH2:38][CH2:39]1)[CH2:36][NH:35][CH2:34]2
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2C(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12)N1C2CCC1CNC2
Reaction time: 15 h
Yield: 15.4 %

Procedure:
TFA (1.2 mL) was added to a solution of tert-butyl 8-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (200 mg, 0.37 mmol) in DCM (2 mL) at 0° C. and stirring was continued at 20-35° C. for 15 h. The reaction mixture was concentrated under reduced pressure to afford the crude, which was diluted with EtOAc, washed with saturated NaHCO3 solution, dried over anhydrous sodium sulphate to afford the crude. The crude compound was purified by recrystallisation from mixture of DCM and n-Hexane to afford 25 mg of the title compound.
Reaction SMILES: O.[NH:2]1[CH:9]=[CH:8][C:6](N)=[N:5][C:3]1=[O:4].[OH-].[Mg+2].[OH-].[C@@H:13]1([N:21]2[CH:28]=[CH:27][C:25](N)=[N:24][C:22]2=[O:23])[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[CH2:14]1>C(O)(=O)C.C1CCCCC1>[NH:2]1[CH:9]=[CH:8][C:6](=[O:16])[NH:5][C:3]1=[O:4].[C@@H:13]1([N:21]2[CH:28]=[CH:27][C:25](=[O:4])[NH:24][C:22]2=[O:23])[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[CH2:14]1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Agent: [Mg+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCCCC1
Solvent: O
Product: O=c1cc[nH]c(=O)[nH]1
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
To the mixture of water (96.4 g) and 4.8 g of cyclohexane, were added 6.96 g (62.6 mmol) of cytosine, 18.7 g (75.4 mmol) of 2′-deoxyribose-1-phosphate diammonium salt, 7.58 g (132 mmol) of magnesium hydroxide and the frozen cell mass (2.0 g) prepared in Reference Example 3. The reaction took place at 45° C. for 18 hours, controlling the solution at pH 8.8 with acetic acid. The HPLC analysis after the reaction demonstrated that 10.03 g (70.5 mol %/cytosine) of 2′-deoxycytidine was produced as object compound. At the same time, 0.73 g (10.4 mol %/cytosine) of uracil and 1.80 g (12.6 mol %/cytosine) of 2′-deoxyuridine were produced as byproduct, respectively.
Reaction SMILES: N1C=CC(C2SC=C(C([N:14]=[N+:15]=[N-:16])=O)N=2)=CC=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1C1SC=C(C(O)=O)N=1.[OH-].[Na+:32].C(Cl)(=O)C(Cl)=O>O>[N-:14]=[N+:15]=[N-:16].[Na+:32].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:14]=[N+:15]=[N-:16]
Reactant: O=C(O)c1csc(-c2ccccn2)n1
Reactant: [N-]=[N+]=NC(=O)c1csc(-c2ccncc2)n1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [N-]=[N+]=Nc1ccccn1
Product: [N-]=[N+]=[N-]

Procedure:
In a manner similar to that described for the preparation of 2-(4-pyridinyl)-4-thiazolyl-carbonylazide, 2-(2-pyridinyl)-4-thiazolylcarboxylic acid (1.0 g)was treated successively with NaOH, oxalyl chloride and a solution of NaN3 in water to give the 2-pyridinyl azide as a pale brown solid: m.p. 112-114° C. MS m/z: 232 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(Cl)[Cl:29].C(=O)([O-])[O-].[Na+].[Na+].[C:38](Cl)([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>O>[C:38]([N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:9]1[CH:8]=[CH:7][C:3]([C:4]([Cl:29])=[O:6])=[C:2]([F:1])[CH:10]=1)([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Reactant: ClC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1ccc(C(=O)Cl)c(F)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. 2-fluoro-4-(hexadecylamino)benzoic acid in 200 ml. warm chloroform is added a solution of 15 g. of sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g. carbobenzyloxy chloride. After 2 hours stirring at 40° C., the layers are separated, washed three times with 1 N hydrochloric acid, dried, and evaporated to an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. thionyl chloride and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time, ultimately to yield N-carbobenzyloxy-2-fluoro-4-(hexadecylamino)benzoyl chloride as a viscous, orange oil.
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.C[NH:25]OC.C1C=NC2N(O)N=NC=2C=1.CCN(CC)CC.C(Cl)CCl>C(Cl)Cl>[C:1]([NH2:25])(=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC=CCC=CCCCCCCCCCC(=O)O
Reactant: CNOC
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCC=CCC=CCCCCCCCCCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
11,14-Eicosadienoic acid, (11Z,14Z)- (50 g, 162 mmol), N,O-Dimethylhydroxylamine hydrochloride (31.6 g, 324 mmol), HOAt (44.1 g, 324 mmol), Et3N (45.2 mL, 324 mmol), and EDC (62.1 g, 324 mmol) were mixed in DCM (810 mL) and stirred overnight at ambient temperature. Reaction was then washed 5×700 mL water, then washed 1×600 mL 1 M NaOH, dried with sodium sulfate, filtered through celite and evaporated to obtain 53.06 g (93%) 11,14-eicosadienamide, N-methoxy-N-methyl-, (11Z,14Z) as a clear golden oil. 1H NMR (400 MHz, CDCl3) δ 5.35 (m, 4H), 3.68 (s, 3H), 3.18 (s, 3H), 2.77 (m, 2H), 2.41 (t, J=7 Hz, 2H), 2.05 (m, 4H), 1.63 (m, 2H), 1.40-1.26 (m, 18H), 0.89 (t, J=7 Hz, 3H).