Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[C:6]=2[N:13]=1)[CH3:2].[S:23]([N:33]=[C:34]=[O:35])([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C>C(Cl)Cl>[CH2:1]([C:3]1[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:34]([NH:33][S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:35])=[CH:18][CH:19]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[C:6]=2[N:13]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1nc2c(C)nc(C)cc2n1-c1ccc(CCN)cc1
Solvent: ClCCl
Product: CCc1nc2c(C)nc(C)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 41.1 %

Procedure:
To a clean and dry 12 L 3-neck round-bottom flask were charged 2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanamine (422 g, 1.43 moles) and CH2Cl2 (3.37 L). Tosyl isocyanate (217 mL, 1.43 moles) dissolved in CH2Cl2 (851 mL) was added to the reaction keeping the temperature below 21° C. and was stirred for at least 90 minutes. The reaction was deemed complete by HPLC and activated charcoal (DARCO KB-B, 4.2 g) was added. The resulting slurry was filtered through a 0.5-micron filter into a speck free 5 L 3-neck round-bottom flask and the filter washed with CH2Cl2 (421 mL). The reaction was atmospherically concentrated to a minimum stirable volume and displacement continued with speck freed acetone until an internal temperature of 58° C. to 62° C. was achieved and final volume was ˜1.3 L. The reaction was cooled to at least 30° C. and seed of N-[({2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide Polymorph Form A was added. The reaction was allowed to granulate between 20° C. and 25° C. for at least 10 hours. After cooling reaction to 0° C. to 5° C. and granulating for at least 2 hours, the reaction was filtered on a speck free filter. The solids were washed two times with speck free acetone (1.68 L) cooled to 0° C. to 5° C. The wet-cake was returned to a speck free 12 L 3-neck round-bottom flask and speck free ethyl acetate (4.4 L) was added. The slurry was heated to at least 75° C. and held for at least 2 hours. The reaction was cooled to at least 30° C. and the solids were filtered on a speck free filter. The solids were washed with speck free ethyl acetate (1.6 L). The wet-cake was returned to the same speck free 12 L 3-neck round-bottom flask and speck free ethyl acetate (4.4 L) was added. The slurry was heated to at least 75° C. and held for at least 2 hours. The reaction was cooled to at least 30° C. and the solids were filtered on a speck free filter. The solids were washed with speck free ethyl acetate (1.6 L). The product was dried at 45° C. to 50° C. for at least 24 hours to yield 289 g the title product, Polymorph Form A (41.4% yield, 98.68% purity by HPLC).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:9]3[O:11][C@@:12]45[CH2:22][CH2:21][C@H:20]([OH:23])[C:19]([CH3:25])([CH3:24])[C@@H:18]4[CH2:17][CH2:16][C@H:15]([CH3:26])[C@@:13]5([CH3:27])[CH2:14][C:8]=3[C:7]([OH:28])=[CH:6][C:5]=2[C:4](=[O:29])[NH:3]1.[C:30]1(C)[CH:35]=CC(S([O-])(=O)=O)=C[CH:31]=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(O)CC>[OH:28][C:7]1[C:8]2[CH2:14][C@:13]3([CH3:27])[C@@H:15]([CH3:26])[CH2:16][CH2:17][C@H:18]4[C:19]([CH3:25])([CH3:24])[C@@H:20]([OH:23])[CH2:21][CH2:22][C@@:12]34[O:11][C:9]=2[C:10]2[CH:2]([O:1][CH2:31][CH2:30][CH3:35])[NH:3][C:4](=[O:29])[C:5]=2[CH:6]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(O)cc4c2C(O)NC4=O)C[C@]13C
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCCO
Product: CCCOC1NC(=O)c2cc(O)c3c(c21)O[C@@]12CC[C@H](O)C(C)(C)[C@@H]1CC[C@H](C)[C@@]2(C)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 207.7 %

Procedure:
To a solution of Compound (30a) (33 mg, 0.08 mmol) in 3.0 ml of 1-propanol was added 6 mg of pyridinium p-toluenesulfonate, and the mixture stirred at room temperature for one hour. To the reaction was added 20 ml of ethyl acetate. The mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by a column chromatography (Merck, Lobar column, size A; ethyl acetate), and by crystallization from ethyl acetate to give 22 mg (60%) of Compound (30c).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
9.3 g (50 mmol) of 3-chloro-4-hydroxylphenylacetic acid was dissolved in 100 ml of N,N-dimethylformamide, and 15.2 g (110 mmol) of potassium carbonate was added thereto. The mixture was stirred at 100° C. for one hour. Then, 10.9 g (60 mmol) of 2-chloro-5-trifluoromethylpyridine was added thereto, and the mixture was stirred for 8 hours at 120° C. After cooling, the reaction solution was poured into water and washed twice with ethyl acetate. The obtained aqueous layer was adjusted to pH 4 with citric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 8.3 g of the desired product as a white powder (melting point: 138° to 139° C.).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[N:2][OH:3]
Reactant: NO
Reactant: O=Cc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=Cc1ccccc1Cl
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Hydroxylamine hydrochloride (35.6 g) was added to a 0° C. mixture of 2-chlorobenzaldehyde (60.0 g) and sodium carbonate (22.6 g) in methanol (1.0 L)-water (1.0 L). The reaction was stirred overnight and then concentrated to half volume. The mixture was extracted twice with ethyl acetate. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (65.4 g) having the following physical data.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[C:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH2:24][S:23][CH:22]2[C:26](Cl)=[O:27])(=[O:20])=[O:19])=[CH:14][CH:13]=1>O.C1COCC1>[C:12]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH2:24][S:23][CH:22]2[C:26]([NH:1][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])=[O:27])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: NC(C(=O)O)c1ccccc1
Reactant: O=C(Cl)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
Intermediate VIII (Scheme 3), e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (1.747 g, 5 mmol) was dissolved in DCM (20 mL). The resulting solution was cooled down to −10° C. and oxalyl chloride (0.645 mL, 7.5 mmol) was added slowly. DMF (0.1 mL) was added carefully. The reaction mixture was allowed to warm to RT over 1 h and stirred an additional hour at RT. As the reaction was complete, the solvents were evaporated. Toluene was added and evaporated to remove residual oxalyl chloride. This process was repeated twice, affording intermediate XXX, e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride as a yellow solid (1.839 g, quantitative yield). α-Aminophenylacetic acid (831 mg, 5.5 mmol) was dissolved in water (20 mL). TEA (2.77 mL, 20 mmol) was added carefully. THF (25 mL) was added to reaction mixture. The reaction mixture was cooled to 0° C. Acid chloride previously prepared XXX, e.g. 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride dissolved in THF (25 mL) was added dropwise. The reaction mixture was stirred 15 min at 0° C. and overnight at RT. Solvents were concentrated and the resulting aqueous fraction was acidified with HCl 5N and extracted with 3 portions of EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated. The crude product was recrystallized in acetone/Et2O mixture, affording carboxylic acid Ia, e.g., ({[3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)(phenyl)acetic acid in 97% purity by HPLC (943 mg, 39% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=2[CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:41]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:41])[C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:21])[CH3:22])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C:12]=2[CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:10])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)Nc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)N(C)c1ccc(Br)cc1
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
To a stirred solution of ethyl 3-{3-[(4-bromophenyl)carbamoyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (100 mg, 0.18 mmol) in DMF (2 mL) is added NaH (60% dispersion in mineral oil, 7.7 mg, 0.19 mmol) at 0° C. The suspension is stirred for 10 minutes then iodomethane (12.0 μl 0.19 mmol) is introduced and the reaction mixture is stirred overnight. The mixture is quenched with water, extracted with EtOAc, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 40% EtOAc in hexanes) gives ethyl 3-{3-[(4-bromophenyl)(methyl)carbamoyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (75 mg, 73%) that is dissolved in THF (8 mL), MeOH (1 mL), and water (1 mL) and treated with 10M aqueous NaOH (0.1 mL). The mixture is stirred for 16 h then concentrated and acidified with HOAc. The resulting solid is filtered, washed with water, collected, and dried to give the title compound (50 mg, 70%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13].O>CN1C(=O)CCC1>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNC
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C)c1ccc([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitropyridine (1.0 eq) and dimethylamine (2 M in EtOH, 4.6 eq) in NMP were heated for 2 h at 100° C. The solution was then poured slowly into H2O. The filtrate that formed was filtered and dried to give 2-(dimethylamino)-5-nitropyridine.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:42][CH:43]([OH:65])[CH2:44][O:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:22][CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:73](Cl)(=[O:87])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:42][CH:43]([O:65][C:73](=[O:87])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH2:44][O:45][C:46]([C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH2:22][CH2:23][O:24][Si:25]([C:38]([CH3:39])([CH3:40])[CH3:41])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](OCCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(=O)OC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Another batch of IX was prepared as follows: to a solution of VIII (1.60 g, 1.78 mmol), Et3N (0.50 mL, 3.56 mmol) and DMAP (22 mg, 0.178 mmol), in CH2Cl2 (12 mL) was added dropwise myristoyl chloride (0.53 mL, 1.96 mmol) at 0° C. The reaction mixture was allowed to warm up slowly to room temperature. After stirring 24 h at room temperature, the reaction mixture was diluted with CH2Cl2 (50 mL), washed sequentially with 5% aqueous sodium bicarbonate (15 mL), water (15 mL), and saturated aqueous NaCl (15 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, elution with 0.2% MeOH in CHCl3) furnished 17 (1.60 g, 81%) as oily liquid. NMR spectra coordinates are as follows: 1H NMR (CDCl3): δ 7.34-7.05 (m, 35H), 5.05-4.96 (m, 1H), 3.53-3.42 (m, 4H), 3.08 (dd, J=10.0, 3.2 Hz, 1H), 2.99 (dd, J=10.0, 6.0 Hz, 1H), 2.68-2.54 (m, 6H), 2.25 (t, J=8.0 Hz, 2H), 1.64-1.55 (m, 2H), 1.35-1.14 (m, 20H), 0.98 (s, 118H), 0.88 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)[CH3:3].[K+].[F:7][C:8]([F:14])([F:13])[C:9]([O:11][CH3:12])=O.CO/C=C/C(=O)C>C(OCC)C>[F:7][C:8]([F:14])([F:13])[C:9]1[O:11][CH:12]=[CH:1][C:2](=[O:5])[CH:3]=1
Reactant: COC(=O)C(F)(F)F
Reactant: CC(C)(C)[O-]
Agent: CO/C=C/C(C)=O
Agent: [K+]
Solvent: CCOCC
Product: O=c1ccoc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of KOtBu (729 mg, 6.49 mmol) in diethyl ether (10 mL) at 5° C. were added methyl 2,2,2-trifluoroacetate (767 mg, 5.99 mmol) and (E)-4-methoxybut-3-en-2-one (500 mg, 4.99 mmol). The reaction mixture was stirred at rt for 3 h, and quenched with water and then extracted with ether. Combined organic portions were dried over Na2SO4, filtered and concentrated. The residue was dissolved in isopropanol (150 mL) and 35% solution of hydrochloric acid (0.5 mL) and refluxed for 45 min. Then the solution was concentrated to remove alcohol and fractionated at reduced pressure to get the title product as yellow oil.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH3:23])=[N:20][CH:21]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][N:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][N:20]=2)[CH3:23])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: CNc1ccc(F)cn1
Product: COC(=O)c1cc(Cl)ccc1CN(C)c1ccc(F)cn1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 22 from methyl 2-(bromoethyl)-5-chlorobenzoate and 5-fluoro-N-methylpyridin-2-amine (step 1):
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[N:15][NH:16][C:17]([NH2:19])=[S:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:20]([O-])(=O)[CH3:21].[Na+].ClCC=O>CO>[S:18]1[CH:21]=[CH:20][N:19]=[C:17]1[NH:16][N:15]=[C:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: CC(=O)[O-]
Reactant: NC(=S)NN=c1c2ccccc2[nH]c2ccccc12
Agent: O=CCCl
Agent: [Na+]
Solvent: CO
Product: c1ccc2c(=NNc3nccs3)c3ccccc3[nH]c2c1

Procedure:
6.24 g of 9-acridanone thiosemicarbazone, 3.5 g of sodium acetate and 5.2 ml of chloroacetaldehyde (50 percent aqueous solution) in 200 ml of methanol are heated to boiling under reflux for 6 hours. After evaporation of the solvent, the residue is treated with water. The precipitated product is filtered and washed successively with water, a small amount of ethanol, ether and petroleum ether. There is obtained 9-acridanone (2-thiazolyl)hydrazone of melting point 208°-210° (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-])=O)=[C:7]([CH:10]=1)[CH:8]=[O:9].CC([O-])=O.[Na+].CCN(C(C)C)C(C)C.[C:28]([O:31][CH2:32][C:33](Cl)=[O:34])(=[O:30])[CH3:29]>CCOC(C)=O.O=[Pt]=O>[C:28]([O:31][CH2:32][C:33]([NH:11][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:10][C:7]=1[CH:8]=[O:9])=[O:34])(=[O:30])[CH3:29]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=[Pt]=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)COC(C)=O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
To the solution of 5-methoxy-2-nitrobenzaldehyde (6 g, 0.33 mol) in EtOAc (100 mL) was added 20% PtO2/C (1.2 g, 20%) and NaOAc (1.2 g, 20%). The reaction was stirred under hydrogen at room temperature for 0.5 h. The mixture was filtered through a Celite pad, and the filtrate was dried over anhydrous Na2SO4. After filtration, the solution was cooled to −78° C., and to which was added DIPEA (6.4 g, 0.5 mol, 1.5 eq) and 2-chloro-2-oxoethyl acetate (4.5 g, 0.33 mol, 1.0 eq). The resulting mixture was gradually warmed up to room temperature and stirred overnight. The reaction mixture was washed with water twice, dried over Na2SO4 and evaporated most of the solvent in vacuum. Then the solid separating out was collected by filtration to give 2-(2-formyl-4-methoxyphenylamino)-2-oxoethyl acetate (5.6 g, yield: 71%) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])=[CH:11][CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][Br:21])=[CH:11][CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccnn1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nccc1CBr
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 5-methyl-pyrazole-1-carboxylic acid tert-butyl ester in CCl4 (40 mL) was added NBS (3.3 g, 18.5 mmol) and benzoylperoxide (450 mg, 1.86 mmol). The reaction mixture was heated to reflux for 4 h and cooled to rt. The insoluble material was filtered off and the solution was diluted with EtOAc. The organics were washed with saturated NaHCO3 and H2O, dried with Na2SO4, and concentrated. The crude product was purified by combi-flash to give 1.67 g of 5-bromomethyl-pyrazole-1-carboxylic acid tert-butyl ester in 52% yield.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:15]O>>[CH3:15][O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2](=[O:1])[NH:3][CH:4]=1)=[O:8]
Reactant: CO
Reactant: O=C(O)c1ccc(O)nc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(=O)[nH]c1

Procedure:
6-Hydroxynicotinic acid (4) reacts with thionyl chloride and methanol to give methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (5), which is coupled with phenylboronic acid in the presence of copper(II) acetate monohydrate, pyridine and molecular sieves in dichloromethane to give methyl-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (6). Compound 6 is hydrolyzed with lithium hydroxide monohydrate in tetrahydrofuran water, to give 6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylic acid 7. Acid 7 reacts with isobutyl chloroformate in the presence of N-methylmorpholine in tetrahydrofuran to give a mixed anhydride which is reduced with sodium borodeuteride in tetrahydrofuran to give d2-5-(hydroxymethyl)-1-phenylpyridine-2(1H)-one (8). Compound 8 is converted to d2-5-bromomethyl-1-phenyl-1H-pyridin-2-one (9) by reacting with phosphorus tribromide in dichloromethane. Bromide 9 is reduced with lithium aluminum deuteride to give d3-5-(methyl)-1-phenylpyridine-2(1H)-one (10) of Formula (I).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1.CO.[H][H]>[Pd].[O-]S([O-])(=O)=O.[Ba+2].C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]=[N:3][C:4]([C:20]#[N:21])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2cnc(C#N)c(-c3ccccc3)c2c1
Reaction time: 8 h

Procedure:
A mixture of 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile (200 mg), 5% Pd/BaSO4 (50 mg), and 20 mL methanol was stirred under 1 atm hydrogen for 18 h. 5 mL of CH2Cl2 was then added, as was an additional 50 mg Pd/BaSO4. After stirring overnight, the reaction was filtered, concentrated, and purified by flash chromatography (30% EtOAc/hexanes) to give the titled compound.
Reaction SMILES: O[C:2]1([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH:7]2[CH2:9][CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2.S(Cl)(Cl)=O.[OH-].[K+]>C(O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:2]2[CH:3]3[CH2:9][CH:7]([CH:8]=2)[CH2:6][NH:5][CH2:4]3)[CH:16]=1
Reactant: CCOC(=O)N1CC2CC(C1)C(O)(c1cccnc1)C2
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: C1=C(c2cccnc2)C2CNCC1C2
Temperature: 25 °C
Yield: 47 %

Procedure:
To ethyl 6-hydroxy-6-(3-pyridinyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (1.10 g, 4.0 mmol) was added thionyl chloride (5 ml) and the mixture was heated to reflux for 1 h under nitrogen. Thionyl chloride was removed by azeotropic rotary evaporation with toluene to give a dark brown oil, which was suspended in a 20% solution of potassium hydroxide in ethanol (10 ml) and refluxed for 18 h. The reaction mixture was cooled to room temperature and concentrated by rotary evaporation. Then saturated sodium chloride solution (10 ml) was added. The mixture was filtered. The collected solids were washed with chloroform (25 ml), and the filtrate was extracted with chloroform (3×25 ml). The combined chloroform extracts were dried over sodium sulfate, filtered, concentrated by rotary evaporation, and distilled on a Kugelrohr apparatus to yield a light brown oil (350 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[H-].[Na+].Cl[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Reactant: CC(C)=CCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCOc1c(I)cc(C(C)O)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2-Chloro-3-hydroxy-6-(1-hydroxyethyl)-4-iodo-pyridine (2.99 g, 10 mmole) was dissolved in 15 ml dry dimethylformamide in an oven dried 100 ml two neck round bottom flask under nitrogen. The solution was cooled to 0° C., was treated with sodium hydride (400 mg, 10 mmole), and the mixture was stirred 1 h at room temperature. The mixture was treated with 1-chloro-3-methyl-2-butene (1.2 ml, 11 mmole) and sodium iodide (150 mg, 1 mmole) and the reaction mixture was stirred 18 h at room temperature. The reaction mixture was diluted with 100 ml ethyl acetate, was washed with 4×50 ml 50% saturated 1:1 sodium chloride/sodium bicarbonate, and was dried over anhydrous potassium carbonate. The dried organics were concentrated in vacuo to a yellow oil which was crystallized from 25 ml hexane to give 3.2 g (87%) of 2-chloro-3-(3-methyl-2-butenyloxy)-6-(1-hydroxyethyl)-4-iodo-pyridine as an off-white solid, Melting Point: 80-81° C.