Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([C:25](=[O:36])[C:26]([CH3:35])([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[CH3:27])=[C:9]12)C1C=CC=CC=1.C(O)C.[H][H]>C1COCC1.[Pd]>[CH3:20][C:11]1([CH3:21])[N:10]2[N:22]=[CH:23][C:24]([C:25](=[O:36])[C:26]([CH3:27])([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[CH3:35])=[C:9]2[NH:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12]1
Reactant: [H][H]
Reactant: Cc1ccc(C(C)(C)C(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C(C)(C)C(=O)c2cnn3c2NC(c2ccccc2)CC3(C)C)cc1
Reaction time: 1 h
Yield: 84 %

Procedure:
To 0.060 g (0.126 mmol) of 6 dissolved in 4 mL of 1:1 THF:ethanol was added 0.080 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 1 h, the catalyst was removed via filtration and the filtrate concentrated to a cream colored solid. Purification by flash chromatography eluting with 90% hexanes/ethyl acetate gave 0.041 g (84%) of the title compound as a white solid. 1H NMR (CDCl3) δ 1.49 (s, 3H), 1.54 (s, 9H), 2.04-2.11 (m, 2H), 2.32 (s, 3H), 4.63 (dd, J=4.1, 10.7 Hz, 1H), 6.66 (s, 1H), 7.12-7.26 (m, 5H), 7.31-7.44 (m, 5H). MS Calcd.: 387; Found: 388 (M+H).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(=O)([O-])O.[Na+].O.[CH2:19]1[O:21][CH:20]1[CH2:22][OH:23]>CO>[CH2:19]([O:6][C:5]1[C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[O:8][C:2](=[O:1])[C:3]=1[OH:4])[CH:20]([CH2:22][OH:23])[OH:21]
Reactant: OCC1CO1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1O
Temperature: 50 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
Under an argon atmosphere, L-ascorbic acid (300 g) and sodium hydrogen carbonate (42.9 g) were added to water and the resultant mixture was stirred at room temperature for 30 minutes, then, glycidol (126 g) was added thereto. Thereafter, the mixture was heated up to 50° C. and stirred for 5 hours. Thereto, methanol was added and filtration was performed. The filtrate was concentrated under reduced pressure, and 457 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:65/35/5), and concentration was performed under reduced pressure to obtain 3-O-glyceryl ascorbic acid (296 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH:17]1([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2CC2)C1

Procedure:
(S)-tert-butyl pyrrolidin-3-ylcarbamate (415 mg), (1-ethoxycyclopropoxy)trimethylsilane (1.8 mL) and molecular sieves (500 mg) were combined in methanol (4.5 mL). Acetic acid (1.3 mL) was added, followed by sodium cyanoborohydride (420 mg). The resulting mixture was heated to reflux for 4 hours. Insoluble material was filtered off and reaction was made basic to pH 14 with addition of 6M aqueous NaOH solution. The solution was extracted three times with diethyl ether, and the combined extracts were dried over MgSO4, filtered and concentrated to obtain an oil, which was purified by flash chromatography, eluting first with 100% dichloromethane, followed by 5% methanol/dichloromethane and 10% methanol/dichloromethane.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH:8]=1>S(=O)(=O)(O)O>[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N+:1]([O-:4])=[O:2])[CH:10]=[N:9][CH:8]=1
Reactant: Brc1cncc2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2cncc(Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium nitrate (5.34 g; 0.052 mol) was added to 20 ml of concentrated sulfuric acid and slowly dissolved by careful heating. The resulting solution was added dropwise to a solution of 4-bromoisoquinoline (10 g; 0.048 mol) dissolved in 40 ml of the same acid at 0° C. After removal of the cooling bath, the solution was stirred for one hour at room temperature. The reaction mixture was then poured onto crushed ice (400 g) and made basic with ammonium hydroxide. The resulting yellow precipitate was collected by filtration and the filtrate was extracted with diethyl ether (3×500 ml), dried (Na2SO4), and concentrated to give a yellow solid that was combined with the initial precipitate. Recrystallization from methanol gave 12.1 g (89%) of slightly yellow crystals: mp 172-174° C.; 1H NMR: (300 MHz, CDCl3): 9.27 (s, 1H); 8.87 (s, 1H); 8.21 (dd, 1H, J=6.6, 1.2 Hz); 7.96 (dd, 1H, J=6.6, 1.2 Hz); 7.73 (t, 1H, J=7.5 Hz). CIMS m/z: 253 (M+H+, 100%); 255 (M+H++2, 100%). Anal. Calc'd for C9H5BrN2O2: C, 42.72; H, 1.99; N, 11.07. Found: C, 42.59; H, 1.76; N, 10.87.
Reaction SMILES: [NH:1]([C:25]([O:27]C(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:33](C(O)=O)[CH3:34]>>[NH:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:33]([C:25]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:27])[CH3:34]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 82.9 %

Procedure:
By using 7.53 g of Boc-Ser(Bzl)-Leu-OEt and 3.50 g of Boc-Ala-OH, and the same procedure as in Reference Example 15 was repeated to obtain 7.26 g (yield: 82.9%) of the above-mentioned objective product.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH3:12][C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=[O:8])=[CH:17][CH:18]=1)([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: O=C1CCCCC1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(SC2CCCCC2=O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-chlorocyclohexanone (6.1 g, 0.046 moles) in tetrahydrofuran (250 ml) cooled to +5° C. by an ice bath was added 4-t-butyl-thiophenol (6.6 g, 0.040 moles). After stirring for 15 minutes, triethylamine (13 ml) was added. The ice bath was removed and the mixture was stirred at room temperature for 60 hours. The mixture was filtered to remove a white solid. The filtrate was concentrated to an oil, and the product was purified by silica gel chromatography to give a white solid which was recrystallized from hexane (DSC 64.25° C.). The structure was supported by NMR and Ir.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:7]=1[CH2:8][N:9]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:17])[CH2:12][CH2:11][C@H:10]1[C:34](O)=[O:35].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:3][CH2:2][CH2:1][NH:4][C:34]([C@H:10]1[N:9]([CH2:8][C:7]2[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:6]=2[F:5])[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:17])[CH2:12][CH2:11]1)=[O:35]
Reactant: NCCN
Reactant: COc1cccc(F)c1CN1C[C@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(F)c1CN1C[C@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CC[C@H]1C(=O)NCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
ethane-1,2-diamine (18 mg, 0.290 mmol) was added to a stirred mixture of (2S,5R)-1-(2-fluoro-6-methoxybenzyl)-5-(3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamido)-piperidine-2-carboxylic acid (50 mg, 0.097 mmol), N,N-DIISOPROPYLETHYL-AMINE (0.084 ml, 0.483 mmol), HATU (73.5 mg, 0.193 mmol) in dimethylformamide and the mixture was stirred at room temperature for Overnight. The reaction was rotovap to dryness and the residue was purified by column chromatography on silica gel Isolute Flash Si; 50 g prepacked, eluting with 5% MeOH/NH3(2M)CH2Cl2 to give the desired (48.1 mg, 0.085 mmol, 88% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
4-Nitrophenol (13.9 g, 100 mmol) was dissolved in N,N-dimethylformamide (20 ml), and t-butyl bromoacetate (29.3 g, 150 mmol) and potassium carbonate (27.6 g, 200 mmol) were added, which was followed by stirring at 70° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water, and the aqueous layer was extracted with ethyl acetate. The extract and the previously-obtained organic layer were combined. The mixture was washed with water and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography. (n-hexane/ethyl acetate=5/1) and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 21.8 g of t-butyl 4-nitrophenoxyacetate as pale-yellow crystals (86%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][C:6](=O)[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl.C(O)C.[BH4-].[Na+]>CO>[CH3:1][CH:2]([CH3:3])[CH2:4][CH2:5][CH:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: NCCCCCCCN1CCCCC1
Reactant: CC(C)CCC(=O)CCC(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)CCC(CCC(C)C)NCCCCCCCN1CCCCC1

Procedure:
To a solution of 1.70 g of 2,8-dimethylnonan-5-one and 1.98 g of 1-(7-aminoheptyl)piperidine in 50 ml of methanol was added 6 N hydrochloric acid-ethanol to have a pH value of approx. 7 (pH test paper). To the resulting solution was added under cooling 1.26 g of sodium borohydride all at once. The resulting mixture was stirred under chilling with ice for one hour, and then stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was extracted with chloroform after addition of water and an aqueous sodium hydroxide solution. The chloroform portion was dried and evaporated under reduced pressure to remove the solvent, yielding an oily product. The oily product was purified by silica gel column chromatography (eluent: chloroform-methanol 80:1 to 40:1) to give the desired compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[O:17])[CH:25]=1)[CH3:19]
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (131)(50 mg, 0.19 mmol) was coupled to aniline (60)(40 mg, 0.21 mmol) using Method D. The residue was triturated with TBME (3 ml) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]([NH:32][OH:33])=[NH:31])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:34].N1C=CC=CC=1.Cl[C:42](OCC(CC)CCCC)=[O:43]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]3[NH:31][C:42](=[O:43])[O:33][N:32]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:34]
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: Cc1cc(F)ccc1-c1nc(NCCC(=N)NO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(F)ccc1-c1nc(NCCc2noc(=O)[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
Under Ar, to a soln of the product of Example 242, 3-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-N-hydroxy-propionamidine (100 mg, 0.20 mmol), and pyridine (0.048 mL, 0.6 mmol), was added 2-ethylhexyl chloroformate (0.039 mL, 0.2 mmol). The mixture was stirred at room temperature for 2 h, then diluted with H2O and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was diluted with xylene (10 mL) and heated to reflux for 18 h to give the crude material, which was purified by preparative hplc to give the desired product 28 mg (28%). LC-MS: 495.0 (MH+, m/z), 1.96 (Rt, min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]I.[Na+].[Cl-]>C1COCC1.CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])[CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Nc1ccc(S(=O)(=O)NCCOCCO)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CN(CCOCCO)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 3.3 g (31 mmol) of 2-(2-aminoethoxy)ethanol in 30 mL of MeOH was added 7.0 g (30 mmol) of N-acetylsulfanilyl chloride, followed by 3.3 g (33 mmol) of TEA. The reaction mixture was stirred for 30 min at rt and then acidified with 5 mL (60 mmol) of concentrated HCl and stirred at reflux for 75 min. After cooling, the mixture was diluted with 40 mL of water and made basic with solid NaHCO3. MeOH was removed on a rotary evaporator, and the residual aqueous solution was extracted with four 50-mL portions of EtOAc. The combined extracts were dried over Na2CO3, and the solvent was removed on a rotary evaporator to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide as a viscous oil (7.5 g, 96%): 1H NMR (DMSO-d6): δ 2.77 (q, J=6.0 Hz, 2H), 3.30 (t, J=4.9 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.41 (q, J=5.2 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.89 (s, 2H), 6.57 (d, J=8.7 Hz, 2H) 7.10 (t, J=7.37 (d, J=8.6 Hz, 2H); ESI−MS m/s 259 (M−H)−. To a solution of 0.63 g (2.4 mmol) of 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide in 10 mL of THF was added 0.10 g (2.5 mmol) of 60% sodium hydride. The mixture was stirred for 1 h at rt, 1 mL of DMSO and ˜0.2 mL (˜3 mmol) of methyl iodide were added to the resulting suspension. The reaction mixture was stirred 2 h at rt and then poured into 15 mL of half saturated NaCl solution and extracted with 30 mL of EtOAc. The organic solution was dried with MgSO4 and concentrated on a rotary evaporator. The residue was chromatographed on silica gel with EtOAc to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)N-methyl-benzenesulfonamide as an oil (0.43 g, 65%): 1H NMR (DMSO-d6): δ 2.59 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 4.55 (t, J=5.4 Hz, 1H), 5.99 (s, 2H), 6.59 (d, J=8.7 Hz, 2H), 7.34 (d, 8.8 Hz, 2H); APCI−MS m/z 297 (M+Na)+. The title compound was prepared from 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide and 8ethoxymethylene-6,8-dihydro-I-thia-3,6-diaza-as-indacen-7-one according to Procedure J: mp 165° C.; 1H NMR (DMSO-d6): δ 2.71 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 3.37 (t, J=5.0 Hz, 2H), 3.44 (dt, J=5.1, 5.0 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.56 (brt, J=5.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.06 (d, J=12.0 Hz, 1H), 9.25 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.0 Hz, 1H); APCI−MS m/z 474 M−. Anal. Calcd for C21H22N4O5S2.H2O: C, 51.21; H,4.91; N, 11.37. Found: C, 51.18; H, 4.88; N, 11.33.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:39])([F:38])[C:12]([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])([OH:32])[CH2:13][NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[CH2:35]([N:34]([CH2:33][C:12]([CH2:13][NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)([OH:32])[C:11]([F:10])([F:38])[F:39])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:36][CH3:37]
Reactant: O=C(O)c1ccccc1
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 1 from benzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:15]#[N:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]#[N:16]
Reactant: N#CCc1ccccc1
Reactant: Clc1ccccn1
Product: N#CC(c1ccccc1)c1ccccn1

Procedure:
The dl-threo-ritalinic acid used in step (i) may be prepared through multi-step process in which 2-chloropyridine and benzyl cyanide initially are coupled to form α-pyrid-2-yl-phenylacetonitrile. The resulting α-pyridyl-2-ylphenylacetonitrile then is hydrated in the presence of acid to yield α-pyrid-2-ylphenylacetamide which in turn is catalytically hydrogenated to yield α-piperid-2-ylphenylacetamide and then is hydrolysed and epimerized to dl-threo-ritalinic acid. The solvent used in the step (i) along with water may be selected from organic solvents. The solvent used to dissolve ester of tartaric acid may be selected from organic solvents. Conventional esters of tartaric acid used, may include dibenzoyltartaric acid and ditoluoyltartaric acid, the preferred one being (+)-dibenzoyltartaric acid of 0.2 to 1.6 eq to that of ritalinic acid, preferably, 1.06 eq in a solvent, preferably methanol adding at a temperature ranging preferably below 50° C., for a period preferably ranging from 5 min to 5 h. Heating the mass in step (ii) at reflux temperature preferably in 1 h to 2 h and filtering the mass through hyflo bed. The filtrate is cooled to a temperature preferably 20° C. to 25° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.N1CCCCC1>C(O)C>[SH:7][C:4]1[S:3][C:2]2=[N:1][C:10]([CH3:12])=[CH:9][C:8](=[O:13])[N:6]2[N:5]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nnc(S)s1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(=O)n2nc(S)sc2n1
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a solution of 2-amino-5-mercapto-l,3,4-thiadiazole (4.0 g) and ethyl acetoacetate (4.3 g) in 50 ml ethanol, piperidine (2.55 g) was slowly added. The mixture was refluxed for seven hours and then allowed to stand overnight at room temperature. The formed crystals were collected by filtration and dissolved in 100 ml of water. The pH was adjusted to 2.0, and the formed crystals were collected and washed with 20 ml of water, affording 3.8 g of the objective compound as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:14]=[N:15][N:16]([CH3:18])[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:18][N:16]1[CH:17]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[N:14]=[N:15]1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cn1cc(Br)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(CO)cc2)nn1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
A mixture of [4-(hydroxymethyl)phenyl]boronic acid (7.10 g), 4-bromo-1-methyl-1H-1,2-3-triazole (5.00 g), sodium carbonate (6.59 g) and tetrakis(triphenylphosphine)palladium(0) (3.59 g) in a mixed solvent of water (30.0 mL)-1,4-dioxane (100 mL) was heated with reflux for 16 hr under nitrogen atmosphere. The reaction mixture was allowed to be cooled to room temperature, the organic layer was concentrated under reduced pressure, and the residue was extracted with dichloromethane (×3). The combined extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.40 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7](Cl)[N:6]=1)=[O:4].[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].N(C(C)C)C(C)C>C1COCC1.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.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:6]=1)=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1nc(Cl)c(Cl)c(F)c1Nc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1nc(C#C[Si](C)(C)C)c(Cl)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5,6-dichloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent), TMS-acetylene (1.20 equivalents), Pd(PPh3)2Cl2 (0.10 equivalents), CuI (0.10 equivalents), and i-Pr2NH (2.00 equivalents) in THF is stirred for 16 hours at room temperature. THF is evaporated in vacuo. The reaction mixture is diluted with EtOAc and washed with saturated aqueous NH4Cl and brine. The organic layer is dried over MgSO4, filtered, and concentrated to give the crude material that is purified by flash column chromatography to afford the desired product.