Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[N:10][N:11]([CH3:12])[C:7]=2[CH:6]=[C:5]([C:13]2[CH:32]=[CH:31][C:16]([O:17][CH2:18][CH2:19][CH:20]3[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[C:15]([C:33]([F:36])([F:35])[F:34])[CH:14]=2)[N:4]=1)#[N:2].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl.C(#N)C>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH:22]1[CH2:23][CH:20]([CH2:19][CH2:18][O:17][C:16]2[CH:31]=[CH:32][C:13]([C:5]3[N:4]=[C:3]([C:1]#[N:2])[C:8]4[N:9]=[N:10][N:11]([CH3:12])[C:7]=4[CH:6]=3)=[CH:14][C:15]=2[C:33]([F:36])([F:34])[F:35])[CH2:21]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CN(C(=O)OC(C)(C)C)C4)c(C(F)(F)F)c3)cc21
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CNC4)c(C(F)(F)F)c3)cc21
Reaction time: 0.5 h
Yield: 62 %

Procedure:
tert-Butyl 3-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate (86 mg) was dissolved in DCM (2000 μl) and acetonitrile (500 μl). Trifluoroacetic acid (400 μl) was added and the reaction stirred for 30 minutes. Solvent was evaporated under reduced pressure and the resulting residue dissolved in a minimum volume of EtOAc. Ether was added dropwise until the solution clouded then the mixture was allowed to stand for 30 minutes and filtered. Solid was washed with ether and dried to afford the desired product 6-(4-(2-(azetidin-3-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile 2,2,2-trifluoroacetate (62% yield).
Reaction SMILES: [OH-].[K+].[Br:3][CH2:4][CH2:5]Br.[C:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:10])([CH3:9])[CH3:8].O>CO.C(Cl)(Cl)Cl>[C:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:5][CH2:4][Br:3])=[CH:16][CH:17]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: BrCCBr
Reactant: CC(C)(C)Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Oc1ccc(OCCBr)cc1
Yield: 29.3 %

Procedure:
A solution of KOH (0.224 g, 4 mmol) in MeOH (3 mL) was added, over the course of 30 min, to a warmed (70° C.) mixture of 1,2-dibromoethane (3 g, 0.016 mol) and 4-(tert-butoxy)phenol (0.66 g, 0.004 mol). The mixture was stirred at 70° C. for 15 h before water and CHCl3 were added. The layers were separated, the organic layer washed with 10% aqueous NaOH and then dried (Na2SO4) and concentrated in vacuo to give 0.32 g (28%) of the sub-title compound.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH:41][CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[N:29][CH:28]=[N:27]4)=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:35][CH:34]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-n2cncn2)cc1)N1CCC(NCCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A catalytic amount of p-toluenesulfonic acid was added to a solution of 0.45 g of 4-oxo-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine and 0.39 g of 2-(4-chlorophenyl) ethylamine in 10 ml of toluene. The mixture was refluxed by heating, for 5 hours while removing the generated water using a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure. To the residue was added 10 ml of ethanol. Thereto was added 70 mg of sodium borohydride at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was made acidic with concentrated hydrochloric acid and then concentrated under reduced pressure. To the residue was added ice water. The mixture was made basic with an aqueous sodium hydroxide solution and extracted with two 30-ml portions of ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution in this order, dried with sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluant: methylene chloride/methanol=25/1) and then recrystallized from ethyl acetate to obtain 4-[2-(4-chlorophenyl)ethylamino]-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][C:8]1[O:9][C:10]([C:14](=[O:17])[CH2:15][CH3:16])=[C:11]([CH3:13])[N:12]=1>>[CH3:7][C:8]1[O:9][C:10]([C:14]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:17])[CH2:15][CH3:16])=[C:11]([CH3:13])[N:12]=1
Reactant: CCC(=O)c1oc(C)nc1C
Reactant: Brc1ccsc1
Product: CCC(O)(c1ccsc1)c1oc(C)nc1C

Procedure:
Starting with 3-bromothiophene and 2,4-dimethyl-5-propionyloxazole and following the general method of Example 4 the title compound was prepared. Purification by preparative HPLC gave a white solid. M.p. 81°-83° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10].Cl[CH2:18]Cl>>[CH2:9]([O:11][C:12](=[O:13])[NH:14][C:15](=[S:16])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:18])[N:3]=1)[CH3:10]
Reactant: Nc1cccc(Br)n1
Reactant: ClCCl
Reactant: CCOC(=O)N=C=S
Product: CCOC(=O)NC(=S)Nc1cccc(C)n1
Temperature: 24 °C
Reaction time: 21 h

Procedure:
To an ice-cooled solution of 2-amino-6-bromopyridine (25.0 g, 0.144 mmol, 1 equiv) in dichloromethane (400 mL) was added ethoxycarbonyl isothiocyanate (19.9 g, 0.152 mmol, 1.05 equiv) dropwise. The reaction mixture was warmed to 24° C. After 21 h, the reaction mixture was concentrated in vacuo (˜20 mm Hg). The residue was diluted with ethyl acetate (600 mL), and the resulting organic solution was washed sequentially with water (2×200 mL) and saturated aqueous sodium chloride solution (200 mL). The organic was dried over magnesium sulfate, filtered, and concentrated to afford product as a yellow solid (43.7 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([NH:28][C:29]3[N:34]=[C:33]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[N:32]=[C:31]([NH:41][C:42]4[CH:64]=[CH:63][C:45]([C:46]([NH:48][CH2:49][CH:50]5[CH2:54][CH2:53][CH2:52][CH:51]5[NH:55][C:56](=[O:62])[C:57](OCC)=[O:58])=[O:47])=[CH:44][CH:43]=4)[N:30]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>CCO>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([NH:28][C:29]3[N:34]=[C:33]([O:35][CH2:36][C:37]([F:38])([F:39])[F:40])[N:32]=[C:31]([NH:41][C:42]4[CH:43]=[CH:44][C:45]([C:46]([NH:48][CH2:49][CH:50]5[CH2:54][CH2:53][CH2:52][CH:51]5[NH:55][C:56](=[O:62])[C:57]([NH:15][C:14]5[CH:16]=[CH:17][C:11]([F:10])=[CH:12][CH:13]=5)=[O:58])=[O:47])=[CH:63][CH:64]=4)[N:30]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)NC1CCCC1CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(Nc1ccc(F)cc1)C(=O)NC1CCCC1CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 155 °C
Reaction time: 72 h

Procedure:
iPr2NEt (0.2 mL) and 4-fluoroaniline (39.2 mg) added into the solution of ethyl 2-((2-((4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)methyl)cyclopentyl)amino)-2-oxoacetate (40 mg) in EtOH (2 mL) and the reaction was stirred at 155° C. for 3 days. The product was isolated by preparative HPLC system.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])C1C=CC=CC=1.C1CCCCC=1.Cl>C1COCC1.[C].[Pd]>[OH:8][CH2:9][C@@H:10]([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)[C@@H](COCc1ccccc1)Cc1cccc2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: C1CCOC1
Product: O=C(O)[C@@H](CO)Cc1cccc2ccccc12

Procedure:
(2R)-3-benzyloxy-2-(1-naphthylmethyl)propionic acid was dissolved in 6 ml of THF, and 3 ml of cyclohexene, 2.5 ml of 1N hydrochloric acid and 400 mg of 10% palladium carbon were added thereto. The mixture was refluxed under heating for 48 hours. After filtration, the solvent was distilled off under reduced pressure, and the residue was divided with ethyl acetate and a 4% sodium hydrogencarbonate aqueous solution. The aqueous layer was adjusted to pH2 with 1N hydrochloric acid under cooling with ice and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water, and a saturated sodium chloride aqueous solution and dried over anhydride sodium sulfate to obtain 212 mg of (2R)-3-hydroxy-2-(1-naphthylmethyl)propionic acid as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]#N)=[CH:10][C:9]=2[CH3:17])=[O:7])=[CH:4][CH:3]=1.[CH2:20]([SH:22])[CH3:21].[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:14]([C:11]1[N:12]([CH3:13])[C:8]([C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([CH3:17])[CH:10]=1)[CH3:15].[S:22]1[CH:20]=[CH:21][CH:24]=[C:25]1[CH2:26][C:27]([O-:23])=[O:7]
Reactant: C1CCOC1
Reactant: CCS
Reactant: Cc1cc(CC#N)n(C)c1C(=O)c1ccc(Cl)cc1
Product: CCc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Product: O=C([O-])Cc1cccs1
Temperature: -25 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
To a dry 100 ml 3-necked round-bottom flask under nitrogen is added 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetonitrile (1.4 g. 0.0051 mole) and 25 ml of dry tetrahydrofuran (THF). The solution is cooled to -25° C., ethyl mercaptan (0.39 ml, 0.0051 mole) is added, and hydrogen chloride is bubbled into the reaction mixture. After 1.5 hrs the reaction mixture is saturated with HC1 and the temperature is raised to and maintained at 0° C. for three hrs. The reaction mixture is then poured into toluene and steam is bubbled into the toluene mixture. The toluene layer is then separated, washed with brine and dried over anhydrous MgSO4. The toluene solvent is rotoevaporated to give 1.7 g of crude product which is recrystallized twice from methanol to yield 0.57 g (33.5%) of pure ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-thiolacetate; m.p. 90.5°-92° C.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH:13]=O.[BH4-].[Na+].O>CO>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:13][NH:2][CH3:1]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1[nH]c2ccccc2c1C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
Methylamine (0.34 mL, 8.4 mmol, 33% in ethanol) was added to a solution of 3-methylindole-2-carboxaldehyde (447 mg, 2.8 mmol) in methanol (10 mL) and stirred for 5 hours. Sodium borohydride (104 mg, 2.8 mmol) was slowly added at 0° C. The resultant mixture was warmed to room temperature and stirred overnight. Water (2 mL) was added slowly at 0° C. and the mixture was evaporated to a paste. The paste was partitioned between water (2 mL) and dichloromethane (15 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic phases were dried and evaporated to afford title compound (348 mg, 71%). NMR (400 MHz, DMSO-d6): 10.63 (s, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.92 (t, J=6.6 Hz, 1H), 3.73 (s, 2H), 2.25 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[OH:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].ClC(Cl)(Cl)C(O)=O.[CH:40]([O:42][CH2:43][CH3:44])=[CH2:41]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[CH2:40]([O:42][CH:43]([O:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32])[CH3:44])[CH3:41]
Reactant: O=C1CCCN1CO
Reactant: C=COCC
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(C)OCN1CCCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4 g of dl-5-hydroxymethyl-2-pyrrolidone are dissolved in 20 ml of chloroform, and 0.1 g of trichloroacetic acid and 16 ml of vinylethylether are added thereto. The solution is stirred at room temperature for 4 hours. After the reaction, the solution is cooled with ice-water, and washed with an aqueous sodium bicarbonate solution. The washings is extracted with chloroform. Then, the reaction solution and chloroform extract are combined, and the combined mixture is washed with water saturated with ammonium sulfate, dried and evaporated to remove solvent. The residue thus obtained is distilled under reduced pressure. dl-5-[1-(Ethoxy)ethoxy-methyl]-2-pyrrolidone is obtained as pale yellow oil. Yield: 6.45 g. B.p. 137°-138° C./1.5 mmHg
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC(S([CH2:20][N+:21]#[C-])(=O)=O)=CC=1.[H-].[Na+].[CH3:26]S(C)=O>CCOCC.O>[C:4]1([C:3]2[C:2]([C:20]#[N:21])=[CH:1][NH:10][CH:26]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC=Cc1ccccc1
Reactant: CS(C)=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#Cc1c[nH]cc1-c1ccccc1

Procedure:
To a mixture of 5.0 g (39 mmol) of cinnamonitrile and 7.6 g (39 mmol) of (p-tolylsulfonyl)methyl isocyanide in 35 mL of DMSO and 65 mL of ether is added over a 20 minute period a suspension of 1.86 g of a 60% oil suspension of sodium hydride (1.11 g; 46 mmol) in 80 mL of ether. The reaction mixture is maintained under nitrogen for an hour and then diluted with ether and water. The ether layer is separated, dried over magnesium sulfate, and concentrated in vacuo. The resulting oil is chromatographed on silica gel using 1:1 chloroform ethyl acetate to give 2.5 g of cream-colored solids. Recrystallization from ether-hexane affords 1.15 g, m.p. 123°-125° C.; NMR M86-1077.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH2:24]1[CH2:33][C@H:32]2[N:27]([CH2:28][CH2:29][CH2:30][C@H:31]2[CH2:34]O)[CH2:26][CH2:25]1.[I-].C(C[P+](C)(C)C)#N>C(#N)CC>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:34][C@H:31]2[C@@H:32]3[N:27]([CH2:26][CH2:25][CH2:24][CH2:33]3)[CH2:28][CH2:29][CH2:30]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: OC[C@@H]1CCCN2CCCC[C@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Temperature: 120 °C
Reaction time: 22 h
Yield: 108.1 %

Procedure:
3 (3 g, 15 mmol) is dissolved in 150 ml of propionitril. Ethyldiisopropylamine (10.2 ml, 60 mmol), (−)-lupinine (2.5 g, 15 mmol) and cyanomethyl-trimethyl-phosphonium iodide (Zaragoza reagent, 7.3 g, 30 mmol) are added. The reaction mixture is heated to 120° C. and stirred for 22 hours. Then the mixture is evaporated under reduced pressure. The residue is dissolved with ethyl acetate, washed 10% K2CO3- and NaCl-solution, and dried over Na2SO4. Evaporation gave 5.7 g of a brown oil. The crude product is purified by Flash-chromatography (ethyl acetate, then methanol/ethyl acetate (4:6), silicagel).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8](C2C=CC(Cl)=C(Cl)C=2)[N:7]=1)=[O:5].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][C:24]=1B(O)O>>[CH3:1][O:2][N:3]([CH3:21])[C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8]([C:24]2[CH:25]=[C:26]([S:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH:27]=[CH:28][C:23]=2[CH3:22])[N:7]=1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1B(O)O
Reactant: CON(C)C(=O)c1nc(-c2ccc(Cl)c(Cl)c2)cnc1N
Product: CON(C)C(=O)c1nc(-c2cc(S(=O)(=O)N3CCOCC3)ccc2C)cnc1N

Procedure:
This compound is prepared in an analogous manner to intermediate B substituting 3,4 dichlorophenyl boronic acid with 2-methyl-5-(N-morpholinylsulfonyl) phenyl boronic acid in step 2. The title compound is obtained as an off-white solid. [M+H]+ 422.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].O>O1CCCC1>[C:15]([N:14]1[CH2:13][CH2:12][NH:11][C:10]1=[N:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: Clc1ccc(N=C2NCCN2)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)N1CCNC1=Nc1ccc(Cl)cc1Cl

Procedure:
A mixture of 11.5 g 2-(2,4-dichlorophenylimino)imidazolidine 1.7 g sodium hydride (80 percent dispersion in oil) and 80 ml dry tetrahydrofuran was stirred and refluxed for one and a half hours, and a solution of 5.9 g isobutyryl chloride in 20 ml dry tetrahydrofuran was then added dropwise. The mixture was stirred and refluxed for five hours and then cooled and poured into iced water to give a solid which was dried over phosphorus pentoxide. Recrystallisation with charcoal from ethanol gave the novel compound 1-isobutyryl-2-(2,4-dichlorophenylimino)imidazolidine, melting point 147°-148° C.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].C(OCC)(=O)C.[C:35]([OH:43])(=[O:42])[C@H:36]([CH2:38][C:39]([OH:41])=[O:40])[OH:37]>C(O)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:35]([O-:43])(=[O:42])[C@H:36]([CH2:38][C:39]([O-:41])=[O:40])[OH:37]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C([O-])C[C@H](O)C(=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a 250 ml round bottom flask, equipped with a magnetic stirrer and a reflux condenser, was added Sitagliptin base (12.0 g) and ethyl acetate (120 ml). The mixture was heated to 60° C. for dissolution. A solution of L-malic acid (3.95 g) in absolute ethanol (24 ml) was added to the above solution dropwise over 15 minutes. During the addition, the heating was stopped and the mixture was cooled slowly. When the addition was completed the temperature in the oil bath was 43° C. The solution was cooled to room temperature (˜20° C.) and stirred overnight. After 3 days about 60 g of solvents were distilled out and the solution was stirred at room temperature over 10 days, during this time precipitation as a soft white block occurred. Ethyl acetate (110 ml) was added in order to facilitate filtration and the mixture was stirred for several minutes. The product was isolated by vacuum filtration, washed with ethyl acetate (40 ml) and dried in a vacuum oven at 50° C. for 24 hours and then for additional 48 hours at room temperature (15-25° C.) to obtain Sitagliptin L-malate crystalline form I3 (13.86 g, 87% yield).
Reaction SMILES: [C:1](O)(=O)CCCCCCCCCCCCCCC.[C:19]([OH:38])(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.CC/C=C\C/C=C\C/C=C\CCCCCCCC(O)=O>>[CH3:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]/[CH:28]=[CH:27]\[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]([O:38][CH3:1])=[O:37]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC

Procedure:
Fatty acid methyl ester mixture based on a fatty acid mixture with the following composition: 5% palmitic acid, 1% stearic acid, 67% oleic acid, 11% linolenic acid (a product of Henkel KGaA).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([CH3:21])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C([O-])=O.[NH4+].ClCCl>[Pd].O>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([CH3:21])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1cc(OCCOCc2ccccc2)ccc1N
Reaction time: 1 h
Yield: 103.8 %

Procedure:
A 500 ml round bottomed flask fitted with a teflon stirrer bar was charged with 4-(2-(benzyloxy)ethoxy)-2-methyl-1-nitrobenzene (5.15 g) and methanol (200 ml) and stirred to dissolve all material. The reaction mixture was charged with 10% palladium on charcoal (50% water w/w) and stirred at room temperature. Ammonium formate (20.5 g) was added in one lot and the reaction mixture was stirred at room temperature. After 1 hour, additional ammonium formate (20.5 g) was added, and the progress of the reaction was followed by TLC (silica, dichloromethane). After 4 hours, the reaction was found to be complete. The reaction mixture was then filtered through a plug of Celite, which was washed with methanol (2×50 ml). The resulting filtrate was evaporated under reduced pressure to give a solid. This material was dissolved in water (300 ml), extracted with diethylether (3×100 ml). The combined ethereal solutions were washed with water (2×100 ml) and saturated sodium chloride solution (2×100 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 4.79 g of 4-(2-(benzyloxy)ethoxy)-2-methylaniline, 1H-NMR (CDCl3) 7.39 (m, 2H), 7.37 (s, 1H), 7.31 (m, 2H), 6.33 (m, 1H), 6.30 (s, 1H), 6.23 (m, 1H), 5.85 (bs, 2H), 4.63 (s, 2H), 4.11 (m, 2H), 3.79 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([O:11][CH3:12])(=[O:10])[C:8]#[CH:9].C[O-].[Na+].[C:16](O)(=O)[CH2:17][C:18](CC(O)=O)(C(O)=O)[OH:19]>CO.C(Cl)Cl>[OH:4][CH2:3][C:2]([N:1]1[C:18](=[O:19])[CH:17]=[CH:16][C:8]([C:7]([O:11][CH3:12])=[O:10])=[CH:9]1)([CH3:6])[CH3:5]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C#CC(=O)OC
Reactant: CC(C)(N)CO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(=O)n(C(C)(C)CO)c1
Temperature: 120 °C

Procedure:
A solution of 2-amino-2-methyl-1-propanol (2 mL, 24 mmol) and methyl propiolate (5 mL, 61 mmol) in MeOH (10 mL) was appropriately sealed and heated to 120° C. for 30 min with microwaves. Sodium methoxide (25 wt. % in methanol, 4 mL, 73 mmol) was added and the solution was sealed and heated again to 120° C. for 30 min with microwaves. The mixture was partioned between CH2Cl2 (60 mL) and 10% citric acid (20 mL). The aqueous was repeatedly extracted with CH2Cl2 (4×15 mL). Combined organics dried over MgSO4 then concentrated onto dry silica (20 g). The residue was purified on 120 g silica eluting with 10-40% of 5% MeOH/CH2Cl2, and isolated as a yellow solid. MS (ESI pos. ion) m/z (MH+): 226. Calc'd exact mass for C11H15NO4: 225. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.66 (s, 6 H) 3.86 (s, 3 H) 3.98 (s, 2 H) 6.49 (d, J=9.54 Hz, 1 H) 7.77-7.89 (m, 1 H) 8.42 (s, 1 H). 13C NMR (101 MHz, Chloroform-d) δ ppm 22.70, 50.08, 65.04, 66.57, 107.88, 119.17, 135.92, 138.43, 162.56, 162.98.