Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[C:9]#[N:10].C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(F)ccc1CBr
Reaction time: 8 h
Yield: 65.9 %

Procedure:
N2 was passed through a mixture of 5-fluoro-2-methylbenzonitrile (28.51 g, 211 mmol), NBS (41.31 g, 232 mmol) and AIBN (2.5 g, 15 mmol) in CCl4 (845 mL) for 10 min after which the reaction was heated at reflux for 8 h. After standing at room temperature overnight, the reaction mixture was filtered and the filter cake washed with CCl4 (500 mL). The combined filtrate was evaporated to give a yellow oil. Flash chromatography (SiO2) using 5-25% ethyl acetate/Hexanes as eluent afforded the title compound (29.74 g, 66% yield) as a pale yellow oil. 1H NMR (500 MHz, CDCl3) δ: 7.55 (1H, dd, J=8.6, 5.2 Hz), 7.37 (1H, dd, J=7.9, 2.8 Hz), 7.32-7.28 (1H, m), 4.61 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:8]=[CH:9][CH:10]=1.[CH:30](=O)[CH3:31]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][N:20]([CH2:30][CH3:31])[CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC=O
Reactant: COC(=O)Cc1cccc(-c2c(CNCCN3CCOCC3)cccc2OC)c1
Product: CCN(CCN1CCOCC1)Cc1cccc(OC)c1-c1cccc(CC(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: {6′-methoxy-2′-[(2-morpholin-4-yl-ethylamino)-methyl]-biphenyl-3-yl}-acetic acid methyl ester and acetaldehyde.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[OH-].[Na+].[S:11]([O-:15])([O-:14])(=[O:13])=[O:12].[Ca+2:16].C([O-])(=O)/C=C/C([O-])=O.[C:25](=[O:28])([O-:27])[O-:26].[NH3:29].S([O-])([O-])(=O)=O>>[C:25](=[O:26])([O-:28])[O-:27].[Ca+2:16].[S:11]([O-:15])([O-:14])(=[O:13])=[O:12].[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:29]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: N
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Product: [NH4+]

Procedure:
Thomsen (U.S. Pat. No. 3,030,276) describes the manufacture of fumaric acid from lignified cellulose which comprises; digesting said lignified cellulose with a solution of caustic soda under the conventional limitations as to alkali concentration, time and. temperature, until substantially all the non-cellulose portion shall have been dissolved; separating the spent cooking liquor for subsequent conventional regeneration and recycling to said digestion step from the cellulose residual and saccharifying the latter with dilute sulphuric acid under the conventional limitations as-to acid concentration, time and temperature; commingling the resultant sugar solution with a recirculated excess of calcium carbonate produced in a subsequent step and with a micro-organism suitable for the conversion of sugar into fumaric acid; commingling the resultant mixture of calcium sulphate, fumarate and carbonate with sufficient carbonated ammonia to decompose all such sulphate and fumarate forming calcium carbonate and sulphate and fumarate of ammonium; separating and recycling such calcium carbonate and evaporating the resultant solution to substantial saturation and acidifying said solution of ammonium sulphate and ammonium fumarate with the stoichiometric amount of sulphuric acid to decompose all resident fumarate and crystallizing out the liberated fumaric acid from the residual solution of ammonium sulphate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([NH:21][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of p-Nitrobenzenesulfonylchloride (274 g, 1.2 eq) in DCM (1 l), was added to a solution of benzylamine (500 g, 1 eq) and triethylamine (469 ml, 1.5 eq) in DCM (1 l) at 4° C. in small portions and then stirred for 1 h. Afterwards the mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was washed with a mixture of DCM/PE (1/1) at 4° C., filtered and dried in vacuo to give N-Benzyl-4-nitrobenzenesulfonamide. Yield 90%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[N:16]=2)[N:11]=[CH:10][C:9]=1[OH:20].[CH2:21]([O:28][C:29](=[O:41])[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37](=[O:40])[CH2:38]Br)[CH2:33][CH2:32]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([O:28][C:29](=[O:41])[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]2([OH:40])[NH:7][C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[N:16]=4)[N:11]=[CH:10][C:9]=3[O:20][CH2:38]2)[CH2:33][CH2:32]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(N[C@H]1CC[C@H](C(=O)CBr)CC1)OCc1ccccc1
Reactant: COc1ccc2ncc(O)c(N)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2n1)NC(O)([C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1)CO3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (246 mg, 1.78 mmol, 2.0 eq) is added at room temperature to a stirred solution of 4-amino-6-methoxy-[1,5]naphthyridin-3-ol (170 mg, 0.89 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL), followed by [trans-4-(2-bromo-acetyl)-cyclohexyl]-carbamic acid benzyl ester (315 mg, 0.89 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×20 mL) and a saturated ammonium chloride aqueous solution (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford [trans-4-(3-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid benzyl ester (2.33 g, 88% Yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[S:31]([CH3:30])(=[O:33])=[O:32])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1S(C)(=O)=O
Yield: 61 %

Procedure:
Using a similar procedure to that described in Example 29, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-pyrrolidin-2-yl]methoxy}quinazoline hydrochloride (300 mg) was reacted with methane sulfonyl chloride to give the title product (200 mg, 61%); 1H NMR Spectrum: (DMSO d6) 1.88-2.17 (m, 4H); 2.98 (s, 3H); 3.38 (m, 2H); 3.93 (s, 3H); 4.02 (m, 1H); 4.15 (m, 2H); 7.20 (s, 1H); 7.20-7.30 (m, 1H); 7.42-7.53 (m, 2H); 7.81 (s, 1H); 8.37 (s. 1H); 9.62 (s, 1H); Mass Spectrum: (M+H)+ 481.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCOCC1>[Cl:18][C:4]1[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[C:2]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: C1CCNC1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Cl)nc(Cl)c2)cc1
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)c2cc(Cl)nc(N3CCCC3)c2)cc1
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
16.8 g (0.0554 Mol) 4-(2,6-dichloro-pyridine-4-sulfonyl)-phenylamine were dissolved in dioxane (165 ml), 23.0 ml (0.2753 Mol) pyrrolidine were added at ambiente temperature and stirred for 1.5 h. The reaction mixture was then poured onto water (600 ml), stirred for 1 h and filtered. The residue on the filter was washed with water (150 ml), dissolved in tetrahydrofuran (250 ml) and treated with Na2SO4 (20.0 g) and Norit-SX-1 (1.7 g). After filtration the residue on the filter was washed with tetrahydrofuran (100 ml) and subsequently dried in a high vacuum. It was obtained 18.4 g (98%) 4-(2-chloro-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine as a bright yellow powder; mp.: 225-226° C.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31]C)=[O:30])[CH2:25][CH2:24]2)[N:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)[N:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(Cc2ncc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CCC(C(=O)O)CC4)ncc3c2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 1-((6-(trans-4-tert-butylcyclohexyloxy)quinazolin-2-yl)methyl)piperidine-4-carboxylate (150 mg, 0.34 mmol) and NaOH (27 mg, 0.68 mmol, 2.0 eq) in EtOH (5 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, 1N HCl (5 ml) aqueous solution was added to adjust pH=3˜4. Solvent was evaporated in vacuum. The residue was purified by prep-HPLC (MeOH in 0.05% TFA/H2O 30-95% v/v as mobile phase) to give 1-((6-(trans-4-tert-butylcyclohexyloxy)quinazolin-2-yl)methyl)piperidine-4-carboxylic acid (105 mg, yield: 75%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.[CH2:16]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH:29]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na]>ClC(Cl)C.O>[CH2:16]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH2:29][NH:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(OCCOCc2ccccc2)c(C=O)c1
Reactant: Nc1cc(F)ccc1Oc1ccccc1
Agent: [Na]
Solvent: CC(Cl)Cl
Solvent: O
Product: COc1ccc(OCCOCc2ccccc2)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Yield: 78 %

Procedure:
To stirred solution of 4.6 g (23 mmol) 1b, 6.3 g (23 mmol) 2a and one drop of glacial acid in 35 ml dichloroethane (pH=5) were added 7.4 g (35 mmol) sodium tris-acetoxy hydro borane. The reaction mixture was stirred over night and diluted with 3 ml water. The pH value was adjusted with aqueous sodium hydroxyd solution to pH=8-9. The mixture was extracted three times with dichloromethane. The combined organic phases were washed with water and brine and were dried with magnesium sulfate. The desired crude product 2b was obtained in 78% yield (8.5 g, 17.9 mmol) as yellow oil. The crude product 2b was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]1[C:11]([O:32][CH3:33])=[CH:12][C:13]([O:30][CH3:31])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1>C(#N)C.Cl[Pd]Cl>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[C:9]1[C:10]1[C:11]([O:32][CH3:33])=[CH:12][C:13]([O:30][CH3:31])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1
Reactant: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1C#Cc1ccccc1N
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
Ex-35E: 4-{3E-[5-(2-Aminophenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35D, 0.91 g, 1.97 mmol) was dissolved in acetonitrile (100 ml), heated to reflux, and then PdCl2 (0.035 g, 0.197 mmol) was added. The reaction mixture was kept at reflux for 10 min and cooled to room temperature. Upon cooling, the mixture was filtered to remove any solid material and the filtrate was treated with 3-mercaptopropyl-functionalized silica gel (1.0 g) under stirring for 0.5 h. The mixture was then filtered and concentrated to give crude product, which was recrystallized from EtOAc/hexanes to yield 0.75 g (83%) of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide as a yellow solid, mp 185–187° C. 1H-NMR (DMSO-d6) δ 11.15 (brs, 1H), 8.33(s, 1H), 8.24 (d, J=8 Hz, 2H), 8.07 (d, J=15 Hz, 1H), 7.98 (d, J=8 Hz, 2H), 7.80 (d, J=15 Hz, 1H), 7.41–7.55 (m, 4H), 7.03–7.08 (m, 1H), 6.93–6.99 (m, 2H), 6.83 (s, 1H), 4.04 (s, 3H), 3.99(s, 3H), MS m/z: 463 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][N:29]([CH3:37])[C:30](=[O:36])[CH2:31][CH2:32][C:33](O)=[O:34]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH2:31][C:30]([N:29]([CH3:37])[CH3:28])=[O:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CN(C)C(=O)CCC(=O)O
Agent: Cl
Product: CN(C)C(=O)CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (103 mg, 90%), MS (ISP) m/z=458.6 [(M+H)+], mp 177.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-(dimethylamino)-4-oxobutanoic acid.
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:29]([OH:37])(=[O:36])[C@H:30]([CH2:32][C:33]([OH:35])=[O:34])[OH:31]>C(OCC)(=O)C.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:29]([O-:37])(=[O:36])[C@H:30]([CH2:32][C:33]([O-:35])=[O:34])[OH:31]
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: CCO
Solvent: CCOC(C)=O
Product: O=C([O-])C[C@H](O)C(=O)[O-]
Temperature: 60 °C

Procedure:
A 250 mL round flask was charged with Sitagliptin free base (5 g, 12 mmol) and a mixture of ethyl acetate:ethanol (5:0.8 v/v, 25 mL) was added. The mixture was mechanically stirred and heated to 60° C. until complete dissolution. The solution was then cooled to room temperature. In parallel, L-malic acid (1.65 g, 12 mmol) was completely dissolved in a mixture of ethyl acetate:ethanol (5:0.8 v/v, 10 mL) at 60° C. and then cooled to room temperature. The solution of the L-malic acid was then added dropwise to the solution of Sitagliptin free base over a period of 10 minutes while stirring at room temperature with the rotation speed of 310 rpm. The obtained white gel-paste reaction mixture was stirred at room temperature for about 69 hours. The obtained massive white precipitate was isolated by vacuum filtration, washed with cold mixture of ethyl acetate:ethanol (5:0.8 v/v, 2×10 mL) and dried in a vacuum oven at 40° C. for 23 hours to give Sitagliptin L-malate (5.99 g, 92% w/w yield).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=O)[CH:4]=[CH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:24]=[C:25]([NH2:27])[CH3:26].[H-].[Na+]>CN(C)C=O.[Cl-].[NH4+].[Cl-].[Na+]>[CH3:26][C:25]1[N:27]=[C:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:1])[NH:7][N:6]=2)[O:10][N:24]=1
Reactant: O=C(O)c1ccc(=O)[nH]n1
Reactant: CC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(=O)[nH]n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A solution of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (1.4 g) and 1,1′-carbonylbis(1H-imidazole) (2.1 g) in N,N-dimethylformamide (80 mL) was stirred at 60° C. for 1 hr. The mixture was cooled to room temperature, and N′-hydroxyethanimidamide (963 mg) was added. Sodium hydride (520 mg) was slowly added, and the mixture was stirred at 100° C. for 8 hr. The mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride solution (100 mL) and saturated aqueous sodium chloride solution (100 mL), and the mixture was extracted 3 times with ethyl acetate-tetrahydrofuran (1:1, v/v, 100 mL). The organic layers were combined, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in diethyl ether and diisopropyl ether and the precipitate was collected by filtration to give the object product (1.1 g, 60%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][CH2:14]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([N:18](CC)CC)C.CS(Cl)(=O)=O.Cl>C(OCC)(=O)C>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][CH2:14][C:16]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: OCCCc1cnoc1-c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: N#CCCCc1cnoc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 3-(5-phenyl-4-isoxazolyl)propan-1-ol (15.00 g) and triethylamine (21.0 ml) in ethyl acetate (500 ml) was gently added methanesulfonyl chloride (9.0 ml) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. A mixture of the residue, sodium cyanide (7.33 g), sodium iodide (13.48 g) and N,N-dimethylformamide (150 ml) was stirred at 70° C. for 5 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-(5-phenyl-4-isoxazolyl)butyronitrile (13.47 g, yield 86%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). NMR (CDCl3) δ: 1.91–2.09 (2H, m), 2.36–2.46 (2H, m), 2.78–2.94 (2H, m), 7.44–7.58 (3H, m), 7.64–7.74 (2H, m), 8.22 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>CN(C)C=O>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)=[CH:14][CH:13]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(Cc2ccc(Cl)cc2)n1
Yield: 81.8 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, 4-chlorobenzylbromide (473 mg, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 1-(4-chloro-benzyl)-3-nitro-1H-pyrazole (344 mg, 82%) as a white solid: H1-NMR (400 MHz, CDCl3) δ: 5.33 (2H, s), 6.90 (1H, d, J=2.3 Hz), 7.22 (2H, d, J=8.4 Hz), 7.34 (2H, d J=8.6 Hz), 7.40 (1H, d, J=2.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([NH:20][CH3:21])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:20]([C:19]2[CH:22]=[CH:23][C:16]([O:15][C:14]([F:13])([F:24])[F:25])=[CH:17][CH:18]=2)[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Product: CN(c1ccc(OC(F)(F)F)cc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 4-trifluoromethoxy-N-methylaniline (20 μL, 0.302 mmol) by a procedure similar to example 1b and was isolated as white powder (22 mg, 44%). 1H NMR (CDCl3): 7.93 (dd, J=8.4, and 0.6 Hz, 1H), 7.61 (ddd, J=8.4, 4.5 and 1.2 Hz, 1H), 7.29-7.22 (m, 4H), 7.06 (ddd, J=8.4, 4.5 and 1.2 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 3.65 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:31])[CH2:29]I)[CH2:20][C@@:19]2([CH3:32])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:33])[CH2:16][C@@:15]2([CH3:34])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(Cl)Cl>[OH:1][C@@H:2]1[C@@H:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:31])[CH2:29][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:20][C@@:19]2([CH3:32])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:33])[CH2:16][C@@:15]2([CH3:34])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCOC(=O)CI)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: C1COCCN1
Solvent: ClCCl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCOC(=O)CN5CCOCC5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3α-Hydroxy-2β-(4'-iodoacetoxy-n-butoxy)-5α-pregnane-11,20-dione (467 mg.) was dissolved in dried methylene chloride (30 ml.) and morpholine (1 ml.) added to this solution. The mixture was stirred at room temperature for 1 hour, a white precipitate forming in this time. The mixture was filtered and the filtrate evaporated to a yellow oil which was purified by preparative tlc in ethyl acetate (run twice) to give the title compound (220 mg.) as a colourless oil. [α]D + 57.1° (c 0.49).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7][Cl:8])=[O:6].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([OH:6])[CH2:7][Cl:8]
Reactant: COC(=O)CC(=O)CCl
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: COC(=O)C[C@@H](O)CCl

Procedure:
Methyl-4-chloroacetoacetate (VII) (100 mg) was incubated with 29 units of porcine heart (EC 1.1.1.35), B-hydroxyacyl CoA dehydrogenase (Sigma, H4626), and 1.36 g of NADH (Sigma, 90%) in 30 ml of 0.1 M sodium phosphate buffer, pH 6.5.