Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=2)[C:18]#[N:19])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-:26].[Na+].Cl.[NH2:29]O.Cl>C1(C)C=CC=CC=1.O.CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:26][N:29]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=3)[C:18]#[N:19])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: [OH-]
Reactant: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1F
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
2.50 g of toluene and 1.50 g of N-methyl-2-pyrrolidone were added to 0.50 g (1.29 mmol) of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-fluorobenzonitrile, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the solution which was prepared by adding 0.52 g of water to 0.21 g (5.16 mmol) of sodium hydroxide, and then adding the solution in which 0.099 g (1.42 mmol) of hydroxylamine hydrochloride was dissolved into 0.21 g of water in dropwise, the mixture was stirred for 2 hours at 0° C. The aqueous solution which was prepared from 0.81 g (7.74 mmol) of 35% hydrochloric acid and 2.42 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. 10 ml of toluene was added and separation operation was performed. The toluene phase was washed twice with 5 ml of water. The solvent was distilled off under reduced pressure to obtain 0.48 g of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluorobenzonitrile (yield 92.9%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32](NC1CCN(C2C=CN=C(S(C)=O)N=2)CC1)=[O:33].Cl.[NH2:51][CH:52]1[CH2:57][CH2:56][N:55]([C:58]2[CH:59]=[C:60]([CH:64]=[C:65]([Cl:67])[N:66]=2)[C:61]([NH2:63])=[O:62])[CH2:54][CH2:53]1>CN(C=O)C>[Cl:67][C:65]1[CH:64]=[C:60]([CH:59]=[C:58]([N:55]2[CH2:54][CH2:53][CH:52]([NH:51][C:32]([C:26]3[NH:27][C:28]([CH3:31])=[C:29]([Cl:30])[C:25]=3[Cl:24])=[O:33])[CH2:57][CH2:56]2)[N:66]=1)[C:61]([NH2:63])=[O:62]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ccnc(S(C)=O)n3)CC2)c(Cl)c1Cl
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)c(Cl)c1Cl
Reaction time: 8 h
Yield: 30 %

Procedure:
Diisopropylethylamine (0.063 ml, 0.37 mmol), EDC (0.095 g, 0.31 mmol) and HOAT (0.042 g, 0.31 mmol) were added to a stirred solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3, 0.060 g, 0.31 mmol) in DMF (1.0 ml) at room temperature. The resultant solution was stirred for 30 mins and a solution of 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70, 0.096 g, 0.37 mmol) in 1 ml of DMF was added. The reaction was stirred overnight, then concentrated under vacuum and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts were washed with 1 N HCl, water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by reverse phase chromatography to give the desired product as a white solid (40 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[N:22](COCC[Si](C)(C)C)[S:21]3(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH:13]=1.I[CH:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1>>[CH:57]1([N:52]2[CH2:53][CH2:54][N:49]([C:46]3[CH:45]=[CH:44][C:43]([C:40]4[CH:41]=[CH:42][C:37]([CH2:36][C:11]5[N:12]([C:14]6[CH:15]=[CH:16][C:17]([N:20]7[CH2:24][C:23](=[O:25])[NH:22][S:21]7(=[O:35])=[O:34])=[CH:18][CH:19]=6)[CH:13]=[C:9]([C:3]6[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=6[Cl:1])[N:10]=5)=[CH:38][CH:39]=4)=[CH:48][CH:47]=3)[CH2:50][C:51]2=[O:55])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1
Reactant: IC1CCCCC1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNC(=O)C5)cc4)cc3)cc2)S1(=O)=O
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCN(C6CCCCC6)C(=O)C5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
4-[4′-(4-(2,4-Dichloro-phenyl)-1-{-4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperazin-2-one (17 mg, 0.02 mmol) was treated as described in general procedure L [using iodocyclohexane (13 mg, 0.06 mmol)] and general procedure W stepwise to give 1-cyclohexyl-4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-piperazin-2-one.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Cl>O1CCCC1.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Reaction time: 6 h
Yield: 95.6 %

Procedure:
To 1.3 L (liters) of dry tetrahydrofuran (THF) was added 162 g of 60% sodium hydride (NaH) and 342 g of diethyl carbonate. To this mixture was added a solution of 200 g p-fluoroacetophenone in 440 ml dry THF dropwise over about 1 hour while refluxing, followed by 6 hours of refluxing. This reaction mixture was cooled, poured into iced water, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate (MgSO4), and concentrated. The residue was distilled under reduced pressure to provide 291 g of ethyl 3-(4-fluorophenyl)-3-oxopropionate as pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[S:17][C:16]=3[NH:15][C:14]3[CH:26]=[CH:27][CH:28]=[CH:29][C:13]=3[N:12]=2)[CH2:6]1.C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:46]C(Cl)C>C(=O)(O)[O-].[Na+]>[ClH:46].[ClH:46].[CH3:1][O:2][CH2:3][CH2:4][C@@H:5]1[N:10]([CH3:32])[CH2:9][CH2:8][N:7]([C:11]2[C:20]3[N:19]=[C:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[S:17][C:16]=3[NH:15][C:14]3[CH:26]=[CH:27][CH:28]=[CH:29][C:13]=3[N:12]=2)[CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(Cl)Cl
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C4CCCC4)nc32)CCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C4CCCC4)nc32)CCN1C
Product: Cl
Yield: 91 %

Procedure:
Combine (S)-10-[3-(2-methoxyethyl)-piperazin-1-yl]-2-cyclopentyl-4H-3-thia-1,4,9-triazabenzo[f]azulene (0.364 g, 0.884 mmol), formaldehyde (93 μL, 1.15 mmol, 37%), and sodium triacetoxyborohydride (0.281 g, 1.33 mmol) in dichloroethane (15 mL) and stir at room temperature for 4 hours. Dilute the mixture with saturated aqueous sodium bicarbonate and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give a solid residue. Purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 6% 2N ammonia-methanol in dichloromethane, to obtain the free base of the title compound (0.342 g; 0.804 mmol, 91%) as a yellow oil: mass spectrum (APCI): m/z=386.4 (M+1). Isolate the clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow foam in ethanol (5 mL) and add a solution of about 5 equivalents of hydrochloric acid in ethanol (5 mL); then remove the solvent under vacuum: Exact Mass, Calc: 426.2328; Found: 426.2329.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH:17]([Sn])=[CH2:18]>C1(C)C=CC=CC=1.CN(C)C=O.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:17]=[CH2:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Reactant: C=C[Sn]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Yield: 53.3 %

Procedure:
A mixture of 12.28 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.866 g of tetrakis (triphenylphosphine)palladium, 0.015 g of 2,6-di-t-butyl-4-methylphenol in 75 ml of toluene and 20 ml of N,N-dimethylformamide is treated with 13.06 g of vinyltin followed by heating at reflux for 4 hours. The reaction mixture is cooled and concentrated in vacuo. The residue is diluted with hexanes and filtered. The filter cake is washed with hexanes and the remaining tacky solid dissolved in 100 ml of chloroform-methanol (8:2) and purified by chromatography on silica gel with 1:3 ethyl acetate-hexanes to afford 4.55 g of the desired product as a yellow solid. CI MASS SPEC 229(MH+).
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:25][O:24][C:8]2([CH2:13][CH2:12][CH2:11][CH:10]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:9]2[CH3:23])[O:7]1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][OH:56].[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:25]1[CH2:6][O:7][C:9]2([CH3:23])[C:10]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][OH:56])([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:11][CH2:12][CH2:13][CH:8]2[O:24]1
Reactant: OCCCCCCCCCCBr
Reactant: CC1C(S(=O)(=O)c2ccccc2)CCCC12OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC12OCCOC1CCCC2(CCCCCCCCCCO)S(=O)(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A solution of n-butyl lithium (1.02 ml) was added dropwise to a solution of 304 mg of 1,1-(ethylenedioxy)-2-methyl-3-(phenylsulfonyl)-cyclohexane and 4 mg of triphenylmethane in 5 ml of THF at −78° C. under an argon stream. After stirring for 10 minutes, the reaction was effected at room temperature for 1 hour. HMPA (1 ml) was added to the reaction mixture. It was then recooled to −78° C., followed by the dropwise addition of a solution of 90 mg of 10-bromo-1-decanol in 2 ml of THF. After reaction at −20° C. for 2 hours, the reaction mixture was poured into a saturated solution of ammonium chloride. The resulting mixture was extracted with ethyl ether. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 1,2-(ethylenedioxy)-3-(10-hydroxydecyl)-2-methyl-3-(phenylsulfonyl)-cyclohexane was obtained in the form of a colorless oil. Yield: 92%, TLC: (hexane-AcOEt: 6-4) Rf=0.2
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[I:12]C>ClCCl>[I-:12].[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[NH+:8][CH:9]=[CH:10][CH:11]=1
Reactant: CI
Reactant: c1cncc(C2OCCO2)c1
Solvent: ClCCl
Product: [I-]
Product: c1c[nH+]cc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.1 %

Procedure:
3-(1,3-Dioxolan-2-yl)pyridine (1.00 g, 6.62 mmol) was dissolved in dichloromethane (20.0 mL). To this, iodomethane (494 μL, 7.94 mmol) was added under a nitrogen atmosphere at room temperature and the mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated, and the residue was subjected to slurry purification using diisopropyl ether, to give 3-(1,3-dioxolan-2-yl)-1-pyridinium iodide (1.85 g, yield: 96%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:26])=[O:20]>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:26])=[O:20]
Reactant: Oc1nc2ccccc2s1
Reactant: CN(CCCNC(=O)CBr)Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCNC(=O)COc1nc2ccccc2s1)Cc1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 59.3 %

Procedure:
0.0756 g (0.5 mmol) 1,3-benzothiazol-2-ol is dissolved in 5 ml dimethylformamide, 0.15 g (1.1 mmol) dry potassium carbonate is added and under stirring at room temperature 0.18 g (0.5 mmol) 2-bromo-N-{3-[(3,4-dichlorobenzyl)(methyl)amino]propyl}acetamide in 2 ml dimethylformamide is added dropwise. Stirring is continued for 24 hours. The reaction mixture is poured onto ice-water mixture, the precipitated crystals are filtered off, washed with water to obtain 0.13 g title compound. Mp: 113-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[N:14]([CH:15]=1)[CH:13]=[CH:12][O:11]2.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[N:14]([C:15]=1[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][O:11]2
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccccc1-c1cn2ccoc2n1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1c(-c2ccccc2Cl)nc2occn12
Temperature: 135 °C
Yield: 83 %

Procedure:
To a mixture of 6-(2-chlorophenyl)-imidazo[2,1-b]oxazole (1.0 g, 4.57 mmol) and acetic anhydride (23 ml) is added 3 drops of concentrated sulfuric acid. The reaction mixture is heated at 135° C. for 1 hour. The reaction mixture is then poured onto 50 ml of ice, and diluted with 100 ml of water and the resulting mixture is extracted three times with 75 ml each of ethyl acetate. The combined extracts are dried with magnesium sulfate, filtered and concentrated in vacuo, to give a brown oil. The product is purified by flash chromatography on silica gel (hexane/ethyl acetate 3:1), yielding 994 mg of an off-white solid (83%). M.p.=121-122° C.; 300 MHz 1H NMR (CDCl3) δ: 8.02 (d, J=1.6 Hz, 1H), 7.56-7.38 (m, 5H), 2.05 (s, 3H). LCMS: 261 [M+H]; calc. for C13H9ClN2O2: C, 59.84; H, 3.48; N, 10.74; found. C, 60.18; H, 3.16; N, 10.61.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:18]5[C:13](=[N:14][CH:15]=[N:16][C:17]=5[NH2:19])[N:12]([CH3:20])[N:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(Cl)cc(Cl)c2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (89 mg, 0.293 mmol), (3,5-dichlorophenyl)acetic acid (60 mg, 0.293 mmol), HATU (111 mg, 0.293 mmol), DIEA (0.204 mL, 1.171 mmol) was stirred at room temperature overnight. The crude was poured into water and stirred for 30 minutes. The precipitate that formed was collected by filtration, washed with water and dried at the pump for 30 minutes. The crude was adsorbed onto silica and purified by flash chromatography (0-10% methanol in DCM), concentrated and dried overnight in a vacuum oven to afford 3-{1-[(3,5-dichlorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg) as a white solid. LCMS (ES) m/z=453, 455 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.29 (t, J=9.60 Hz, 2H), 3.94 (s, 3H), 3.97 (s, 2H), 4.26 (t, J=8.59 Hz, 2H), 7.40 (d, J=2.02 Hz, 2H), 7.45 (d, J=8.08 Hz, 1H), 7.53 (d, J=1.77 Hz, 2H), 8.17 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [CH2:1](C1C=C2C=NNC2=CN=1)[CH3:2].[C:12]([C:15]1[C:23]2[C:18](=[CH:19][N:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][C:25]([OH:27])=[O:26])[N:16]=1)(=[O:14])[NH2:13]>>[C:12]([C:15]1[C:23]2[C:18](=[CH:19][N:20]=[C:21]([CH2:1][CH3:2])[CH:22]=2)[N:17]([CH2:24][C:25]([OH:27])=[O:26])[N:16]=1)(=[O:14])[NH2:13]
Reactant: CCc1cc2cn[nH]c2cn1
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Product: CCc1cc2c(C(N)=O)nn(CC(=O)O)c2cn1

Procedure:
was prepared from 5-ethyl-1H-pyrazolo[3,4-c]pyridine by using the same procedures as for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid (Scheme A26). MS (LC-MS): 249 [M+H]+, tR (HPLC conditions k): 0.49 min.
Reaction SMILES: O1CCCC1.[CH2:6]([O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18](Cl)=[N:19][OH:20])[CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH3:9].[C:22]([C:24]1[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23].C(N(CC)CC)C>O>[CH2:6]([O:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=2)[O:20][N:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1cccc(CC(Cl)=NO)c1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOc1cccc(Cc2cc(-c3cccnc3N)on2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-butoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.621 mmol) described in Manufacturing Example 65-1-4 and 3-ethynyl-pyridin-2-ylamine (47 mg, 0.396 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (216 μL, 1.55 mmol) at room temperature, which was stirred for 2 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (33 mg, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[C:13]1([N:19]2[C:23]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:22](=[O:29])[NH:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:26]1[CH2:25][CH2:24][C:23]3([N:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][NH:21][C:22]3=[O:29])[CH2:28][CH2:27]1)[CH2:8][CH2:7]2
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C1CCc2cccc(Cl)c2C1
Product: Cl
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCc3cccc(Cl)c3C1)CC2

Procedure:
The title compound, m.p. 286-290° C. was prepared in accordance with the general method of example 1 from 8-chloro-2-tetralone and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][NH:8][CH3:9].Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[N:14]=[C:13]([S:25][CH2:26][CH3:27])[C:12]=1[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)=[O:29].CCCCCC>CN(C=O)C.O>[CH3:7][N:8]([CH3:9])[C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[N:14]=[C:13]([S:25][CH2:26][CH3:27])[C:12]=1[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)=[O:29]
Reactant: CNC
Reactant: CCSc1nc2cc(C(F)(F)F)ccc2c(Cl)c1C(=O)NCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(N(C)C)c1C(=O)NCc1cccc(F)c1
Yield: 60 %

Procedure:
60 mg (0.45 mmol) K2CO3 and 0.7 ml (1.36 mmol, 2M in THF) dimethylamine were added at RT to a solution of 200 mg (0.45 mmol) 4-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-7-(trifluoromethyl)-quinoline-3-carboxamide (example 122) in DMF (3 ml) and the mixture was then heated in a closed vessel for 150 min at 80°. Then it was diluted with water and extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 17:3) of the residue yielded 120 mg (0.27 mmol, 60%) 4-dimethylamino-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-7-(trifluoromethyl)-quinoline-3-carboxamide. MS: m/z 452.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:11]=[N+:12]=[N-:13])[CH3:10].[C:14]([C:17]([OH:19])=[O:18])#[C:15]C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:11]1[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[N:13]=[N:12]1)[CH3:10]
Reactant: CC(N=[N+]=[N-])c1c(F)cccc1F
Reactant: CC#CC(=O)O
Solvent: Cc1ccccc1
Product: CC(c1c(F)cccc1F)n1cc(C(=O)O)nn1

Procedure:
6.5 g (35 millimoles) of 1-(2,6-difluorophenyl)ethyl azide and 2.45 g (35 millimoles) of propinecarboxylic acid in 50 ml of toluene are heated for 24 hours to 60°-70° C. The cooled reaction mixture is extracted with 100 ml of 1N sodium hydroxide solution and the extract is acidified with hydrochloric acid to give 1-[1-(2,6-difluorophenyl)ethyl-1H-1,2,3-triazole-4-carboxylic acid with a melting point of 135°-138° C. (dec.). 7.1 g (26.6 millimoles) of 1-[1-(2,6-difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxylic acid, 150 ml of ethanol and 1 ml of sulfuric acid are heated for 10 hours to reflux. Working up gives ethyl 1-[1-(2,6-difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxylate with a melting point of 118°-121° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].Br[Mg][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(OCC)C.Cl.O>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]([CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[OH:8]
Reactant: Cc1oc(-c2ccccc2)cc1C=O
Reactant: Br[Mg]C1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1oc(-c2ccccc2)cc1C(O)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 2-methyl-5-phenylfuran-3-carbaldehyde (1.9 g) in tetrahydrofuran (30 mL) was added dropwise bromo(tetrahydro-2H-pyran-4-yl)magnesium-diethyl ether solution (30 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 30 min. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (10% ethyl acetate/hexane to 40% ethyl acetate/hexane) to give the title compound (2.3 g, 86%) as an oil.
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]>CC(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: CC(C)O
Product: O=C([O-])C[C@H](O)C(=O)[O-]
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Sitagliptin base (150 mg) was suspended in 2-propanol (2.5 mL). L-malic acid (49 mg) was added and the mixture was stirred for one hour at ambient temperature and 2 hours at 40° C. The mixture was allowed to cool to ambient temperature and stirred for 24 hours at this temperature. The solid was filtered and dried at ambient temperature.