Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:23])=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C:7]([O:13][CH3:14])=[C:8]([CH:10](Cl)[CH3:11])[CH:9]=1.[NH2:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]2[NH:31][N:32]=[CH:33][C:26]=12.O>CN(C)C=O>[NH2:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]2[N:31]([CH:10]([C:8]3[C:7]([O:13][CH3:14])=[C:6]([C:15]4[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=4)[C:5]([CH3:23])=[C:4]([Cl:3])[CH:9]=3)[CH3:11])[N:32]=[CH:33][C:26]=12
Reactant: Nc1ncnc2[nH]ncc12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)n2ncc3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (20.0 mg, 0.50 mmol) was added to a mixture of 4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (from Example 16, Step 3) (90 mg, 0.28 mmol), 4-aminopyrazolo[3,4-d]pyrimidine (from Acros Organics) (57 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL) and the reaction was stirred at 30° C. overnight. The mixture was treated with water and then filtered to provide the desired product. LCMS calculated for C21H19ClN7O (M+H)+: m/z=420.1; Found: 420.1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:17]1[CH2:20][CH2:19][CH2:18]1.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:3]=1[F:9]
Reactant: BrC1CCC1
Reactant: Fc1cc(S)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(SC2CCC2)ccc1Br
Temperature: 70 °C
Yield: 95.2 %

Procedure:
A stirred mixture of 4-bromo-3-fluorobenzenethiol (Preparation 26, 400 mg, 1.93 mmol), cesium carbonate (691 mg, 2.12 mmol) and bromocyclobutane (287 mg, 2.12 mmol) in DMSO (8 mL) was heated at 70° C. for 19 hours. The mixture was cooled to room temperature, poured into water (30 mL) and extracted with 2-methoxy-2-methylpropane (30 mL), washed with water (30 mL), dried over sodium sulfate and concentrated in vacuo. This gave the title compound as a colourless oil 95% yield, 480 mg.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:12])[CH:5]=[C:6]([S:10][CH3:11])[C:7]=1[C:8]#[N:9].[H-].[Na+].Br[CH2:16][C:17]([NH2:19])=[O:18]>CN(C=O)C>[C:8]([C:7]1[C:6]([S:10][CH3:11])=[CH:5][C:4](=[O:12])[NH:3][C:2]=1[S:1][CH2:16][C:17]([NH2:19])=[O:18])#[N:9]
Reactant: NC(=O)CBr
Reactant: CSc1cc(=O)[nH]c(S)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(=O)[nH]c(SCC(N)=O)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of the above 2-mercapto-4-methylsulfanyl-6-oxo-1,6-dihydro-pyridine-3-carbonitrile (12.5 g, 63.0 mmol) in DMF (300 mL), cooled to 0° C., was added sodium hydride (2.60 g, 65.0 mmol) as a 60% dispersion in mineral oil. The mixture was stirred at 0° C. for 30 min then 2-bromoacetamide (8.80 g, 63.8 mmol) was added as a solid in one portion. The mixture was allowed to slowly warm to room temperature and stirred for 15 h. The mixture poured into ice—H2O and stirred until all of the ice had melted, during which time a solid precipitated from solution. The mixture was acidified with 2N HCl then cooled to 0° C. and the solid collected by filtration. The material was washed with Et2O followed by hexanes to provide 11.2 g (69.9%) of 2-(3-cyano-4-methylsulfanyl-6-oxo-1,6-dihydro-pyridin-2-ylsulfanyl)-acetamide as a tan solid.
Reaction SMILES: P([O-])(OCC1C=CC=CC=1)OCC1C=CC=CC=1.[P:19]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]CCCCC)([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]CCCCC)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]CCCCC.C(P(CCCCCCCCCCCC)CCCCCCCCCCCC)CCCCCCCCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(P(CC1C=CC=CC=1)CC1C=CC=CC=1)C1C=CC=CC=1>>[P:19]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CCCCCCCCCCCCOP(OCCCCCCCCCCCC)OCCCCCCCCCCCC
Agent: CCCCCCCCCCCCP(CCCCCCCCCCCC)CCCCCCCCCCCC
Agent: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(CP(Cc2ccccc2)Cc2ccccc2)cc1
Product: c1ccc(COP(OCc2ccccc2)OCc2ccccc2)cc1

Procedure:
dibenzyl phosphite; trilauryl phosphite; trilauryl phosphine; triphenyl phosphine; tribenzyl phosphine.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[N:20]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:29][CH2:28][CH2:27][CH2:26][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: NCCCN1CCOCC1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(NCCCN2CCOCC2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 3-morpholin-4-ylpropan-1-amine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (500 MHz, CDCl3): δ 7.58 (bs, 1H), 7.58-7.52 (m, 2H), 7.48-7.40 (m, 3H), 3.84-3.78 (m, 4H), 3.70 (t, 2H), 2.98-2.92 (m, 2H), 2.50-2.38 (m, 6H), 1.86-1.80 (m, 2H), 1.62-1.52 (m, 2H), 1.50-1.40 (m, 2H), 0.98 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 159.3, 136.4, 131.8, 129.5, 128.7, 125.7, 105.9, 66.9, 58.3, 54.0, 45.6, 40.2, 30.5, 24.1, 20.3, 13.8; Mass Spectrum: M+H+ 408.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[Br:12].[Cl:13]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([Cl:13])=[CH:4][C:3]=1[Br:12]
Reactant: COC(=O)c1ccc(Br)c(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: COC(=O)c1nc(N)c(Br)cc1Cl
Yield: 95.5 %

Procedure:
To a solution of methyl 6-amino-5-bromopyridine-2-carboxylate (20.04 g) in acetic acid (900 mL) was added N-chlorosuccinimide (13.96 g) and the resultant solution was heated to 120° C. for 1 hour. The solution was then evaporated and treated with excess aqueous sodium bicarbonate and extracted with dichloromethane. The organic fraction was dried and evaporated to give the product (21.98 g).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:11])=[O:10])=[CH:5][CH:4]=1.Br.[OH2:13]>CS(C)=O>[CH2:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:10])[CH:11]=[O:13])=[CH:5][CH:4]=1)[CH3:1]
Reactant: O
Reactant: CCc1ccc(C(C)=O)cc1
Agent: Br
Solvent: CS(C)=O
Product: CCc1ccc(C(=O)C=O)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
4-Ethylacetophenone (26.72 mmol, 4 mL) was dissolved in dimethyl sulfoxide (27 mL), and 48% hydrobromic acid (11 mL) was gradually added at room temperature. After overnight stirring at 70° C., the reactor was cooled to room temperature. The reaction solution was poured into water (50 mL) and stirred for about 1 hour. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a white solid (2.44 g, yield 56%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:22]3[CH:21]=[CH:20][C:19]4[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=4[C:17]=3[N:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]2[CH:30]=[CH:29][CH:28]=[CH:27][C:14]=23)=[CH:5][CH:4]=1.Cl.[NH+]1C=CC=CC=1.O>C(Cl)(Cl)Cl>[CH:27]1[C:14]2[C:15]3[N:16]=[C:17]4[C:22]([CH:21]=[CH:20][C:19]5[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=54)=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=4)[C:10]=3[CH:11]=[CH:12][C:13]=2[CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Oc1ccc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)cc1
Temperature: 210 °C
Reaction time: 72 h

Procedure:
In a pressure vessel a mixture of 18 (1.00 g, 2.6 mmol, 1 eq) and pyridiniumhydrochloride (1.75 g, 15.1 mmol, 5.8 eq) was heated to 210° C. under an inert atmosphere and vigorously stirred at this temperature over a three days period. The mixture was allowed to cool down to room temperature. The solidified melt was dissolved in chloroform (50 mL) and water (50 mL) and treated in an ultrasonic bath for 5 minutes. The layers were separated and the aqueous layer was extracted with chloroform (3×50 mL). Afterwards, the combined organic layers were washed with a saturated aqueous sodium hydrogencarbonate solution (5×50 mL) followed by water (3×50 mL) and dried over magnesium sulphate. Evaporation of the solvent at 40° C. led to an old rose coloured solid. The product was directly used in the next step without any further purification.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][N:16]([C:19]3[CH:27]=[CH:26][C:25]4[C:21](=[CH:22][N:23]([CH2:28][CH2:29][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)[CH:20]=3)[C:15]2=[O:35])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CC(O)=O.[Pd]>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:27]=[CH:26][C:25]4[C:21](=[CH:22][N:23]([CH2:28][CH2:29][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)[CH:20]=3)[C:15]2=[O:35])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc2nn(CCN3CCCC3)cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1N(c2ccc(Oc3ccccc3)cc2)CCN1c1ccc2nn(CCN3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-(4-phenoxyphenyl)-3-[2-(2-pyrrolidin-1-ylethyl)-2H-indazol-5-yl]-1,3-dihydro-2H-imidazol-2-one (Example 84) (0.100 g, 0.215 mmol) was taken up in 20 mL of AcOH along with 100 mg of Pd/C (10% mol/mol) and the mixture was subjected to an atmosphere of hydrogen gas at a pressure of 60 psi in a Parr shaker apparatus. The mixture was shaken at room temperature for 6 hours after which the mixture was filtered through a bed of celite, and the solvents removed under reduced pressure. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.75–2.06 (m, 4 H) 3.02–3.15 (m, 2 H) 3.47–3.63 (m, 2 H) 3.74–3.87 (m, 2 H) 3.93–4.12 (m, 4 H) 4.82 (t, J=5.76 Hz, 2 H) 6.94–7.01 (m, 2 H) 7.03–7.14 (m, 3 H) 7.34–7.34 (m, 2 H) 7.62–7.70 (m, 4 H) 7.86 (dd, J=9.49, 2.03 Hz, 1 H) 8.39–8.46 (m, 1 H); MS (ESI) m/z 468 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH2:20][O:21][CH3:22])[N:4]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][O:21][CH2:20][N:5]1[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:7][C:3]([CH2:2][N:23]2[CH2:28][CH2:27][N:26]([CH2:2][C:3]3[CH:7]=[C:6]([C:8]4[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=4)[N:5]([CH2:20][O:21][CH3:22])[N:4]=3)[CH2:25][CH2:24]2)=[N:4]1
Reactant: C1CNCCN1
Reactant: COCn1nc(CCl)cc1-c1cc(OC)c(OC)c(OC)c1
Product: COCn1nc(CN2CCN(Cc3cc(-c4cc(OC)c(OC)c(OC)c4)n(COC)n3)CC2)cc1-c1cc(OC)c(OC)c(OC)c1

Procedure:
3-Chloromethyl-1-methoxymethyl-5-(3,4,5-trimethoxyphenyl)pyrazole (101 mg) and piperazine (13 mg) were reacted in the same manner in Example 1 to obtain the title compound.
Reaction SMILES: [CH:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].[CH2:30]([O:41][C:42](Cl)=[O:43])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CC(N(C)C)=O>[CH2:30]([O:41][C:42]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)=[O:43])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCOC(=O)Cl
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
In 130 ml of dimethylacetamide, 7.3 g of arabinofuranosylcytosine is dissolved and to the resultant solution is added 40 ml of a toluene solution containing 7.56 g of sodium hydrogen carbonate and 7.0 g of undecyloxycarbonyl chloride. The mixture is then stirred at room temperature for 3 hours. After the reaction is over, the solvent is removed under reduced pressure and ice-water is added to the residue, whereby the cyrstals are precipitated. The crystals are filtered and washed with water, followed by sufficient drying. Recrystallization of the product is performed twice, using 80 ml of chloroform-n-hexane, to give 4.0 g of N4-undecyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:30%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][O:5][CH3:6]>CCOC(C)=O.CCO.[Pd]>[CH3:6][O:5][CH2:4][C:3]1[C:2]([CH3:1])=[C:10]([CH:9]=[CH:8][CH:7]=1)[NH2:11]
Reactant: COCc1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCc1cccc(N)c1C
Yield: 78.7 %

Procedure:
A mixture of methyl 2-methyl-3-nitrobenzyl ether (0.19 g, 1.05 mmol), and 5% Pd/C (70 mg) in EtOAc/EtOH 1:1 (14 ml) was hydrogenated at 1 atm over night. The mixture was filtered through Celite, and the filtrate was concentrated to give the title compound 125 mg (78%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:6]=[C:5]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)c1c[nH]c2ccc(F)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1cn(S(C)(=O)=O)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 5-fluoro-1H-indole-3-carboxylate (500 mg, 2.125 mmol) and triethylamine (1721 mg, 17.00 mmol) in THF (5 ml) was added methanesulfonyl chloride (0.658 ml, 8.50 mmol). The mixture was stirred at RT for 2 h. The reaction mixture was then poured into water and extracted twice with Et2O. The organic extracts were combined, filtered through MgSO4, concentrated, and purified by column chromatography (SiO2; EtOAc/hex) to afford the title compound as a white solid.
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][NH:5][C:6]1[CH:32]=[CH:31][C:9]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:25])[NH2:24])[CH:19]=3)[C:14]=2[CH2:26][CH2:27][C:28](=[O:30])N)=[O:11])=[CH:8][CH:7]=1.Cl.CS(O)(=O)=[O:36]>>[ClH:1].[ClH:1].[NH2:2][N:3]=[CH:4][NH:5][C:6]1[CH:32]=[CH:31][C:9]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:25])[NH2:24])[CH:19]=3)[C:14]=2[CH2:26][CH2:27][C:28]([OH:30])=[O:36])=[O:11])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)O
Reactant: N=C(N)c1ccc2c(CCC(N)=O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Agent: Cl
Product: N=C(N)c1ccc2c(CCC(=O)O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Reaction time: 6 h

Procedure:
300 Milliliters of 3.6% hydrochloric acid was added to 3.3 g of 6-amidino-1-(2-carbamoylethyl)-2-naphthyl 4-aminoiminomethylaminobenzoate.methanesulfonic acid hydrochloride, followed by stirring for 6 hours at 75°-80° C. Furthermore, the reaction mixture was stirried for 24 hours under cooling with ice. Then, the precipitate was collected by filtration and washed with a small amount of 15% hydrochloric acid and acetone to obtain 1.58 g of the desired product.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[C:6]([CH3:14])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]([CH3:14])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)C)nc1C
Agent: [Li+]
Agent: [OH-]
Product: Cc1nn(C(C)C)cc1C(=O)O
Yield: 79 %

Procedure:
In a procedure analogous to Example B6, ethyl 1-isopropyl-3-methyl-1H-pyrazole-4-carboxylate from Example B14 (91 mg, 0.464 mmol) and lithium hydroxide (78 mg, 1.855 mmol) were combined to afford 1-isopropyl-3-methyl-1H-pyrazole-4-carboxylic acid (62 mg, 79% yield). MS (ESI) m/z: 169.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[OH:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:36]4[CH2:37][CH2:38][CH2:39][CH:34]([CH2:33][OH:32])[CH2:35]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: OCC1CCCNC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: OCC1CCCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)C1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 3-hydroxymethylpiperidine (55.9 mg; 0.48 mmol) to give Example 140 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.5, 1.6 Hz), 7.97-7.87 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.7 Hz), 7.55-7.48 (4H, m), 4.40 (1H, t, J=5.2 Hz), 3.61-3.48 (2H, m), 3.34-3.27 (1H, m), 3.25-3.17 (1H, m), 2.87 (1H, d, J=9.3 Hz), 2.74 (1H, d, J=10.9 Hz), 1.96 (1H, t, J=11.0 Hz), 1.76-1.62 (4H, m), 1.50 (1H, d, J=12.6 Hz), 0.92 (1H, d, J=12.3 Hz). LC/MS (Method C): 512 (M+H)+. HPLC (Method E) Rt 2.16 min (Purity: 99.3%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=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.[CH:53]1([CH2:56][NH:57][CH2:58][C:59]2[NH:60][C:61](=[O:69])[C:62]3[CH2:68][O:67][CH2:66][CH2:65][C:63]=3[N:64]=2)[CH2:55][CH2:54]1>CN(C=O)C>[CH:53]1([CH2:56][N:57]([CH2:58][C:59]2[NH:60][C:61](=[O:69])[C:62]3[CH2:68][O:67][CH2:66][CH2:65][C:63]=3[N:64]=2)[C:15](=[O:17])[CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH2:55][CH2:54]1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
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: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC2CC2)CC1
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-acetic acid (169 mg, 0.64 mmol) was added with HATU (364 mg, 0.96 mmol) in DMF (2 mL) and DIEA (0.28 mL, 1.60 mmol) was added. This was sonicated, stirred for 30 min and then 2-[(cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (150 mg, 0.64 mmol) in 1 mL DMF was added to the mixture. The mixture was stirred at room temperature for 16 h, concentrated to dryness, purified by silica gel column (eluted with 0-10% methanol in dichloromethane) then triturated with methanol to give a white solid as the title compound (66 mg, 0.14 mmol, 21% yield). m/z=483.3 (M+H).
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15]([Cl:21])(=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]>>[ClH:21].[C:9]1([N:6]2[CH:7]=[CH:8][C:3](=[N:2][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:4]=[N:5]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCC(=O)Cl
Reactant: N=c1ccn(-c2ccccc2)nc1
Agent: Cl
Product: CCCCC(=O)N=c1ccn(-c2ccccc2)nc1
Yield: 40 %

Procedure:
6.0 g (28.9 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 40 ml of valeryl chloride were kept at 120° C. for 20 hours, while stirring. The mixture was cooled and then filtered under suction, and the residue was washed with acetone and recrystallized first from ethanol/methyl tert.-butyl ether and then from ethanol/acetone. 3.4 g (40% of theory) of 1,4-dihydro-1-phenyl-4-(valerylimino)-pyridazine hydrochloride were isolated as pale yellowish crystals of melting point 180°-182° C.
Reaction SMILES: [C:1]1([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:18](OCC)C>>[CH:9]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:10][NH2:11])[CH2:8][CH2:18]1
Reactant: CCOCC
Reactant: N#CC1(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC(c1ccccc1)C1CC1
Temperature: 0 °C

Procedure:
1-Phenyl-1-cyclopropanecarbonitrile (1.0 g, 6.98 mmol) was added to a stirred suspension of lithium aluminum hydride in anhydrous diethyl ether (25 mL). The suspension was refluxed for 2 h, then cooled to 0° C., and the excess hydride was destroyed by careful addition of water. After treatment with sodium hydroxide (1 N), the mixture was filtered and the filtrate extracted with diethyl ether. After drying of the organic phase with and evaporation 2 (719 mg, 70% ) was obtained as a clear liquid and used without further purification. 1H NMR (DMSO-d6): δ 7.28 (m, 4 H), 7.17 (m, 1 H), 2.70 (s, 2 H), 1.45 (bs, 2 H); 0.78 (dd, J=6.2, 3.8 Hz, 2 H); 0.67 (dd, J=6.2 Hz, 3.8 Hz, 2 H). MS: (m/z) 148 (M+1)+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([F:12])[C:6]=1[N:13](C(=O)C)[C:14](=[O:16])[CH3:15])C.[OH-].[Na+]>CO.C(OCC)(=O)C.O>[C:14]([NH:13][C:6]1[C:7]([F:12])=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[C:4]([OH:20])=[O:3])(=[O:16])[CH3:15]
Reactant: CCOC(=O)c1cc(Cl)cc(F)c1N(C(C)=O)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)Nc1c(F)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 5-chloro-2-diacetylamino-3-fluorobenzoic acid ethyl ester (185 mg, 0.61 mmol) in MeOH (4 ml) was added 1N NaOH (1288 μl, 1.29 mmol) and the reaction mixture was refluxed for 2 h. The reaction mixture was cooled to RT and then diluted with ethyl acetate and water. The organic phase was separated and the aqueous phase was made acidic with 1N HCl to pH3 and then extracted with ethyl acetate (2×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the desired product (130 mg, 92%) as a white solid which did not require further purification. MS (ISP) 230.1 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C1CCN2C(=NCCC2)CC1.F[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([N+:31]([O-:33])=[O:32])=[CH:23][CH:22]=1>C(#N)C>[N+:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:22][CH:23]=1)([O-:33])=[O:32]
Reactant: Nc1cc(O)ccn1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a stirred suspension of 2-aminopyridin-4-ol (53.9 g, 489 mmol) in acetonitrile (500 mL) was added DBU (102 mL, 678 mmol) dropwise over 30 min. The resulting solution was stirred at RT for 30 min and was then treated dropwise with a solution of 1-fluoro-4-nitronaphthalene (72.0 g, 377 mmol) in acetonitrile (400 mL) over 50 min. After stirring overnight at RT the reaction was heated at 50° C. for 2 hr. The reaction was removed from the heat, but not cooled and with stirring, treated with water (6×100 mL). The mixture was allowed to cool to RT over 2 hr and was then cooled further to 0° C. The yellow precipitate was collected by filtration and washed sequentially with a mixture of water and acetonitrile (1:1, 2×100 mL) and then with water (500 mL) to give the title compound as a yellow solid (76.0 g, 70%): m/z 283 (M+H)+ (ES+).