Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:30][Si:31]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34]>C1(C)C=CC=CC=1>[CH2:36]([O:35][Si:31]([CH2:30][O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([O:38][CH2:39][CH3:40])[O:32][CH2:33][CH3:34])[CH3:37]
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: CCO[Si](CO)(OCC)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCO[Si](COC(=O)C=Cc1ccc(OC)cc1)(OCC)OCC

Procedure:
100 g of p-methoxycinnamic acid (Aldrich) was dissolved in 500 mL of toluene and 118 g of dicyclohexylcarbodiimide (DCC) (Aldrich) was added. After adding 100 g of hydroxymethyltriethoxysilane (Gelest), the toluene solution was stirred for about 18 hours at about 40° C. After evaporating the solvent under reduced pressure and adding 200 mL of acetone, insoluble byproduct (dicyclohexylurea) was removed by filtering. After removal of acetone, triethoxysilylmethyl-(p-methoxycinnamate) was obtained. The new product could be identified by thin-layer chromatography.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>CN(C)C=O>[F:45][C:44]([F:47])([F:46])[CH2:43][O:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(CN2CCC(CCOc3noc4cccc(O)c34)CC2)CCOCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(CN2CCC(CCOc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a stirred mixture of methyl 4-[(4-{2-[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]ethyl}piperidin-1-yl)-methyl]tetrahydro-2H-pyran-4-carboxylate (0.63 g, 1.5 mmol, EXAMPLE 7, step 6) and potassium carbonate in N,N-dimethylformamide (3.0 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.26 mL, 1.8 mmol) at 70° C. After being stirred at 70° C. for 3 h, the mixture was cooled to room temperature. The mixture was extracted with ethyl acetate (50 mL×2) and washed with water and brine. The extracts were combined and dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 2:1) to give 0.69 g (92%) of the title compound as a colorless viscous oil.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([N:9]([CH2:22][CH3:23])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20][CH3:21])[CH2:14][CH2:13]1)=[O:11])[CH3:8].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([N:20]([CH3:21])[CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[N:9]([CH2:22][CH3:23])[CH2:7][CH3:8])[CH2:13][CH2:14]1)=[O:4]
Reactant: CCN(CC)C(=O)N1CCN(CCNC)CC1
Reactant: CN(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)N1CCN(CCN(C)C(=O)N(C)C)CC1
Temperature: 100 °C

Procedure:
5.4 g (0.05 mole) of dimethyl carbamic acid chloride dissolved in 20 cc. of toluene are added dropwise with stirring at room temperature to a solution of 12.1 g (0.05 mole) of 1-diethylcarbamoyl-4-(2-methylamino ethyl)-piperazine and 5.1 g (0.05 mole) of triethylamine in 40 cc. of toluene. Thereafter, the reaction mixture is stirred for another hour at about 100° C. The reaction mixture is cooled and the precipitated triethylamine hydrochloride is filtered off with suction and the filtrate is evaporated. The residue is dissolved in 150 cc. of ether, the ethereal solution is washed twice with 150 cc. of 5 n NaOH each time and the resulting solution is dried over anhydrous Na2SO4. Upon evaporation of the ether, 15.3 g (97.6% of the theoretical) of the oily crude urea are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:34])[CH2:17][N:16]([CH2:18][CH2:19][N+:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])([CH3:22])[CH3:21])[C:15](=[O:33])[NH:14]1.C(O[Cl:40])(C)(C)C>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[Cl:40][N:14]1[C:13]([CH3:34])([CH3:12])[CH2:17][N:16]([CH2:18][CH2:19][N+:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])([CH3:22])[CH3:21])[C:15]1=[O:33]
Reactant: CC(C)(C)OCl
Reactant: COCCOCCOCC[N+](C)(C)CCN1CC(C)(C)NC1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: COCCOCCOCC[N+](C)(C)CCN1CC(C)(C)N(Cl)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
A solution of 2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-N,N-dimethylethanaminium 4-methylbenzenesulfonate (162 mg, 0.32 mmol) in methanol (1 ml) was cooled to 0° C. tert-Butylhypochlorite (45 ul, 0.4 mmol) was added. The resulting solution was stirred for 2 hours at 0° C. and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC eluting from a C18 column with a gradient of 5 to 95% CH3CN in water (with 0.01% acetic acid) to give 75 mg of a clear oil. 1H NMR (D2O, 400 MHz) δ 1.21 (s, 6H), 2.29 (s, 3H), 3.09 (s, 6H) 3.26 (s, 3H), 3.31 (s, 2H), 3.48-3.36 (m, 14H), 3.84 (br m, 2H), 7.25-7.27 (d, J=8.1 Hz, 2H), 7.58-7.60 (d, J=8.2 Hz, 2H). 13C NMR (D2O, 100 MHz) δ 161.2, 142.4, 139.6, 129.4, 125.3, 70.9, 69.7, 69.4, 69.4, 63.9, 63.6, 62.4, 61.1, 58.0, 55.5, 51.8, 38.9, 22.3, 20.5; LRMS (ESI/APCI) m/z 366 [M]+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10](=[O:19])[NH:9][C:8](=[O:20])[CH:7]=1.C(=O)(O)[O-].[Na+]>O.Cl>[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)[C:10](=[O:19])[NH:9][C:8](=[O:20])[C:7]=1[N:1]=[O:3]
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccncc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1Cc1ccncc1
Reaction time: 0.25 h

Procedure:
2.6 ml of 4N sodium nitrite was added to a solution of 2.35 g of 6-amino-1-(4-picolyl)-uracil in 25 ml of water and 4 ml of 5N HCl. After 15 minutes, 10 ml of 1N sodium bicarbonate was added. The solid was collected, washed and dried to give the title compound (2.15 g).
Reaction SMILES: NC(N)=O.[CH2:5]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])[CH2:6][CH3:7].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])=[O:30])=[C:13]([OH:20])[C:12]=1[S:9]([NH:8][CH2:5][CH2:6][CH3:7])(=[O:11])=[O:10]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=O
Product: CCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O
Yield: 49.8 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-propyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (186 mg, 0.71 mmol) and 2-chlorophenylisocyanate (108 mg, 0.71 mmol) were coupled to form the desired urea (148 mg, 50%). LC-MS (m/z) 418.2 (M+).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16].[N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>ClCCl>[OH:19][N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC=O
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of pentanal (86 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.Cl.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:10]([C:7]1[CH:6]=[C:5]([CH2:4][C:3]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: NCCc1c[nH]c2ccc(Br)cc12
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Br)cc12)c1cc(Cc2cc(F)ccc2F)on1
Yield: 59.9 %

Procedure:
A solution of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.104 g, 0.435 mmol), 2-(5-bromo-1H-indol-3-yl)ethanamine hydrochloride (0.120 g; 0.435 mmol), HATU (0.166 g; 0.435 mmol) and N,N diisopropylethylamine (0.201 mL; 1.09 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.120 g (60%) of N-(2-(5-bromo-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[CH3:32][N:33]([CH3:38])[C:34](=[O:37])[CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:35][C:34]([N:33]([CH3:38])[CH3:32])=[O:37]
Reactant: CN(C)C(=O)CCl
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CC(=O)N(C)C)c3ccccc32)cc1
Yield: 6.9 %

Procedure:
A mixture of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g), N,N-dimethyl-2-chloroacetamide (0.19 g) and potassium carbonate (0.22 g) is refluxed for 24 hours. The reaction solution is concentrated and water is added to the resulting residue. The mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-[N-methyl-N-(dimethylaminocarbonylmethyl)amino]-1-[4-(2-methylbenzoyl amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.05 g) as colorless amorphous.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4].Cl>CS(C)=O>[CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:9][C:7]1=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCN1C(=O)C(=O)c2ccccc21
Agent: Cl
Solvent: CS(C)=O
Product: CC(C)CCN1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
The above 1-isopentylisatin was redissolved in DMSO (15 mL). N2H4-xH2O (3 mL) was added dropwise over 10 min. After addition, the reaction mixture was stirred for 5 min at rt, then 2 h at 140° C. (oil temp.) before cooling to rt. Ice/H2O (30 mL) was added, followed by 6 M HCl (10 mL, 60 mmol) and the resulting mixture was stirred for 30 min at rt. Additional ice/H2O (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The crude product was purified by flash chromatography (gradient: EtOAc/hex 0 to 20%) to afford the title compound as an orange red liquid (4.30 g, 71% over two steps). 1H NMR (400 MHz, DMSO-d6) δ 7.27-7.22 (m, 2H), 7.02-6.95 (m, 2H), 3.65 (t, J=7.4 Hz, 2H), 3.33 (s, 2H), 1.60-1.52 (m, 1H), 1.44 (q, J=7.2 Hz, 2H), 0.92 (d, J=6.4 Hz, 6H); MS ESI 203.9 [M+H]+, calcd for [C13H17NO+H]+ 204.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:27][C:28]([NH:30]C(=O)OCC2C=CC=CC=2)=[S:29])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[Li+].[OH-]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:27][C:28]([NH2:30])=[S:29])([C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(NC(=S)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=S)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Yield: 77.1 %

Procedure:
To benzyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylcarbamothioylcarbamate (269 mg, 0.483 mmol) in Methanol/THF (2 mL/2 mL) was added LiOH (2M, 483 mL, 0.966 mmol). The reaction was refluxed for 40 minutes. The solvents were removed and the residue dissolved in EtOAc. The resulting solution was washed with H2O, brine, dried over MgSO4 and concentrated. The crude mixture was purified by silica gel ISCO chromatography (12 g column) using hexanes/EtOAc (0-50% over 18 min) to give 1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)thiourea as a pale yellow foam (169 mg, 78% yield). LCMS: 3.8 min [M+1] 454.2 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 5.62 (s, 3H), 6.71 (d, J=7.34 Hz, 3H), 7.11 (d, J=8.56 Hz, 6H), 7.32 (s, 2H), 7.50-7.57 (m, 1H), 7.69 (dd, J=8.56, 2.20 Hz, 1H), 8.28 (s, 1H), 8.64 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:20]4[CH2:28][CH2:27][NH:26][CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:20]4[CH2:28][CH2:27][N:26]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(Nc2ncnc3c2CCNC3)cc1-c1cc2ccccc2cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Nc2ncnc3c2CCN(S(C)(=O)=O)C3)cc1-c1cc2ccccc2cn1
Reaction time: 8 h

Procedure:
To a solution of N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (20 mg, 0.055 mmol) in DCM (0.4 ml) is added DIEA (21 mg, 0.121 mmol) and methylsulfonyl chloride (6.2 mg, 0.055 mmol) subsequently. The reaction mixture is stirred overnight. After concentrated by rotary evaporation, the residue is subject to HPLC to afford N-(3-(isoquinolin-3-yl)-4-methylphenyl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine as a white solid. LC-MS m/z: 446.2 (M+1); 1H NMR 400 MHz (CDCl3) δ 9.32 (s, 1H), 8.53 (s, 1H), 8.01 (d, 1H, J=8.0 Hz), 7.85 (d, 1H, J=8.0 Hz), 7.77 (s, 1H), 7.72 (t, 2H, J=6.6 Hz), 7.64-7.60 (m, 2H), 7.31 (d, 1H, J=8.4 Hz), 6.47 (s, 1H), 4.35 (s, 2H), 3.64 (t, 2H, J=6.0 Hz), 2.89 (s, 3H), 2.68 (t, 2H, J=5.6 Hz), 2.39 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6](C2CCCCO2)[N:5]=[CH:4][C:3]=1[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])C#N>Cl.C(O)(=O)C.O>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][N:5]=[CH:4][C:3]=1[CH2:15][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:26])([F:27])[F:25]
Reactant: N#CC(c1ccccc1C(F)(F)F)c1cnn(C2CCCCO2)c(=O)c1Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]ncc(Cc2ccccc2C(F)(F)F)c1Cl
Temperature: 120 °C
Yield: 60.2 %

Procedure:
A mixture of [5-chloro-6-oxo-1-(tetrahydro-pyran-2-yl)-1,6-dihydro-pyridazin-4-yl]-(2-trifluoromethyl-phenyl)-acetonitrile (550 mg, 1.38 mmol) in concentrated hydrochloric acid (8.4 mL), glacial acetic acid (2.1 mL) and water (2.1 mL) (4:1:1, 0.11 M) was heated to 120° C. overnight. After this time, the reaction was cooled to 25° C. and then poured onto ice, followed by rinsing with minimal water. The resulting aqueous mixture was brought to pH=4-5 by treatment with a 4N aqueous sodium hydroxide solution. The resulting tan solids were collected by filtration. The solids were subsequently washed with water (2×10 mL) and dried in vacuo to afford 4-chloro-5-(2-trifluoromethyl-benzyl)-2H-pyridazin-3-one (0.24 g, 62%) as a tan solid; ES+-HRMS m/e calcd for C12H8N2OF3Cl [M+H+] 289.0350, found 289.0350.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+].Cl>O>[CH2:17]([O:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)CCCCC(=O)c1ccccc1O
Reactant: CCCCCCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCOc1ccccc1C(=O)CCCCC(=O)O
Yield: 0 %

Procedure:
A mixture of 5-(2-hydroxybenzoyl)pentanoic acid (1.5 g, 6.75 moles), hexyl bromide (1.28 g, 7.75 moles), potassium hydroxide (1.3 g) and water (7 ml) is heated under reflux (5 hours). The reaction mixture is neutralized with hydrochloride acid and extracted with ether (3×30 ml). The ether extract is dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on a silica gel column (hexane:ether: acetic acid; 74:25:1) to provide a crude product which on recrystallization from heptane gives 5-(2-n-hexyloxybenzoyl) pentanoic acid (1.0 g) as a white crystalline solid, m.p. 64°-65° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[Cl:11][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[CH2:2][S:19][C:17]1[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: COc1ccc(Cl)c(CBr)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(Cl)c(CSc2nc(C)cc(O)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To the 2-(bromomethyl)-1-chloro-4-methoxybenzene (3.79 g, 16.09 mmol) in anhydrous ethanol (30 mL) at room temperature, 6-methyl-2-sulfanylpyrimidin-4-ol (2.28 g, 16.09 mmol) was added. Triethylamine (1.79 g, 17.7 mmol) was then added. The reaction mixture was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The solvent was evaporated, and the crude residue was suspended in water and sonicated. The white precipitated product was filtered off and washed with water, ether, and ethyl acetate to provide the 2-{[(2-chloro-5-methoxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (4.05 g, 85% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.71 (s, 3H), 4.39 (s, 2H), 5.99 (bs, 1H), 6.88 (d, J=8.9 Hz, 1H), 7.19 (s, 1H), 7.38 (d, J=8.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][CH3:10])[CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: c1c[nH]cn1
Reactant: COc1cc(Cl)ccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1cc(Cl)ccc1-n1ccnc1
Temperature: 110 °C
Yield: 45.5 %

Procedure:
A mixture of 4-chloro-1-iodo-2-methoxy-benzene (0.268 g, 1 mmol), imidazole (0.082 g, 1.2 mmol), 1,0-phenanthroline (0.018 g, 0.1 mmol), CuI (0.01 g, 0.05 mmol), and Cs2CO3 (0.684 g, 2.1 mmol) in dioxane (1.5 mL) was heated at 110° C. for 24 hours. After the reaction mixture cooled to room temperature, it was partitioned between H2O and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc to give 0.095 g of the title compound (46%). MS (APCI) m/e 209 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 7.44 (s, 1H), 7.43 (s, 1H), 7.35 (d, J=2.14 Hz, 2H), 7.15 (d, J=2.14 Hz, 1H), 7.13 (d, J=2.14 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].Cl[CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:30]>>[F:37][C:34]1[CH:33]=[CH:32][C:31]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH:18]([C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])[CH:17]=[CH:16][CH:15]=3)[CH2:19][CH2:20]2)=[CH:36][CH:35]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 4-chloro-1-(4-fluorophenyl)-1-butanone: ESMS m/e: 411.2 (M+H)+.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].C(=N[N+:14]1[CH:18]=[CH:17][N:16]([CH3:19])[C:15]=1[CH3:20])C1C=CC=CC=1.F[B-](F)(F)F.[H+]>O>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:20][C:15]1[N:16]([CH3:19])[CH:17]=[CH:18][NH+:14]=1
Reactant: Cc1n(C)cc[n+]1N=Cc1ccccc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Product: Cc1[nH+]ccn1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.86 g of 1-benzylideneamino-2,3-dimethylimidazolium tetrafluoroborate is suspended in 30 ml of water. The suspension is treated with 1 ml of 50 percent tetrafluoroboric acid and steam-distilled until benzaldehyde no longer passes over. The colorless acidic solution is then treated with 0.45 g of p-(dimethylamino)benzaldehyde and stirred at room temperature for 3 hours. The resulting orange-yellow precipitate is removed by filtration under suction, washed three times with water and three times with diethyl ether and recrystallized from methanol/ethanol. There is obtained 1-[[p-(dimethylamino)benzylidene[amino[-2,3-dimethylimidazolium tetrafluoroborate in the form of yellow needles with a melting point of 248°-251°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Clc1ccc(Br)nc1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6′-methyl-[2,3′-bipyridin]-2′-yl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 436 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([O:10]C(=O)C)[CH:7]=[CH:8][CH:9]=1.C[O:15][C:16]([C:18]1([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([OH:37])[CH:30]=2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17]>>[OH:10][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][O:37][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=2[O:35][CH3:36])[C:28]([NH:27][C:18]2([C:16]([OH:15])=[O:17])[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:26]2)=[O:38])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Oc1cccc(CCO)c1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(O)c1

Procedure:
The compound of step 1 and the compound of step 2 of example 15 were reacted in analogy to step 3 of example 15 and the obtained ester hydrolyzed in analogy to example 16.