Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12](Br)[CH:13]=3)[O:8]2)[CH2:4][CH2:3]1.COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCN(C(OC(C)(C)C)=O)CC1)CC2=O.[C:48]([O:52][C:53](=[O:56])[CH:54]=[CH2:55])([CH3:51])([CH3:50])[CH3:49]>>[C:48]([O:52][C:53](=[O:56])/[CH:54]=[CH:55]/[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][C:5]1([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[CH2:16][C:15]2=[O:17])([CH3:51])([CH3:50])[CH3:49]
Reactant: CN1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Reactant: C=CC(=O)OC(C)(C)C
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: CN1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)OC(C)(C)C)ccc1O2

Procedure:
(E)-3-{1′-Methyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid tert-butyl ester was synthesized starting from 1′-methyl-6-bromo-spiro[chromane-2,4′-piperidine]-4-one (1.62 g, 5.22 mmol) according to the procedure for preparation of Intermediate 1, Step B, using tert-butylacrylate, giving a yellow solid (1.45 g). The resulting product was dissolved in a 20% TFA/DCM mixture (25 ml) and stirred at RT. After 16 h, the solvent was evaporated and the residue was partitioned between DCM and a saturated NaHCO3 solution. Then the aqueous phase was acidified with a 6 M solution of HCl and evaporated. The residue was suspended in a 9:1 DCM/MeOH mixture (70 ml) and the insoluble salts were filtered off. The solvent was dried over Na2SO4 and evaporated, giving (E)-3-{1′-methyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (890 mg) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=[C:6]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=1>C(O)C.O.NN>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([C@@H:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (S)-tert-butyl (1-(3-bromo-5-(1,3-dioxoisoindolin-2-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (30E, 1.5 g, 2.7 mmol) in 27 ml of ethanol, 0.9 ml of hydrazine monohydrate was added and stirred at room temperature for 2 hours. To the reaction mixture, ethanol was added and filtrated, and the filtrate was concentrated. The residue was diluted with ethyl acetate, and washed with water and then with a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the title product. MS (m/z) 427.83 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:22])[CH:3]=1.[H-].[Na+].CO.[CH3:27][N:28](C)[CH2:29]CN>>[CH3:22][C:4]1[CH:3]=[C:2]([N:28]([CH3:29])[CH3:27])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=1
Reactant: Cc1cc(Cl)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: CN(C)CCN
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(N(C)C)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 120 °C

Procedure:
A mixture of 800 mg (2.5 mmol) of compound 13 and 101 mg of 60% NaH (2.5 mmol) in 5 ml N,N-dimethyl ethylendiamine was heated in a sealed tube at 120° C. for six hours. To the cooled reaction mixture was carefully added methanol to quench NaH. The resulting mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 10% MeOH/CH2Cl2 with 1% NH40H) to get 100 mg of compound 14.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH3:17][OH:18]>>[CH3:17][O:18][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: Cc1cccc(C(C)(C)C)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COCc1cccc(C(C)(C)C)c1

Procedure:
For the electrochemical methoxylation of 3-tert-butyltoluene of the formula (II), an electrolyte consisting of 105 g of the compound of the formula (II), 1.9 g of sulfuric acid (96-98%) as conductive salt and 593.1 g of methanol was electrolyzed at 45° C. and at a current density of 34 mA/cm2 in an undivided capillary gap cell having 10 round graphite electrodes (A=32 cm2) until an amount of charge of 15 F/mol of the compound of the formula (II) was reached. Work-up by distillation gave 33.3 g of the compound of the formula (I) and 7.5 g of 3-tert-butylbenzyl methyl ether, corresponding to a total yield of acetal and ether of 30%.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:13]=3[N:14]=2)=[O:7])=[C:4]([OH:24])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl>CC(C)=O.C(OCC)(=O)C>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][O:24][C:4]1[CH:3]=[C:2]([F:1])[CH:23]=[CH:22][C:5]=1[C:6](=[O:7])[NH:8][CH2:9][C:10]1[S:11][C:12]2[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:13]=2[N:14]=1)[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: O=C(NCc1nc2c(F)c(F)cc(F)c2s1)c1ccc(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 45 °C
Yield: 80.7 %

Procedure:
A solution of 4-fluoro-2-hydroxy-N-(4,5,7,-trifluoro-benzothiazol-2-ylmethyl)-benzamide (1.0 g, 2.8 mmol) in acetone (14 mL) was treated with aq 2 N K2CO3 (2.1 mL, 4.2 mmol) and ethyl bromoacetate (2 mL, 19 mmol) and heated to 45° C. for 5 h. After cooling to room temperature, the solution was acidified to a pH 1 with aq 2 N HCl. The resulting solution was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Purification by MPLC (10-100% ethyl acetate in heptane 23 mL/min, 75 min) provided {5-fluoro-2[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)carbamoyl]-phenoxy}-acetic acid ethyl ester (1.0 g, 81%) as a white crystalline solid: 1H NMR (DMSO-d6 300 MHz) δ 9.32 (t, J=5.9 Hz, 1H), 7.94 (dd, J1=9.0 Hz, J2=7.2 Hz, 1H), 7.80-7.70 (m, 1H), 7.13 (dd, J1=11.1 Hz, J2=2.4 Hz, 1H), 6.95 (dt, J1=8.4 Hz, J2=2.5 Hz, 1H), 5.02 (s, 2H), 4.94 (d, J=6 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[C:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1)[CH3:5]>CCOC(C)=O.CN(C=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:44])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]1[C:19]([C:20]([F:22])([F:23])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.7 %

Procedure:
A solution of tert-butyl 4-(4-((4-((2-(1-methoxy-1-oxopropan-2-yl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I52) (0.108 g, 0.177 mmol) in EtOAc (5 mL) and DMF (10 mL) was added to a suspension of 10% Pd/C (80 mg) in EtOAc (5 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered and the solvent removed in vacuo to yield a brown residue. The residue was redissolved in DMF (15 mL) and added to a suspension of 10% Pd/C (55 mg) in DMF (5 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite washing with EtOAc (100 mL). Removal of the solvent under reduced pressure yielded a brown viscous oil which was purified by column chromatography on silica gel (0-15% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I53) (84.3 mg, 77%) as a pale yellow viscous oil; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.59-7.54 (m, 2H), 7.38 (s, 1H), 7.33-7.30 (m, 1H), 7.25-7.17 (m, 5H), 4.25 (s, 2H), 4.11 (q, J=7.1 Hz, 1H), 3.64 (s, 3H), 3.23-3.02 (m, 4H), 2.81 (t, J=12.0 Hz, 2H), 2.64 (tt, J=12.0, 3.4 Hz, 1H), 1.83 (d, J=12.9 Hz, 2H), 1.67-1.59 (m, 2H), 1.50-1.48 (d, J=7.0 Hz, 3H; s, 9H). LCMS Method C: rt 7.15 min; m/z 635 [M+Na]+, 613 [M+H]+, 557 [M-tButyl+2H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=O>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: O=Cc1cccs1
Product: Nc1cc(Br)cc2nc(-c3cccs3)nn12

Procedure:
The title compound, MS m/e (%): 297 (M++2, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 2-thiophenecarboxaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([CH3:10])[CH:3]=1.[OH-:11].[K+].Cl.[OH2:14]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:14])=[O:11])=[C:4]([CH3:10])[CH:3]=1
Reactant: O
Reactant: Cc1cc(F)ccc1C#N
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: Cc1cc(F)ccc1C(=O)O
Yield: 92 %

Procedure:
A mixture of 4-fluoro-2-methylbenzonitrile (19.8 g, 150 mmol), KOH (24.3 g, 380 mmol) and water (300 mL) was heated to reflux for two days. The mixture was then acidified with concentrated HCl while cooling. The product was collected by filtration and the filter cake was washed with water. The solid material was dried standing in the hood for several days. There was obtained 20.8 g (92%) of 4-fluoro-2-methylbenzoic acid as a solid material. 1H NMR (300 MHz, DMSO-d6): 2.5 (s, 3H), 7.0-7.2 (m, 2H), 7.9 (t, 1H), 12.8 (b, 1H).
Reaction SMILES: [ClH:1].CO[N:4]=[CH:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[NH:8][CH:7]=1.C(OCC)C>[Pd].CO>[ClH:1].[ClH:1].[NH2:4][CH2:5][C:6]1[C:10]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[C:9]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[NH:8][CH:7]=1
Reactant: CON=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
10 ml of 10% hydrochloric acid and 0.50 g of 10% palladium on carbon were added to a solution of 497 mg (1.68 mmol) of 5-(4-fluorophenyl)-4-(pyridin-4-yl)-1H-pyrrole-3-carboxaldehyde O-methyloxime [which was prepared as described in step 5(i) above] in 10 ml of methanol. The mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. At the end of this time, the reaction mixture was filtered and the filtrate thus obtained was concentrated by evaporation under reduced pressure. The residue was washed with diisopropylether and then with diethylether to give 391 mg (yield 68%) of the title compound as a yellowish orange powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[CH3:16].C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH2:24])[CH3:16]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccccc1-c1cc(F)ccc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccccc1-c1cc(F)ccc1F

Procedure:
The title compound was prepared from 1-(2′,5′-difluoro-1,1′-biphenyl-2-yl)ethanone (2.0 g, 8.6 mmol), anhydrous methanol (100 mL), ammonium acetate (13.3 g, 172 mmol), and sodium cyanoborohydride (1.08 g, 17.2 mmol) according to the procedure and in the same manner as described in Example 105, step b;
Reaction SMILES: [Si:1]([N:8]1[C:14](=[O:15])[C@@H:13]2[C@H:9]1[C@@H:10]([OH:26])[CH2:11][N:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C([O-])=O)CCCCC>>[CH2:19]([O:18][C:16]([N:12]1[CH2:11][C:10](=[O:26])[C@@H:9]2[C@H:13]1[C:14](=[O:15])[N:8]2[Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H]2[C@H]1[C@@H](O)CN2C(=O)OCc1ccccc1
Agent: CCCCCC(C)C(=O)[O-]
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H]2[C@H]1C(=O)CN2C(=O)OCc1ccccc1

Procedure:
(1S,5 S)-6-(t-Butyl-dimethyl -silanyl)-4,7-dioxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester was prepared from benzyl (1S,4S,5S)-6-(t-butyldimethylsilanyl)-4-hydroxy-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate in the same manner as described for benzyl (1S,5S)-6-(3,4-dimethoxybenzyl)-4,7-dioxo-2,6- diazabicyclo[3.2.0.]heptane-2-carboxylate (Example 7).
Reaction SMILES: Br[C:2]1[C:3](C=O)=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[N:14])[C:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([F:46])[CH:45]=1)[C:42](=[O:47])[NH:41][N:40]=[CH:39]2)([CH3:35])([CH3:34])[CH3:33].C(=O)(O)[O-:49].[Na+]>CS(C)=O>[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([F:46])[CH:45]=1)[C:42](=[O:47])[N:41]([C:2]1[CH:3]=[C:4]([N:8]3[CH:12]=[C:11]([C:13]([NH2:14])=[O:49])[C:10]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)=[N:9]3)[CH:5]=[CH:6][CH:7]=1)[N:40]=[CH:39]2)([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C([O-])O
Reactant: N#Cc1cn(-c2cccc(Br)c2C=O)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3)ncc2c1
Temperature: 120 °C

Procedure:
1-(3-Bromo-2-formylphenyl)-3-(4-(morpholine-4-carbonyl)phenylamino)-1H-pyrazole-4-carbonitrile (34 mg, 0.0708 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one (31.2 mg, 0.142 mmol), cuprous iodide (27 mg, 0.142 mmol) and sodium bicarbonate (14.9 mg, 0.177 mmol) were combined in 1 mL of DMSO. The solution was degassed with argon and then heated in a microwave at 120° C. for 1 hr. The resulting mixture was extracted with ethyl acetate and ammonium chloride solution. The organic layer was concentrated and purified by flash column chromatography using ethyl acetate (containing 5% methanol) in hexanes (5% to 80% linear gradient in 15 minutes, 12 g silica gel) to give the pure desired product. This material was triturated with ether in hexanes and filtered to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carbonitrile (18.2 mg, 41.5% yield) as a pale pink solid. LC/MS clacd for C33H30FN7O3 (m/e) 591.24, obsd 592.0 (M+H, ES+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 3.50 (br., 4H), 3.59 (br., 4H), 7.37 (d, J=8.6 Hz, 2H), 7.59 (d, J=8.3 Hz, 1H), 7.65-7.71 (m, 3H), 7.78 (d, J=13.1 Hz, 1H), 7.87-7.93 (m, 2H), 8.08 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 9.29 (s, 1H), 9.47 (s, 1H).
Reaction SMILES: Cl[Si](C)(C)C.[NH2:6][C:7]1[C:8]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH:35]([CH2:38][OH:39])[CH2:36][OH:37])[C:18](=[O:34])[O:19][CH2:20][CH:21]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:22]3=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>N1C=CC=CC=1>[C:40]([NH:6][C:7]1[C:8]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH:35]([CH2:36][OH:37])[CH2:38][OH:39])[C:18](=[O:34])[O:19][CH2:20][CH:21]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:28]4[C:33]3=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:9]=2[N:10]=[CH:11][N:12]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Nc1ncnc2c(CN(C(=O)OCC3c4ccccc4-c4ccccc43)C(CO)CO)c[nH]c12
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c(CN(C(=O)OCC3c4ccccc4-c4ccccc43)C(CO)CO)c[nH]c12)c1ccccc1
Reaction time: 8 h

Procedure:
Chlorotrimethylsilane (810 μL, 6.3 mmol) was added to a solution of 7 (194 mg, 0.42 mmol) in dry pyridine. After 30 min benzoyl chloride (172 μL, 1.48 mmol) was added and the solution was stirred overnight. The reaction was quenched by the addition of water and concentrated to dryness. The residue was taken up in dichloromethane (10 mL), washed with water, concentrated, stirred for 5 min in methanolic ammonia (7N) and concentrated again. Chromatography of the residue on silica gel eluted with 4% methanol in dichloromethane gave the title compound as a colourless, amorphous solid (160 mg, 2.84 mmol, 67%). ESI-MS+, found 564.2245, calc. for C32H30N5O5 [M+H]+ 564.2245.
Reaction SMILES: [N:1]1([C:7](OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:29]=C(Cl)[N:27]=[CH:26][N:25]=1>ClCCl>[Cl:23][C:24]1[CH:29]=[C:7]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)[N:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1cc(N2CCNCC2)ncn1
Temperature: 25 °C
Yield: 98 %

Procedure:
13.3 g tert-butyl 1-piperazinecarboxylate and 11.2 mL DIPEA were added to 10 g 4, 6 dichloro pyrimidine in 1000 mL dichlormethane was stirred over the weekend at RT. The solvent was removed. The residue was dissolved in 200 mL dichlormethane and 200 mL trifluoro acetic acid was added. The reaction was stirred at RT. The solvent was removed. The residue was dissolved in methanol and passed through HCO3 containing resin. The solvent was removed and the residue was purified by chromatographie on silica (dcyclohexane: ethylacetate 0-40%) to yield 13.07 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[CH3:17]O>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1ccccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 40.0 grams (0.29 mole) of 2-methylbenzoic acid in 200 ml of methanol was added dropwise 20 ml of concentrated sulfuric acid. Upon completion of addition the reaction mixture was heated to reflux where it stirred for 18 hours. The reaction mixture was cooled to ambient temperature and poured into 200 ml of water. The mixture was extracted with three 100 ml portions of methylene chloride. The combined extracts were washed with two 50 ml portions of aqueous saturated sodium bicarbonate solution, then with 50 ml of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 42.7 grams of methyl 2-methylbenzoate.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:13])[NH:7][C:8](=S)[NH:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4].ClCC(O)=[O:17]>>[CH2:1]([C:5]1[C:6](=[O:13])[NH:7][C:8](=[O:17])[NH:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CCl
Reactant: CCCCc1c(C)[nH]c(=S)[nH]c1=O
Product: CCCCc1c(C)[nH]c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
A suspension of 5-butyl-6-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one in 10% aqueous chloroacetic acid (100 mL) is stirred at reflux for 3 hours and then allowed to cool to room temperature. The suspension is cooled in an ice bath for a few minutes and then filtered. The solid is thoroughly washed with H2O and dried, yielding pure 5-butyl-6-methyl-1H-pyrimidine-2,4-dione as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 10.86 (br s, 1H), 10.57 (br s, 1H), 2.17 (m, 2H), 2.01 (s, 3H), 1.25 (m, 4H), 0.85 (t, J=6.9 Hz, 3H) ppm. MS: m/z 183 [M+1 ].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[K+].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: c1cn[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(COc2ccc(Cn3cccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After a mixture of pyrazole (7.73 mmol) and potassium hydroxide (7.73 mmol) in DMF (35 mL) was stirred at room temperature for 30 min., a solution of 1-(benzyloxy)-4-(chloromethyl)benzene (6.44 mmol) in DMF (7 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight and the product obtained from a standard aqueous work up. Column chromatography (1:2 ethyl acetate/hexane) of the residue yielded compound 58.1 as a white solid. LC-MS ESI (pos.) m/e: 265 (M+H); 1H NMR (500 MHz) (DMSO-d6) δ 7.79 (1H, m); 7.46 (3H, m); 7.40 (2H, m); 7.36 (1H, m); 7.21 (2H, d, J=9 Hz)); 5.27 (2H, s); 5.11 (2H, m).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[N:20]1([C:26]([S:28][CH3:29])=[S:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl>[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:8]=1[C:9]([N:23]1[CH2:24][CH2:25][N:20]([C:26]([S:28][CH3:29])=[S:27])[CH2:21][CH2:22]1)=[O:11]
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Reactant: CSC(=S)N1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCN(C(=S)SC)CC2)c(OC)c1OC
Reaction time: 8 h
Yield: 51.6 %

Procedure:
In a nitrogen atmosphere, 10 ml (138 mmol.) of thionyl chloride was added to 1.00 g (4.71 mmol.) of 2,3,4-trimethoxybenzoic acid. The mixture was refluxed under heating for 2 hours. The solvent was distilled off under reduced pressure. To the residue was added 10 ml of dry benzene, and the mixture was placed under reduced pressure to distill off benzene. This procedure was repeated once. To the residue was dropwise added at room temperature a solution of 0.88 g (4.74 mmol., purity 95%) of methyl 1-piperazinecarbodithioate in 12 ml of dichloromethane. In the course of the addition, 0.48 g (4.74 mmol.) of triethylamine was added to the mixture. The resulting mixture was then stirred overnight. The reaction mixture was washed successively with 1-N hydrochloric acid and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under pressure to distill off the solvent. The residue was crystallized from acetone. The crystals were collected by filtration. The filtrate was concentrated, and additional crystals were further precipitated from the concentrated filtrate by addition of a small amount of ethanol. These crystalline portions were combined to give 0.90 g of the desired compound as a white crystalline product, m.p. 149°-150° C. (decomp.), yield 51.6%.