Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[CH3:17][NH2:18].Cl[CH2:20][CH:21]=O>O.C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[N:18]([CH3:17])[CH:20]=[CH:21][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: O=CCCl
Reactant: CN
Reactant: CCOC(=O)CC(=O)CC(OCC)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccn(C)c1CC(OCC)OCC
Reaction time: 5 h

Procedure:
To a solution of 11.8 g of the compound obtained in Step B (50.8 mmol) in 76 mL of water there are added, dropwise at 0° C., 6.6 ml of aqueous 40% methylamine solution (76.2 mmol). The reaction mixture is stirred and gently reheated to ambient temperature over 5 hours. After returning to 0° C., 8.8 mL of aqueous 40% methylamine solution (102 mmol) and then 16.6 mL of aqueous 50% chloroacetaldehyde solution (127 mmol) are each added dropwise at a temperature of less than 10° C. The reaction mixture is stirred at ambient temperature for 16 hours and then diluted with ethyl acetate. The organic phase is washed with brine, dried over MgSO4 and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel using petroleum ether and ethyl acetate as eluants. The title product is obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[C:4](=[O:15])[N:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C)C=O>[F:8][C:7]1[C:2]([N:1]=[CH:18][N:19]([CH3:21])[CH3:20])=[N:3][C:4](=[O:15])[N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[CH:6]=1
Reactant: Nc1nc(=O)n(C2CCC(O)C2)cc1F
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(=O)n(C2CCC(O)C2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
A solution of 4-amino-5-fluoro-1-(3-hydroxy-cyclopentyl)-1H-pyrimidin-2-one (0.346 g, 1.62 mmol) in anhydrous dimethylformamide (3 mL) was treated with dimethylformamide dimethyl acetal (3 mL). The mixture was stirred at room temperature under nitrogen for 12 hours, concentrated in vacuo, loaded on silica gel, and chromatographed on silica gel (3×7 cm SiO2, 4:1 ethyl acetate/methanol) to afford N′-[5-Fluoro-1-(3-hydroxy-cyclopentyl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine 30 as a milky white oil (0.361 g, 83%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][N:14]3C(C)C)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.OC1(C2C=C3C(C=CN3C(C)C)=CC=2)CCN(C)CC1>C(O)(C(F)(F)F)=O.C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1
Reactant: CC(C)n1ccc2ccc(C3=CCN(C)CC3)cc21
Agent: CC(C)n1ccc2ccc(C3(O)CCN(C)CC3)cc21
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CC=C(c2ccc3cc[nH]c3c2)CC1

Procedure:
6-[N-Methyl-1,2,5,6-tetrahydropyridin-4-yl]-1-isopropyl-indole : from 6-[4-Hydroxy-1-methyl-piperidin-4-yl]-1-isopropyl-indole (20 mg, 0.0735 mmol) in 0.1 ml of TFA and 1 ml of THF at 60-64° C. Yield 4.8 mg (26%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[C:24]([CH3:29])[CH:23]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[CH3:31][C:32]1([CH3:39])[CH2:37]C(=O)[O:35][C:33]1=[O:34]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[I:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:31][C:32]([CH3:39])([CH3:37])[C:33]([OH:35])=[O:34])[CH2:13][CH2:12]3)=[N:15][CH:16]=2)=[O:30])=[CH:23][C:24]=1[CH3:29]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Cc1cc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)ccc1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C(=O)O)CC3)nc2)ccc1I
Reaction time: 0.5 h

Procedure:
4-[5-(4-Iodo-3-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (35 mg, 0.07 mmol) was dissolved in 30% TFA in CH2Cl2 solution at room temperature. The mixture was stirred for 30 min and then partitioned between EtOAc and H2O. The water layer was made basic by the addition of Na2CO3. The organic layer was then collected washed with water dried over Na2SO4, filtered and evaporated. The residue was dissolved in CH2Cl2 and treated with 2,2-dimethysuccinic anhydride (13 mg, 0.10 mmol). After stirring at room temperature for 4 h the mixture was concentrated to a residue and washed with excess of hexanes to afford the product. HRMS m/z calcd for C23H27N4O4I [M+H]+: 551.1150. Found: 551.1152.
Reaction SMILES: CC(CC(N[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)=O.[C:14](#[N:18])[CH2:15][C:16]#N>>[CH:14]1[C:15]2[C:8](=[CH:9][CH:10]=[CH:11][CH:16]=2)[CH:13]=[CH:12][N:18]=1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: N#CCC#N
Product: c1ccc2cnccc2c1
Yield: 85 %

Procedure:
The procedure of Reference Example 5 was repeated except that 0.04 mole of acetoacetic anilide (Reference Example 8) or 0.04 mole of malononitrile (Reference Example 9) was employed instead of acetylacetone to give a corresponding isoquinoline derivative with yield of 85%, 65%, respectively. The structures of the obtained isoquinoline derivatives were identified by means of elementary analysis, IR spectrum and 1H-NMR spectrum.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[S:3]1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>ClC=CCl>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:15])[CH2:13][CH3:14])[CH:8]=2)[S:3]1
Reactant: CC1CCc2ccccc2S1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=CCl
Product: CCC(=O)c1ccc2c(c1)CCC(C)S2
Yield: 58 %

Procedure:
83 gr. (0.5M) of 2-methyl-thiochromane are treated with 43.2 ml of propionyl chloride (0.5M) in the presence of 73 gr. of AlCl3 (0.55M) in 750 ml of 1,2-dichloroethylene in the already described preceding examples. 64 gr. of 2-methyl-6-propionyl-thiochromane are obtained.
Reaction SMILES: C1COCC1.II.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[S:25])[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]2)=[CH:11][CH:10]=1>O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]=[C:16]2[CH2:17][CH2:18][CH:19]3[CH:24]([CH:23]=[CH:22][CH2:21][CH2:20]3)[S:25]2)=[CH:13][CH:14]=1
Reactant: S=C(CCC1C=CCCC1)Nc1ccc(Cl)cc1
Agent: II
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(N=C2CCC3CCC=CC3S2)cc1
Temperature: 25 °C

Procedure:
10 ml of THF solution including 2.4 g of iodine was added to 40 ml of THF solution including 2.2 g of N-(4-chlorophenyl)-3-(2-cyclohexene-1-yl) thiopropionamide at 0° C. The temperature was raised to room temperature and the resulting solution was stirred for one night. Then the temperature was cooled to 0° C., and 5 ml of THF solution including 4.1 g of 1,4 diazabicyclo[5,4,0]undec-7-ene(DBU) was dropped into the resulting solution. The solution was stirred at room temperature for one night, and added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.84 of the title compound.
Reaction SMILES: [OH:1]CCN1CCNCC1.C(O)(=O)/C=C/C(O)=O.[Cl:18][C:19]1[S:20][CH:21]=[C:22]2[C:28](N3CCN(CCO)CC3)=[N:27][C:26]3[CH:38]=[CH:39][CH:40]=[CH:41][C:25]=3[O:24][C:23]=12>C1(C)C=CC=CC=1>[Cl:18][C:19]1[S:20][CH:21]=[C:22]2[C:28](=[O:1])[NH:27][C:26]3[CH:38]=[CH:39][CH:40]=[CH:41][C:25]=3[O:24][C:23]=12
Reactant: OCCN1CCNCC1
Reactant: OCCN1CCN(C2=Nc3ccccc3Oc3c2csc3Cl)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2Oc2c1csc2Cl

Procedure:
A 4.0 g. portion of the above product is reacted with 4.0 g. of phosphorus pentachloride in 103 ml. of dry toluene as described in Example 1, giving 3,10-dichloro-thieno[3,4-b][1,5]benzoxazepine which is further reacted with 25 ml. of N-hydroxyethylpiperazine and 25 ml. of dry toluene giving the base compound as a foam which is converted to 4-(3-chlorothieno[3,4-b][1,5]benzoxazepin-10-yl)-1-piperazine-ethanol fumarate, m.p. 144°-145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CN[N:3]=1.C([N:9]([CH2:12][CH3:13])CC)C.[Br:14][CH2:15][C:16](Cl)=[O:17]>CC(C)=O>[Br:14][CH2:15][C:16]([NH:1][C:2]1[CH:6]=[N:9][CH:12]=[CH:13][N:3]=1)=[O:17]
Reactant: O=C(Cl)CBr
Reactant: CCN(CC)CC
Reactant: Nc1cc[nH]n1
Solvent: CC(C)=O
Product: O=C(CBr)Nc1cnccn1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
A stirred solution of amino pyrazole (10 g, 105 mmol) in acetone (100 ml) is treated with triethylamine (16.1 ml, 115 mmol) and then cooled to 0-5° C. using an ice bath. To the cooled solution is added drop-wise bromoacetyl chloride (8.76 g, 105 mmol) in acetone (10 ml). The cooled reaction mixture is stirred for 3 hours and then filtered. The solvent is removed in vacuo and purification by chromatography on silica (eluting with ethyl acetate-iso-hexane, 2:1 increasing to 100% ethyl acetate) affords the titled compound.
Reaction SMILES: [SiH:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[CH2:8]([Cl:12])[C:9](=[CH2:11])[CH3:10]>>[Si:1]([Cl:12])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[Si:1]([CH2:10][CH:9]([CH2:8][Cl:12])[CH3:11])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: C=C(C)CCl
Reactant: CC[SiH](CC)CC
Product: CC[Si](CC)(CC)CC(C)CCl
Product: CC[Si](Cl)(CC)CC
Temperature: 115 °C
Yield: 36.8 %
Yield: 18.7 %

Procedure:
A mixture of Et3SiH (10.5 g, 0.09 mol) and methallyl chloride (8.2 g, 0.09 mol) was combined in a 150 ml apparatus and 0.05 ml Pt catalyst solution added, followed by heating at reflux (115° C.) for 50 hr. Additional Pt catalyst solution (0.025 ml) was added at 40 hr. The incomplete reaction was distilled, yielding 4.98 g (36.8%) of Et3SiCl and 3.48 g (18.7%) of Et3SiCH2CHMeCH2Cl. This example shows that the unpromoted reaction of Et3SiH with methallyl chloride is very slow and endothermic.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][N:19]2[CH:10]([C:11](=[O:36])[NH:12][C:13]3[C:18]2=[N:17][CH:16]=[C:15]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:25][CH2:24]2)[CH:14]=3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:26]2[CH2:25][CH2:24][N:23]([CH2:22][C:15]3[CH:14]=[C:13]4[C:18]([N:19]5[CH:10]([C:11](=[O:36])[NH:12]4)[CH2:9][NH:8][CH2:21][CH2:20]5)=[N:17][CH:16]=3)[CH2:28][CH2:27]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncc(CN4CCN(c5ccc(Cl)cc5)CC4)cc3NC(=O)C2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCNCC12
Temperature: 25 °C
Yield: 8.9 %

Procedure:
7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-10-oxo-1,3,4,9,10,10a-hexahydro-2,4a,5,9-tetraaza-phenanthrene-2-carboxylic acid tert-butyl ester (250 mg, 0.487 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (3 mL) was added while stirring at room temperature. The reaction was stirred for 16 h and concentrated to a residue. The residue was dissolved in DMF and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (17.8 mg, 8.8%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.68 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.14-7.30 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.33 (d, J=11.4 Hz, 1H), 3.97 (dd, J=11.0, 3.4 Hz, 1H), 3.45 (dd, J=12.5, 2.9 Hz, 4H), 3.32-3.36 (m, 4H), 3.16 (d, J=9.6 Hz, 1H), 3.06-3.13 (m, 4H), 2.72-2.87 (m, 3H). [M+H] calc'd for C26H33ClN6O3, 413; found, 413.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[C:16]([N+:17]([O-])=O)=[CH:15][N:14]=[C:13]([NH2:20])[N:12]=2)=[CH:4][CH:3]=1.CN(C=O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CO.O>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[C:16]([NH2:17])=[CH:15][N:14]=[C:13]([NH2:20])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ncc([N+](=O)[O-])c(-n2ncc3ccc(I)cc32)n1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(N)c(-n2ncc3ccc(I)cc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
To a suspension of 4-(6-iodo-1H-indazol-1-yl)-5-nitropyrimidin-2-amine (200 mg, 45% purity, 0.236 mmol) in a mixture of methanol (4 mL), DMF (3 mL) and water (3 mL) was added sodium dithionite (205 mg, 1.178 mmol) and sodium bicarbonate (99 mg, 1.178 mmol). The suspension was stirred at RT for 2 hr. After 2 hr LC-MS (Method B) showed 11% of desired product, 15% of starting 4-(6-iodo-1H-indazol-1-yl)-5-nitropyrimidin-2-amine (16-a) and 67% of degraded by-product. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (2×10 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound; m/z=+352.9 (M+H)+, (purity=11%). This intermediate was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(#N)C.[CH:18]1(/[CH:22]=[CH:23]/[C:24]#[N:25])[CH2:21][CH2:20][CH2:19]1.N12CCCN=C1CCCCC2>>[CH:18]1([CH:22]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23][C:24]#[N:25])[CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#C/C=C/C1CCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C(CC#N)C3CCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.63 g, 0.0496 mol) in acetonitrile (124 mL, 2.37 mol) was added (E)-3-cyclobutylacrylonitrile (5.30 g, 0.0495 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3.70 mL, 0.0248 mol). The resulting mixture was stirred at room temperature overnight, then evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product as a racemic mixture (11.2 g, 75.2%). LCMS (M+H) 302.4.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:52])([CH2:50][OH:51])CO.Cl.NC[C:56](N)=[O:57]>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:42])[N:46]([CH2:56][OH:57])[CH:47]([CH3:52])[CH2:50][OH:51])=[CH:33][CH:32]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NCC(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(N)(CO)CO
Agent: Cl
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)N(CO)C(C)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22]Br>C(#N)C>[Br:19][CH2:20][CH2:21][CH2:22][O:11][C:7]1[C:6]([Br:12])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:9][C:8]=1[Br:10]
Reactant: BrCCCBr
Reactant: CC(=O)c1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(Br)c(OCCCBr)c(Br)c1

Procedure:
A stirred mixture of 3,5-dibromo-4-hydroxyacetophenone (3.0 g, 10.1 mmol), K2CO3 (2.8 g, 20.3 mmol), 1,3-dibromo-propane (4.0 g, 19.8 mmol) in acetonitrile (100 ml) was heated at reflux for 5 hours. The solvent was removed. The crude product was extracted into dichloromethane (150 ml) and the insoluble inorganics were filtered off. The solution was concentrated to dryness again. Purification was carried out by flash chromatography on silica gel (45 g, SiO2 ; eluted with 1:1 hexane:dichloromethane). The material thus obtained (2.8 g) was recrystallized twice from isopropyl ether to give analytically pure 1-[4-(3-bromopropoxy)-3,5-dibromophenyl]ethanone, m.p.=87°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[H-].[Na+].[NH2:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[OH-].[Na+]>CS(C)=O.C(OCC)C.CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:19]1[N:18]=[CH:17][N:16]=[C:15]([NH2:14])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Nc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOCC
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 16.1 %

Procedure:
2-Fluoro-4-nitrophenol (1.736 g) was dissolved in dimethyl sulfoxide (10 ml), and then sodium hydride (400 mg) was added thereto, followed by stirring for 20 min. Then, 4-amino-6-chloropyrimidine (648 mg) was added thereto, followed by stirring at 100° C. for 45 min. The reaction mixture was heated up to 120° C., followed by stirring for 1 hr and 25 min. Then, the reaction mixture was heated up to 140° C., followed by stirring overnight. The reaction mixture was cooled down to room temperature, and then a 1 N aqueous solution of sodium hydroxide (10 ml) was added thereto, followed by stirring and extracting with ethyl acetate. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2). The solvent was evaporated under a reduced pressure to give a residue, which was suspended in diethyl ether (7 ml)-hexane (3.5 ml). The solid was filtered off, and dried under aeration to provide the titled compound (201 mg, 16.0%) as pale brown powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>C1COCC1.C(O)C.[Ni].O>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc(Cl)cc([N+](=O)[O-])c1N
Agent: [Ni]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)cc(N)c1N
Reaction time: 6 h

Procedure:
To a solution of EXAMPLE 44A (4 g) in THF (500 mL) and ethanol (500 mL) was added 50% Raney nickel in water (2 g). The reaction mixture was stirred under hydrogen (balloon) for 6 hours and filtered.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:32]1([CH2:35][C:36]([OH:38])=O)[CH2:34][CH2:33]1.[Cl:39][C:40]1[CH:70]=[CH:69][C:43]([CH2:44][N:45]2[C:49]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[C:52]([F:54])=[CH:53][C:48]=3[N:47]=[C:46]2[CH2:61][O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:42][CH:41]=1>CN(C=O)C.O>[Cl:39][C:40]1[CH:70]=[CH:69][C:43]([CH2:44][N:45]2[C:49]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][N:58]([C:36](=[O:38])[CH2:35][CH:32]5[CH2:33][CH2:34]5)[CH2:57][CH2:56]4)[C:52]([F:54])=[CH:53][C:48]=3[N:47]=[C:46]2[CH2:61][O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:42][CH:41]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Reactant: O=C(O)CC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CC1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
71 mg of TBTU (0.22 mmol), 0.19 ml of ethyldiisopropylamine and 0.022 ml of cyclopropyl-acetic acid were dissolved in 6 ml DMF and stirred for one minute at rt under argon. Then 100 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.22 mmol) were added and the reaction mixture was stirred for 22 h at rt. The reaction mixture was then diluted with 30 ml water and extracted with ethylacetate (twice). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 130 mg of a light red solid (100%). MS (ISP) 533.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[C:4]([CH3:17])[CH:3]=1.[OH-].[Na+].Cl[C:21]([F:26])([F:25])C(O)=O>CN(C=O)C.O.C(OCC)(=O)C>[F:25][CH:21]([F:26])[O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:12])=[O:13])=[C:4]([CH3:17])[CH:3]=1
Reactant: O=C(O)C(F)(F)Cl
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OC(F)F)c([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Temperature: 120 °C
Reaction time: 18 h
Yield: 21.3 %

Procedure:
To a solution of 4-hydroxy-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide (200 mg, 0.77 mmol) in dry DMF (2 mL) was added sodium hydroxide (74 mg, 1.85 mmol) and chlorodifluoroacetic acid (120 mg, 0.92 mmol). The resulting reaction mixture was stirred at 120° C. for 18 h. After cooling, the reaction was diluted with water and ethyl acetate, and the layers were separated. The organics were washed three times with 1 N NaOH, dried and concentrated. The residue was purified by flash chromatography (20% ethyl acetate/hexanes) to provide 4-difluoromethoxy-2-methyl-5-nitro (N,N-dimethyl)-benzenesulfonamide (51 mg, 21%) as a yellow solid, mp 125-126° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:10]=1)=[O:5])[CH3:2].[Cl:14]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH:11]2[CH2:12][CH2:13]2)[C:10]=1[Cl:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C2CC2)n[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]nc(C2CC2)c1Cl
Reaction time: 15 h
Yield: 89.4 %

Procedure:
To a solution of 5-cyclopropyl-2H-pyrazole-3-carboxylic acid ethyl ester (202 mg) in N,N-dimethylformamide (4 ml) was added at 0° C. N-chlorosuccinimide (199 mg) and stirring was continued at 22° C. for 15 hours. For the workup, The mixture was partitioned between water and ethyl acetate, the organic layer was dried, evaporated and the residue purified by chromatography on silica using a 8:1-mixture of n-heptane and ethyl acetate as the eluent to give 4-chloro-5-cyclopropyl-2H-pyrazole-3-carboxylic acid ethyl ester (215 mg) as a pale yellow liquid. MS (ISP): m/z=215.2 [M+H]+. b) To a solution of 4-chloro-5-cyclopropyl-2H-pyrazole-3-carboxylic acid ethyl ester (210 mg) in dioxane (4 ml) was added at 22° C. a solution of sodium hydroxide (3.0 M, 0.65 ml), and stirring was continued at 22° C. for 15 hours and at 60° C. for 3 hours. For the workup, the mixture was partitioned between aqueous hydrochloric acid (1.0 M) and ethyl acetate, the organic layer was dried and evaporated to give the title compound (161 mg) as a pale yellow solid. MS (ISP): m/z=184.8 [M−H]−.