Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH:5](C1C=C(Br)C=CC=1OCC1C=CC=CC=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)C>[C:6]1([CH2:5][CH2:4][C:3]([OH:27])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccccc1

Procedure:
A solution of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenyl-propionic acid methyl ester (0.391 g, 0.92 mmol) in ethanol (5 ml) was treated at 50° C. with excess aqueous sodium hydroxide solution until the milky emulsion became clear. The reaction mixture was then acidified (pH 3), evaporated and extracted with dichloromethane. The organic extract was evaporated and the remaining oil was redissolved in a minimum of boiling ethanol. The precipitation formed after 18 hrs at 4° C. was filtered off and dried in vacuo to yield 0.27 g (71.4%) of (±)-3-(2-Benzyloxy)-5-bromophenyl)-3-phenylpropionic acid, colourless crystals, m.p. 124.9° C.; tlc: (1) 0.15 (starting material methyl ester 0.75); NMR (CDCl3): 39.15, 40.26, 70.25, 113.21, 113.90, 126.62, 127.27, 127.98, 128.17, 128.47, 128.54, 130.46, 130.68, 134.34, 136.45, 142.16, 154.95, 177.65. LC-MS: 412/410 (14/11%, M+.), 394/392 (15/13%), 321/319 (17/22%), 304/302 (17/21%), 259 (24%), 194 (22%), 178 (21%), 167 (65%), 152 (49%), 92 (100%). IR (KBr): 3434, 3030, 1708, 1485, 1452, 1403, 1289, 1243, 1126, 1018, 804, 735, 698, 649. Calculated for C22H19BrO3 (mol-wgt. 411.30): C, 64.25%, H, 4.66%, Br 19.43%, O 11.67%. found: C, 63.72%, H, 4.70%, Br 19.75%, O 11.80%.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]([C:10]1[S:14][C:13]([CH2:15][CH:16]([C:18]2[C:19]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:20][O:21][C:22]=2[CH3:23])O)=[N:12][C:11]=1[CH3:28])=[O:9].[OH-].[Na+]>C(OCC)(=O)C>[CH3:6][O:7][C:8]([C:10]1[S:14][C:13](/[CH:15]=[CH:16]/[C:18]2[C:19]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:20][O:21][C:22]=2[CH3:23])=[N:12][C:11]=1[CH3:28])=[O:9]
Reactant: CCCCc1noc(C)c1C(O)Cc1nc(C)c(C(=O)OC)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Temperature: 90 °C
Yield: 94.1 %

Procedure:
Concentrated sulfuric acid (85 mL) was added to 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-2-hydroxy-ethyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (9.0 g, 26.6 mmol) then the mixture was heated at 90° C. for 2 h. The solution was carefully dropped into 2N sodium hydroxide (1580 mL) and ethyl acetate (100 mL) saturated sodium bicarbonate was added until pH 10 was reached. The reaction mixture was extracted with ethyl acetate then the combined organic extracts were dried, filtered and concentrated, to give the title compound (8.02 g, 94%) as a yellow oil that was used directly without further purification. MS: m/e=321.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][C:17]=2[CH2:25][O:26][C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29](Cl)=[O:30])=[CH:10][CH:9]=1>ClCCl>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=1[O:26][CH2:25][C:17]1[N:18]=[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]2[C:16]=1[C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=1
Reactant: CN(C)CCN
Reactant: O=C(Cl)c1ccccc1OCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1ccccc1OCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
0.896 ml (7.76 mmol) of N,N-dimethylethane-1,2-diamine were solubilized in 8 ml of dichloromethane with magnetic stirring, 0.449 g (0.776 mmol) of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)benzoyl chloride were added and the mixture was stirred at r.t. for 16 h before being concentrated in vacuo. The crude residue was purified by trituration in 20 ml of diisopropyl ether. The solid was isolated by filtration, washed with 10 ml of water and dried in vacuo. 0.178 g (yield=50%) of N-(2-(dimethylamino)ethyl)-2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]-pyridin-2-yl)methoxy)benzamide were obtained as a pale yellow solid. LC-MS: m/z=457 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.68 (d, J=6.7 Hz, 1H), 8.47 (d, J=4.8 Hz, 1H), 7.91 (dd, J=7.7, 1.5 Hz, 1H), 7.72 (dd, J=8.6, 5.2 Hz, 3H), 7.57-7.39 (m, 3H), 7.32 (t, J=8.9 Hz, 2H), 7.17 (t, J=6.6 Hz, 1H), 7.09 (t, J=7.3 Hz, 1H), 5.51 (s, 2H), 2.5 (1H hidden under the solvent peak), 2.25 (t, J=6.5 Hz, 2H), 1.92 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[C:11](/[C:17]#[N:18])\C(OCC)=O)=[CH:4][CH:3]=1.[C-:19]#[N:20].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:11][C:17]#[N:18])[C:19]#[N:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(C#N)=C1\CCc2ccc(Cl)cc21
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC1(C#N)CCc2ccc(Cl)cc21
Temperature: 65 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
A solution of (E)-ethyl 2-cyano-2-(6-chloro-2,3-dihydro-1H-inden-1-ylidene)acetate (Prep38, 15.00 g, 0.06 mol) in ethanol (300 ml) was treated with a solution of KCN (9.75 g, 0.15 mol) in water (90 ml). The mixture was warmed to 65° C., and stirred for 16 h. The mixture was concentrated in vacuo to remove solvent. The residue was extracted with EA (100 ml×3). The organic layers were combined and washed with a saturated solution of NaHCO3, brine and dried over Na2SO4. The crude was purified by FC (P:E=10/1) to obtain the title compound (4.60 g, y=37.1%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[CH:15]2[CH2:19][CH2:20][CH:21]=[CH:22][CH:14]12>>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:13]([C@H:14]1[CH2:22][CH:21]=[CH:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:23])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: O=C1OC(=O)C2CCC=CC12
Product: CCOc1cc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)ccc1OC

Procedure:
Prepared from 1-Bromo-3-ethoxy-4-methoxybenzene and tetrahydrophthalic anhydride as described for compound D. M.p. 132-135° C.
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH4+].[OH-].[CH3:23][C:24]([CH3:26])=O>>[NH2:18][C:17]1[NH:16][C:14](=[O:15])[C:13]2[N:12]=[CH:11][N:10]([CH:1]3[CH:2]4[CH:4]([O:5][C:24]([CH3:26])([CH3:23])[O:3]4)[CH:6]([CH2:7][OH:8])[O:9]3)[C:20]=2[N:19]=1
Reactant: CC(C)=O
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [NH4+]
Agent: [OH-]
Product: CC1(C)OC2C(CO)OC(n3cnc4c(=O)[nH]c(N)nc43)C2O1
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 92 %

Procedure:
To a slurry of guanosine (0.25 g, 1.0 eq) (10) and acetone (15 mL) at room temperature was added 70% HClO4 (0.103 mL, 1.35 eq). The reaction was stirred for approximately 70 minutes, at which time it was clear and colorless. The reaction was then cooled to 0° C. in an ice/water bath and concentrated NH4OH (0.167 mL, 1.41 eq) was added causing the formation of a milky white, gelatinous precipitate. The precipitate was collected on filter paper, resulting in a white papery solid that was dried at reduced pressure and ambient temperature for approximately 1 hour yielding 11 (0.262 g, 92%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[Na+].[I-].[CH3:19][NH2:20]>>[CH3:19][NH:20][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCN(CCCl)CC1
Agent: [I-]
Agent: [Na+]
Product: CNCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
Into a 50-mL sealed tube, was placed tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (300 mg, 1.21 mmol, 1.00 equiv), methylamine (in ethanol) (10 mL), and NaI (100 mg). The resulting solution was stirred for 12 h at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 3 mL of water and adjusted to pH 7-8 with sodium bicarbonate (5%). The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×3 mL of water and 1×3 mL of brine. The resulting mixture was concentrated under vacuum. This resulted in 180 mg (crude) of tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate as brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]([CH2:7][CH2:8][S:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]([OH:6])=[O:5].O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C(Cl)CCl>CC(N(C)C)=O>[CH3:17][N:2]([CH3:1])[CH:3]([CH2:7][CH2:8][S:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]([O:6][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])=[O:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CN(C)C(CCSSc1ccccn1)C(=O)O
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: CN(C)C(CCSSc1ccccn1)C(=O)ON1C(=O)CCC1=O
Yield: 34.4 %

Procedure:
2-(dimethylamino)-4-(pyridin-2-yldisulfanyl)butanoic acid (218) (92 mg, 0.338 mmol), 1-hydroxypyrrolidine-2,5-dione (65 mg, 0.565 mmol) and EDC (185 mg, 0.965 mmol) was stirred in 3 ml of DMA at 50° C. overnight. The mixture was evaporated and purified on a SiO2 column eluted with from 1:10 to 1:4 of methanol/CH2Cl2 to afford 43 mg (35%) of the title product. 1H NMR (CDl3OD) 8.40 (m, 1H), 7.83 (m, 2H), 7.22 (m, 1H), 3.34 (m, 1H), 2.82 (m, 2H), 2.75 (s, 4H), 2.66 (s, 6H), 1.98 (m, 2H); 13C NMR 177.21, 161.78, 161.12, 150.68, 139.37, 122.70, 121.66, 70.80, 44.16, 43.15, 36.06, 27.38; ESI MS m/z+ 369.2 (M+H).
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:20])[CH:9]=2)[N:4]=[CH:3]1.[C:21]1(=[O:35])[N:25]([CH2:26][C:27](Cl)=[O:28])[C:24](=[O:30])[C:23]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:22]12>N1C=CC=CC=1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([C:10]1[CH:9]=[C:8]([F:20])[CH:7]=[CH:6][C:5]=1[N:4]([CH:3]=[N:2][NH:1][C:27](=[O:28])[CH2:26][N:25]1[C:21](=[O:35])[C:22]2[C:23](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:24]1=[O:30])[C:27](=[O:28])[CH2:26][N:25]1[C:24](=[O:30])[C:23]2[C:22](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:21]1=[O:35])=[O:19]
Reactant: NN1C=Nc2ccc(F)cc2C1(O)c1ccccc1Cl
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Product: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 3-amino-6-fluoro-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with α-phthalimidoacetyl chloride to give 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-fluorophenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[CH:24]=[N:23]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:25]3[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cn1cc(C(=O)Cl)cn1
Reactant: CC(=O)c1cc(F)c2cccnc2c1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(F)c2cccnc2c1N1CCN(C(=O)c2cnn(C)c2)CC1
Reaction time: 2 h
Yield: 84.3 %

Procedure:
1-(5-Fluoro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.038 g, 0.14 mmol) was combined with 1-methyl-1H-pyrazole-4-carbonyl chloride (0.030 g, 0.21 mmol) and triethylamine (0.058 mL, 0.42 mmol) in methylene chloride (1.0 mL, 16 mmol) at room temperature and stirred for 2 hrs. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (45 mg, 85%). LCMS calculated for C20H21FN5O2 (M+H)+: m/z=382.2; Found: 382.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].CS(O[CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCCCn1c(-c2ccccc2)nc(Cl)c1C=O
Temperature: 90 °C
Reaction time: 7 h
Yield: 99.1 %

Procedure:
To a solution of 4-chloro-2-phenyl-1H-imidazole-5-carbaldehyde (500 mg) and 4-methoxybutyl methanesulfonate (660 mg) in N,N-dimethylacetamide (10 ml) was added cesium carbonate (2.4 g); and the mixture was stirred at 90° C. for 7 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (702 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].[Na].[CH2:21](I)[CH3:22].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH2:21][CH3:22])=[O:18]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1
Reactant: CCI
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of 2.5 g (0.009 mole) of (2-amino-3-benzoylphenyl)acetic acid, sodium salt in 25 ml of dry dimethylformamide was treated with 5 g of ethyl iodide (0.035 mole) and stirred with a magnetic stirrer at room temperature for 2 hours. The reaction mixture was then added to water and extracted several times with ethyl ether. The ether extracts, after being washed with water, were dried over sodium sulfate and stripped under vacuum to leave a yellow solid residue. This residue was recrystallized from absolute ethyl alcohol to give 1.7 g (61%) of the titled compound as yellow needles, m.p. 77°-78° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH:6](C)[CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1[C:11](=[O:16])/[C:12](/[CH3:15])=[CH:13]/[CH3:14].O1CCOC[CH2:18]1>>[CH3:1][C:2]12[C:13]([CH3:14])=[C:12]([CH3:15])[C:11](=[O:16])[CH:3]1[C:4]([CH3:10])([CH3:9])[CH:5]([CH3:18])[CH2:6][CH2:7]2
Reactant: C1COCCO1
Reactant: C/C=C(\C)C(=O)C1=C(C)CC(C)CC1(C)C
Product: CC1=C(C)C2(C)CCC(C)C(C)(C)C2C1=O

Procedure:
According to the same procedure described in Example 49, a solution of 2,4,6,6-tetramethyl-1-[2-methyl-crotonoyl]-1-cyclohexene (1.0 g.) in 10 ml. of dioxan was heated at 100° under nitrogen with acidic diatomaceous earth (0.2 g.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:32]=[CH:31][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27][C:28](=[O:30])[CH3:29])[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.N1C=CC=CC=1.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>C(Cl)Cl>[CH:39]1([S:42]([N:1]2[CH:5]=[C:4]([C:6]3[CH:32]=[CH:31][C:9]4[N:10]([C:13]5[CH:14]=[C:15]([NH:27][C:28](=[O:30])[CH3:29])[CH:16]=[C:17]([C:19]6[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=6[F:26])[CH:18]=5)[CH:11]=[N:12][C:8]=4[CH:7]=3)[CH:3]=[N:2]2)(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn[nH]c4)ccc32)c1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(S(=O)(=O)C5CC5)c4)ccc32)c1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of the compound of Example 326 (50 mg, 0.116 mmol) in DCM was added pyridine (0.5 ml) followed by cyclopropanesulfonyl chloride (20 mg, 0.139 mmol, 1.2 eq.). The mixture was stirred for 1 h, and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to give the product in 90% yield (42 mg). 1H NMR (400 MHz, CD3OD): δ 8.58 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.74-7.62 (m, 4H), 7.49 (s, 1H), 7.17-7.08 (m, 2H), 3.0 (m, 1H), 2.2 (s, 3H), 1.1 (d, 4H); LC-MS (ESI): Calculated mass: 533.5; Observed mass: 534.1 [M+H]+ (rt: 1.61 min).
Reaction SMILES: C([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)CCCCCCC.[CH2:49]([O:56]C1C=NC(C2C=CC(O)=CC=2)=NC=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>CN(C)C=O>[CH2:49]([O:56][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:38])[F:39])([F:29])[F:28])=[CH:19][CH:20]=2)=[N:13][CH:14]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: CN(C)C=O
Product: CCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (5.5 g, 15.0 mmol, Example 24) with 5-heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.5 mmol) in dimethylformamide and stirring at 120° C. overnight to provide product boiling at 195-210° C. at 0.3 torr (yield of 5.6 g).
Reaction SMILES: [CH:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([NH2:26])=O)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[CH:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:26])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(N2CCN(CCC3CCc4ccccc43)CC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCN(CCC3CCc4ccccc43)CC2)cc1
Reaction time: 2 h

Procedure:
A mixture of 4-[2-(indan-1-yl)ethyl]-1-(4-carboxamido)phenylpiperazine (CXII, EXAMPLE 77, 0.7 g, 2 mmol), phosphorous oxychloride (0.93 ml, 10 mmol) in dimethylformamide (20 ml) is heated at 80° for 2 hr. The mixture is stirred for 2 hr and quenched with sodium hydroxide (20%) until the pH>13. The mixture is extracted with ethyl acetate (800 ml), and the organic phase is washed with saline, dried (magnesium sulfate), filtered and concentrated. The concentrate is purified by liquid chromatography on silica gel 60 (400 g), eluting with hexane/ethyl acetate (1/1). The appropriate fractions homogeneous by TLC are combined and concentrated to give the free base of title compound, which is converted into the hydrochloric acid salt and crystallized from hexane/ethyl acetate to give the title compound, mp 157-158°, NMR (CDCl6, TMS) 7.62-6.92 and 3.94-1.46 δ.
Reaction SMILES: O[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:22]>C1(C)C=CC=CC=1>[Cl:22][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ncnc(O)c2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ncnc(Cl)c2CC1
Temperature: 90 °C

Procedure:
A mixture of tert-butyl 4-hydroxy-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate (4.3 g, 16.2 mmol) and POCl3 (2.3 ml) in toluene (30 mL) is heated at 90° C. for 1 hr. The solvent is removed in vacuo and EtOAc (30 ml) and water (30 ml) are added to the residue. NaHCO3 is carefully added until the pH of the aqueous layer is greater than 7. The layers are separated and the aqueous layer is extracted with EtOAc (2×30 ml). The combined extracts are washed with brine (50 ml) and dried (Na2SO4), and the solvent is evaporated. Flash column purification of the residue with EtOAc/hexane (6:1) provides the title compound as a light yellow solid.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][O:7][CH2:6][N:5]([CH2:9][C:10]2[S:14][C:13](SC3C=CC=CC=3)=[N:12][CH:11]=2)[C:4]1=[N:22][N+:23]([O-:25])=[O:24].ClCl>ClC1C=CC=CC=1>[Cl:1][C:13]1[S:14][C:10]([CH2:9][N:5]2[C:4](=[N:22][N+:23]([O-:25])=[O:24])[N:3]([CH3:2])[CH2:8][O:7][CH2:6]2)=[CH:11][N:12]=1
Reactant: CN1COCN(Cc2cnc(Sc3ccccc3)s2)C1=N[N+](=O)[O-]
Reactant: Cl
Agent: ClCl
Solvent: Clc1ccccc1
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a mixture of 300 g of aqueous hydrochloric acid (32%) and 150 g of chlorobenzene are added with stirring 183 g of 5-methyl-4-nitroimino-3-(2-phenylthiothiazol-5-ylmethyl)-perhydro-1,3,5-oxadiazine within 5 minutes. 124 g of chlorine are then passed into the mixture at 20 to 25° over a period of 4 hours. After stirring for a further 2 hours, the excess of chlorine is removed by introduction of nitrogen, and the aqueous phase (containing the title compound in hydrochloride form) is separated off and adjusted to pH 5 with aqueous sodium hydroxide solution (30%). The crystalline precipitate is filtered off, washed with water and dried at 50° in vacuo, yielding 132 g of the title compound (purity: 97%) melting at 132 to 135°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[C:3]=1[CH2:11][CH3:12].[N:13]#[C:14]Br.O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[C:3]([CH2:11][CH3:12])=[C:4]([CH3:10])[C:5]2[N:6]([C:14]([NH2:13])=[N:9][N:8]=2)[N:7]=1
Reactant: N#CBr
Reactant: CCc1c(Cl)nnc(NN)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1c(Cl)nn2c(N)nnc2c1C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
(6-Chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine (W3.007; 340 mg) was dissolved in ethanol/water (10/2 ml) at RT while stirring. Thereafter, cyanogen bromide (386 mg, dissolved in 5 ml of ethanol and 1 ml of water) was cautiously added dropwise. After stirring at RT for 5 h, the mixture was left to stand overnight and then the solvent was drawn off, and the residue was admixed with water. Once the residue had been alkalized with saturated potassium carbonate solution, it was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after filtering off the desiccant, dried under reduced pressure. 385 mg of the title compound were obtained. LC-MS rt: 0.62 min [M+H]+: 212.1 (met. b)