Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[C:34]([O:38][C:39]([NH:41][C:42]([CH3:62])([CH3:61])[CH2:43][C:44]1[C:52]2[C:47](=[C:48](OS(C(F)(F)F)(=O)=O)[CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.[Cl-].[Na+].O.C(OCC)(=O)C>[C:34]([O:38][C:39](=[O:40])[NH:41][C:42]([CH3:62])([CH3:61])[CH2:43][C:44]1[C:52]2[C:47](=[C:48]([C:2]3[CH:10]=[CH:9][C:5]([C:6](=[O:7])[NH2:8])=[CH:4][CH:3]=3)[CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: CC(C)(Cc1c[nH]c2c(OS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(Cc1c[nH]c2c(-c3ccc(C(N)=O)cc3)cccc12)NC(=O)OC(C)(C)C
Temperature: 20 °C
Yield: 58.5 %

Procedure:
A solution of 4-bromobenzamide (150 mg, 0.75 mmol), bis(pinacolato)diboron (209 mg, 0.825 mmol), potassium acetate (0.221 g, 2.25 mmol) and {1,1′-bis(diphenylphosphino)-ferrocene}dichloropalladium dichloromethane complex (18 mg, 0.0225 mmol) in dimethylsulfoxide (5 mL) is heated to 80° C. for two hours. The mixture is cooled to 20° C. and trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (262 mg, 0.600 mmol), {1,1′-bis(diphenylphosphino)-ferrocene}dichloropalladium dichloromethane complex (18 mg, 0.0225 mmol) and sodium carbonate (1.9 mL, 2M, 3.75 mmol) are added. The mixture is heated to 80° C. overnight. The mixture is diluted with brine and ethyl acetate. The organic fraction is washed seven times with brine, then dried over anhydrous sodium sulfate, filtered and evaporated. The residue is purified using silica gel chromatography (dichloromethane/10% methanol, 0.7M ammonia in dichloromethane gradient elution) to give 143 mg of {2-[7-(4-carbamoyl-phenyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (58%). FDMS m/e=408 (M++1).
Reaction SMILES: [Li]CCCC.CC1C=CC(S(O[CH2:17][C:18]2([CH2:34][OH:35])[O:23][C:22]3[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:21]=3[N:20]3[N:31]=[N:32][N:33]=[C:19]23)(=O)=O)=CC=1>C1COCC1>[N+:28]([C:26]1[CH:25]=[CH:24][C:22]2[O:35][CH2:34][C:18]3([C:19]4[N:20]([N:31]=[N:32][N:33]=4)[C:21]=2[CH:27]=1)[CH2:17][O:23]3)([O-:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)OCC2(CO)Oc3ccc([N+](=O)[O-])cc3-n3nnnc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)-n1nnnc1C1(CO2)CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
nBuLi (1.6 M in hexanes, 110 μL, 0.18 mmol) was added dropwise over 5 min to a stirred solution of (4-(hydroxymethyl)-8-nitro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-4-yl)methyl 4-methylbenzenesulfonate (70 mg, 0.16 mmol) in THF (10 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 hr, then heated to reflux and stirred for 2 hr. After allowing to cool, the mixture was concentrated under vacuum to leave a crude residue. The residue was purified by preparative thin-layer chromatography using DCM/EtOAc (9:1) as eluent to give the product (16 mg, 38% yield) as a solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([CH:10]([OH:12])[CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].[CH3:23]I>CN(C)C=O>[CH3:23][O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[NH:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([OH:12])[CH3:11])[C:4]=1[Cl:3]
Reactant: CI
Reactant: CC(O)c1cccc(Nc2ccccc2C(=O)O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Nc1cccc(C(C)O)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
Sodium hydride (0.48 g, 19.9 mmol) is added to a solution of 2-[[2-chloro-3-(1-hydroxyethyl)phenyl]amino]benzoic acid (5.8 g, 19.9 mmol) in dimethylformamide (15 mL) at room temperature. After 15 minutes, the reaction mixture is cooled to 0° C, and methyl iodide (2.8 g, 19.9 mmol) is added dropwise. The reaction mixture is stirred at room temperature overnight, and then partitioned between water and ether. The organic layer is washed with water and brine, dried over magnesium sulfate, and evaporated. Recrystallization of the residue from ether/hexane gives pure 2-[[2-chloro-3-(1-hydroxyethyl)phenyl]amino]benzoic acid methyl ester (4.6 g, 76%), mp=94-95° C.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH:20]3[CH2:24][CH2:23][O:22][CH2:21]3)=[CH:18][N:19]=[C:14]2[C@H:13]([NH:25]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>O1CCOCC1>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH:20]3[CH2:24][CH2:23][O:22][CH2:21]3)=[CH:18][N:19]=[C:14]2[C@H:13]([NH2:25])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3CCOC3)cnc21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3CCOC3)cnc21
Reaction time: 2.5 h

Procedure:
Hydrochloric acid (4.0 M in dioxane; 3 mL, 12.0 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(tetrahydrofuran-3-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (113 mg, 0.261 mmol) in 1,4-dioxane (3 mL). After 2.5 h, the reaction was concentrated to give the title compound as a bis hydrochloride salt (117 mg). MS 334.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:18]([C:20]1[C:21]([OH:30])=[C:22]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][C:25]=1O)[CH3:19]>>[C:27]([C:22]1[CH:23]=[CH:24][C:25]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])=[CH:7][CH:8]=2)=[C:20]([CH2:18][CH3:19])[C:21]=1[OH:30])(=[O:29])[CH3:28]
Reactant: N#Cc1cncc(Sc2ccc(CO)cc2)c1
Reactant: CCc1c(O)ccc(C(C)=O)c1O
Product: CCc1c(OCc2ccc(Sc3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O
Yield: 37.5 %

Procedure:
Using the method of Preparation 160 using 5-(4-(hydroxymethyl)phenylthio) nicotinonitrile (1.20 g, 4.95 mmol) and 1-(3-ethyl-2,4-dihydroxyphenyl)ethanone (937 mg, 5.20 mmol) affords the title compound (750 mg, 37%): 1H NMR (CDCl3) δ 1.15 (t, J=7.64 Hz, 3H), 2.57 (s, 3H), 2.76 (q, J=7.6 Hz, 2H), 5.22 (s, 2H), 6.47 (d, J=9.0 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H),), 7.52 (d, J=8.2 Hz, 2H), 7.60 (d, J=9.0 Hz, 1H), 7.63 (dd, J=2.0, 2.3 Hz, 1H), 8.64 (t, J=2.0 Hz, 2H), 12.75 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7](CCC(O)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)CCc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2ccccn2)cc1
Temperature: 100 °C
Yield: 91 %

Procedure:
Pd(PPh3)4 (3.0 g, 2.6 mmol) was added to a solution of 2-chloro-3-carboxyethylpyridine (25 g, 134.7 mmol), phenylboronic acid (21.04 g, 172.6 mmol) and K2CO3 (55.1 g, 399 mmol) in 1,4-dioxane (200 mL) and water (200 mL). The reaction mixture was heated at 100° C. for 2 h. The solution was then cooled to room temperature and the dioxane was removed under reduced pressure. The resulting aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (Na2SO4), filtered through celite, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 10-100% EtOAc/hexanes) to get the 2-phenylpyridine derivative in 91% yield (27.98 g). LC-MS Rt (retention time): 2.45 min, MS: (ES) m/z 228 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=2)[N:5]=1)([OH:3])=[O:2].[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:22]=CC=C[CH:18]=1.C(O)C=C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:22]([O:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=2)[N:5]=1)=[O:3])[CH:17]=[CH2:18]
Reactant: O=C(O)c1ccc2cc([N+](=O)[O-])ccc2n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: C=CCO
Product: C=CCOC(=O)c1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of 2-carboxy-6-nitroquinoline (1.5 g; 6.8 mM) in THF (30 ml) was added triphenylphosphine (2.7 g; 10.2 mM), allyl alcohol (0.7 ml; 10.2 mM) and DEAD (1.63 ml; 10.2 mM). After stirring at ambient temperature for 30 minutes, the mixture was extracted with ethyl acetate and purified by subjecting to flash chromatography, eluting with ethyl acetate/petroleum ether (40/60) to give 2-allyloxycarbonyl-6-nitroquinoline (1.2 g; 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=O)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:13][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Solvent: CO
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 83.6 %

Procedure:
4-(3,4-Dinitro-benzyl)-niorpholme (2.815 kg, 10.53 mol, 1.O wt) and methanol (12.00 L, 4.3 vol) were charged to a flask under nitrogen and heated to 65 to 7O° C. The temperature was maintained until complete dissolution. The mixture was then cooled to and aged at 0 to 5° C. for 1 hour. The solids were isolated by filtration. The filter-cake was washed with methanol (2×1.50 L, 2×0.5 vol) and dried under vacuum at 35 to 45° C. to give 4-(3,4-dinitro-benzyl)-morpholine (2.353 Kg, 83.5% based on input Stage 2, 82.5% overall yield based on total input Stage 1 material) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14]#[N:15])=[N:6]1.C[O-].[Na+].[C:23]([OH:26])(=[O:25])[CH3:24].[Cl-].[NH4+:28]>CO>[C:23]([OH:26])(=[O:25])[CH3:24].[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:28])[NH2:15])=[N:6]1
Reactant: [NH4+]
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncncc12
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, 685 mg (purity 84%, approx. 2.273 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile were dissolved in 8 ml of absolute methanol. 127 mg (2.273 mmol) of sodium methoxide were added and the mixture was stirred at RT for 1 h. 532 mg (8.864 mmol) of acetic acid and 299 mg (2.273 mmol) of ammonium chloride were added and the mixture was boiled under reflux for 45 min. The reaction mixture was concentrated, the residue was stirred with 20 ml of 1N sodium hydroxide solution, and the precipitate was filtered off with suction and dried under high vacuum. 610 mg (purity 86%, 86% of theory) of the target compound were obtained.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:66]=[CH:65][N:64]([CH2:67][CH2:68][C:69]5[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=5)[N:63]=4)=[CH:60][N:59](S(C4C=CC(C)=CC=4)(=O)=O)[C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[CH:85]1[CH2:90][CH2:89][N:88]([C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][CH2:86]1.[OH-].[Na+]>C1COCC1.CO.O>[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:66]=[CH:65][N:64]([CH2:67][CH2:68][C:69]5[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=5)[N:63]=4)=[CH:60][NH:59][C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[CH:85]1[CH2:90][CH2:89][N:88]([C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][CH2:86]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(CCc4ccccc4)n3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5ccn(CCc6ccccc6)n5)c4c3)cc2F)CC1
Yield: 84 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(2-fluoro-4-(3-(1-phenethyl-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (102 mg, 0.141 mmol) was hydrolyzed by sodium hydroxide (57 mg, 1.418 mmol) in THF/methanol/water (12/4/4 ml) to yield 67 mg (84% yield) of the titled compound. MS: m/z=566.5 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH:12]3[CH2:14][CH2:15][N:9]2[CH2:10][CH2:11]3)[CH:5]=[N:6][CH:7]=1.[OH-].[NH4+:17]>CO.C(Cl)(Cl)Cl.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:17][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH:12]3[CH2:14][CH2:15][N:9]2[CH2:10][CH2:11]3)[CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncc(C2CC3CCN2CC3)c1
Reactant: [NH4+]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cncc(C2CC3CCN2CC3)c1
Temperature: 180 °C

Procedure:
2-(5-Bromo-3-pyridyl)-1-azabicyclo[2.2.2]octane (120 mg, 0.449 mmol) was mixed with aqueous ammonium hydroxide (20 mL, 28%) in a sealed tube, then copper sulfate (200 mg) was added and the reaction mixture was heated at 180° C. for 14 h. The reaction mixture was allowed to cool to ambient temperature and then extracted with chloroform (4×20 mL). The combined organic extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to afford a dark syrup. This crude product was subjected to column chromatography, using chloroform methanol: triethylamine (9:1:1) as eluent, to yield 2-(5-amino-3-pyridyl)-1-azabicyclo[2.2.2]octane as a light brown solid (20 mg). An impure fraction was also obtained, which afforded a brown solid (40 mg), found to be mostly the desired compound with minor impurities (total yield ˜65%). A sample of the free base (20 mg, 0.098 mmol) was dissolved in ethanolic HCl (2 mL) and the mixture sonicated for 5 min. The solvent was removed by rotary evaporation to yield a viscous oil, which solidified upon standing. Recrystallization from ethanol: ether (9:1) afforded the trihydrochloride salt of the product as a brown solid (20 mg), m.p. 210° C. with decomposition.
Reaction SMILES: [CH3:1][NH2:2].[CH:3]([N:6]1[C:11]([CH3:12])=[CH:10][C:9](=[O:13])[CH2:8][S:7]1(=[O:15])=[O:14])([CH3:5])[CH3:4]>CO>[CH:3]([NH:6][S:7]([CH2:8][C:9](=[O:13])[CH:10]=[C:11]([NH:2][CH3:1])[CH3:12])(=[O:15])=[O:14])([CH3:5])[CH3:4]
Reactant: CC1=CC(=O)CS(=O)(=O)N1C(C)C
Reactant: CN
Solvent: CO
Product: CNC(C)=CC(=O)CS(=O)(=O)NC(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A slow stream of dry methylamine was introduced at 20°-25° during 1 hour into a suspension of 4 g of 2-isopropyl-3-methyl-1,2-thiazin-5(6H)-one 1,1-dioxide in 40 ml of methanol, whereby a clear yellow solution resulted after about 30 minutes. Thereupon, the mixture was stirred further at room temperature for 5 hours, concentrated to dryness under reduced pressure and the crystalline residue was recrystallized from isopropyl. There were obtained 3.8 g of N-isopropyl-4-methylamino-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 83°-85°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([O:29][C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:23]=2[N:24]=1.[CH3:34][NH:35][CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:34][N:35]([CH3:36])[C:16]([CH2:15][CH2:14][NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:19][C:20]3[S:21][C:22]4[CH:28]=[C:27]([O:29][C:30]([F:32])([F:33])[F:31])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])=[O:17]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCC(=O)O)ccc21
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide (38 mg) was prepared by following General Procedure F using 3-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionic acid (48 mg), dimethyl amine (0.3 ml, 1.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 508. 1H NMR (DMSO-d6, 400 MHz): δ 8.41 (t, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.73 (m, 2H), 7.46 (m, 1H), 7.35 (d, 1H), 7.34 (m, 1H), 3.66 (s, 3H), 3.51-3.46 (q, 2H), 2.98 (s, 3H), 2.84 (s, 3H), and 2.62 (t, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>C(OCC)(=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([F:14])([F:15])[F:16])[C:7]([O:9][CH2:22][CH3:23])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1

Procedure:
3-Nitro-4-(trifluoromethyl)benzoic acid (10 g, 43 mmol) was taken up in 100 ml of ethanol and sulfuric acid (11 ml) was added to the mixture. The reaction was heated to reflux for 12 hours. The volatiles were removed in vacuo. The residue obtained was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with an aqueous solution of saturated sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate and the volatiles removed in vacuo to give ethyl 3-nitro-4-(trifluoromethyl)benzoate a clear yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:9]2=[O:37])[S:5][CH:6]=1.[ClH:38]>O1CCOCC1>[ClH:38].[CH3:1][C:2]1[N:3]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:9]2=[O:37])[S:5][CH:6]=1
Reactant: Cc1csc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1csc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of tert-butyl 4-{1-[(4-methyl-1,3-thiazol-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (500 mg; compound B13) in a solution of hydrogen chloride in 1,4-dioxane (7 ml, 4.0 M) is stirred for 2.5 h at RT. The suspension is filtered and the filter cake is washed with 1,4-dioxane to give the title compound as a solid.
Reaction SMILES: [CH:1]1([N:7]([CH2:54][CH2:55]N2CC(C)(C)NC(C)(C)C2=O)[C:8]2[N:13]=[C:12]([N:14]([CH:28]3C[CH2:32][CH2:31][CH2:30][CH2:29]3)CCN3CC(C)(C)NC(C)(C)C3=O)[N:11]=[C:10]([N:34]([CH:48]3[CH2:53][CH2:52]CC[CH2:49]3)[CH2:35][CH2:36][N:37]3[CH2:42][C:41]([CH3:44])([CH3:43])[NH:40][C:39]([CH3:46])([CH3:45])[C:38]3=[O:47])[N:9]=2)[CH2:6][CH2:5]CCC1.C1(NCCN2CC(C)(C)NC(C)(C)C2=O)CCCCC1.N1C(Cl)=NC(Cl)=NC=1Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[N:14]1([C:12]2[N:13]=[C:8]([N:7]3[CH2:1][CH2:6][CH2:5][CH2:55][CH2:54]3)[N:9]=[C:10]([N:34]([CH:48]([CH3:49])[CH2:53][CH3:52])[CH2:35][CH2:36][N:37]3[CH2:42][C:41]([CH3:43])([CH3:44])[NH:40][C:39]([CH3:46])([CH3:45])[C:38]3=[O:47])[N:11]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC1(C)CN(CCN(c2nc(N(CCN3CC(C)(C)NC(C)(C)C3=O)C3CCCCC3)nc(N(CCN3CC(C)(C)NC(C)(C)C3=O)C3CCCCC3)n2)C2CCCCC2)C(=O)C(C)(C)N1
Agent: CC1(C)CN(CCNC2CCCCC2)C(=O)C(C)(C)N1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(C)N(CCN1CC(C)(C)NC(C)(C)C1=O)c1nc(N2CCCCC2)nc(N2CCCCC2)n1
Reaction time: 10 h

Procedure:
In a manner analogous to that described hereinabove, a compound identified as 2,4,6-tris[cyclohexyl[2-(3,3,5,5-tetramethyl-2-oxo-1-piperazinyl)ethyl]amino]-1,3,5-triazine which has the following structure: ##STR27## is prepared by reacting 0.046 mole 1-[2-(cyclohexylamino)ethyl]-3,3,5,5-tetramethyl-2-piperazinone and 0.01 mole cyanuric chloride, 1.2 g sodium hyroxide and 150 ml toluene. The reaction was carried out at 200° C. for 10 hr. The resulting light straw colored solid isolated was recrystallized from acetone and analyzed. It had a m p of 179°-180° C. and was off-white in color.
Reaction SMILES: CS[C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3Cl)[O:11][CH2:12][C:6]2=[N:5][N:4]=1.[CH3:25][O-:26].[Na+]>CO>[O:26]1[CH2:12][CH2:6][N:7]([C:3]2[N:7]3[C:8]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=4[CH:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[O:11][CH2:12][C:6]3=[N:5][N:4]=2)[CH2:3][CH2:25]1
Reactant: C[O-]
Reactant: CSc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Agent: [Na+]
Solvent: CO
Product: Clc1ccc2c(c1)C(c1ccccc1)OCc1nnc(N3CCOCC3)n1-2
Reaction time: 4 h
Yield: 130 %

Procedure:
To a suspension of Compound 15 (0.76 g) prepared in Example 8-(1) in methanol (20 ml) is added sodium methoxide (0.119 g), and the mixture is stirred for 4 hours, allowed to stand overnight, and concentrated. The residue is extracted with chloroform and the extract is washed with water, dried, and concentrated. The residue is washed with ethyl acetate to give Compound 19 (0.5 g) in 66.5% yield.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1.[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:27][CH2:28][N:29]([C:38]([N:33]6[CH2:37][CH2:36][CH2:35][CH2:34]6)=[O:39])[CH2:30][CH2:31]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: O=C(Cl)N1CCCC1
Agent: Cl
Product: CC1Cc2ccc(C3CCN(C(=O)N4CCCC4)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 138 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine HCl salt and 1-pyrrolidinecarbonyl chloride. LCMS (M+H)+: m/z=519.2.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][CH2:14][CH2:15][CH:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH3:13][CH2:14][CH2:15][CH:16]([NH:20][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(N)CCC
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NC(CCC)CCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 4-heptylamine as starting materials to give the aimed compound.