Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][C:10]2([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20](SC)=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Cl[C:27]1C=CC=C(C(OO)=O)C=1.[S:37](=[O:40])(O)[O-:38].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:25])[CH2:9][C:10]2([CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([S:37]([CH3:27])(=[O:40])=[O:38])=[CH:21][CH:22]=3)=[O:16])[CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=S([O-])O
Reactant: CSc1ccc(C(=O)CC2(CC(=O)c3ccc(F)cc3)CCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(=O)CC2(CC(=O)c3ccc(F)cc3)CCC2)cc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of 18.3 g (51.4 mmol) of 1-(4-fluorophenyl)-2-[1-[2-[4-(methylthio)phenyl]-2-oxoethyl]cyclobutan-1-yl]ethan-1-one (prepared in Step 5) in 200 mL of chloroform at 10° C. was slowly treated with 35.6 g (ca. 103 mmol) of solid m-chloroperbenzoic acid (50-60%). The reaction was allowed to stir for 30 minutes and treated with aqueous sodium bisulfite. The chloroform was removed in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate extracts were washed 3 times with saturated sodium bicarbonate and once with brine, dried (MgSO4), and concentrated in vacuo to give 19.27 g (97%) of 1-(4-fluorophenyl)-2-[1-[2-[4-(methylsulfonyl)phenyl]-2-oxoethyl]cyclobutan-1-yl]ethan-1-one as an oil: NMR (CDCl3) δ1.95-2.06 (M, 2H), 2.11 (t, J=7 Hz, 4H), 3.05 (s, 3H), 3.52 (s, 2H), 3.59 (s, 2H), 7.09 (t, J=9 Hz, 2H), 7.92-8.04 (m, 4H), 8.19 (d, J=9 Hz, 2H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:34]1[C:38]2=[N:39][CH:40]=[CH:41][CH:42]=[C:37]2[CH:36]=[CH:35]1.[CH3:43][CH2:44][C:45]([O-:47])=[O:46].[CH3:48][O:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH2:53]O>O1CCCC1>[CH3:48][O:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH2:53][N:34]1[C:38]2=[N:39][CH:40]=[CH:41][CH:42]=[C:37]2[CH:36]=[CH:35]1.[CH3:43][CH2:44][C:45]([O-:47])=[O:46]
Reactant: COc1cccc(CO)c1
Reactant: c1cnc2[nH]ccc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(Cn2ccc3cccnc32)c1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
0.089 mL (0.45 mmol) of diisopropyl azodicarboxylate is added dropwise under argon at 20° C., to a mixture of 260 mg (0.6 mmol) of supported triphenylphosphine (Argonaut PS—PPh3, loading 2.3 mmol/g), 57 mg (0.3 mmol) of 1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate (WO07/010,138) and 62 mg (0.45 mmol) of 3-methoxybenzyl alcohol in 2.5 mL of tetrahydrofuran. The reactor is then sealed and the mixture is stirred for 3 days at 20° C. After this time, the reaction mixture is filtered, the solid residue is washed with 5 mL of tetrahydrofuran and the filtrate is concentrated at reduced pressure to give the expected product, which is used as it is in the rest of the synthesis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.C[C:23](C)(C)[CH2:24][CH2:25][NH2:26].[C:29]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:26][CH:25]([CH2:24][CH3:23])[CH3:29])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: CC(C)(C)CCN
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(NC(C)CC)cc2OC1C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7a, Step 2) (0.5 g, 1.54 mmole) and 3,3-dimethylbutylamine (0.11 g, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil (0.58 g, 98%). No further purification was performed: GCMS m/z 377.00 (M+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([C@@H:25]2[C:29]([CH3:31])([CH3:30])[CH2:28][O:27][C:26]2=[O:32])[CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([C@@H:25]2[C:29]([CH3:30])([CH3:31])[CH2:28][O:27][C:26]2=[O:32])[CH2:14]1)=[O:11]
Reactant: CC1(C)COC(=O)[C@@H]1N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1(C)COC(=O)[C@@H]1N1C[C@H](c2cccc(F)c2)[C@@H](C=O)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 50.4 %

Procedure:
Dimethylsulfoxide (0.121 mL, 1.7 mmol) was added to a solution of oxalyl chloride (0.07 mL, 0.8 mmol) in 10 mL of CH2Cl2 at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 20 min., then a solution of dihydro-3-(R)-(3-(R)-(hydroxymethyl)-4-(S)-(3-fluorophenyl)-pyrrolidin-1-yl)-4,4-dimethyl-2(3H)furanone (200 mg, 0.65 mmol) in 1 mL of CH2Cl2 was added. The mixture was stirred at −78° C. for an additional 45 min., then triethylamine (0.46 mL, 3.3 mmol) was added and the cold bath was removed. After the reaction mixture had warmed to room temperature, it was diluted with CH2Cl2 and washed with 1N NaOH and brine. The solution was dried over Na2SO4, filtered and concentrated to afford 100 mg (50% yield) of the title compound. 1H NMR (400 MHz, CDCl3). δ1.17 (s, 3H), 1.24 (s, 3H), 3.08-3.24 (m, 4H), 3.35 (t, 1H, J=8.4 Hz), 3.55 (dd, 1H, J=5.9, 9.6 Hz), 3.66 (dd, 1H, J=7.9, 16 Hz), 3.91 (d, 1H, J=9.0 Hz), 3.98 (d, 1H, J=9.0 Hz), 6.95-6.97 (m, 1H), 7.04 (dt, 1H, J=2.1, 10 Hz), 7.10 (d, 1H, J=7.8 Hz), 7.27-7.32 (m, 1H), 9.71 (d, 1H, J=2.0 Hz). ESI-MS. M/z; (M+H)=306.2.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.O1CCCC1>[Ni].C(N(CC)CC)C>[C:4]1([C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][O:3]1)=[O:5]
Reactant: O=C1OC(Cl)c2ccccc21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCc2ccccc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A 1-liter lift magnet autoclave is charged with 110 g of 3-chlorophthalide, 10 g of nickel catalyst RCH 55/10 (commercial product of Farbwerke Hoechst AG) and 400 ml of tetrahydrofuran to which 66 g of triethylamine is added. After purging the air with nitrogen, hydrogen is pumped in to a pressure of 10 bars, and the temperature is raised, with stirring, to 65° C. The hydrogen consumption is compensated by additions in the range between 10 and 20 bars for a period of 41/2 hours. After the absorption of hydrogen ceases, the catalyst and precipitated salt are filtered out and the solvent is withdrawn. After distillation of the residue between 88° and 90° C. and 0.2 Torr, 77.5 g of phthalide is obtained, of a melting point of 71° C. (gas-chromatographic analysis 98.95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24]>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:24]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(C(F)(F)F)c4)cc23)CC1
Yield: 72.2 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 17.1 mg (0.09 mMol) 3-trifluoromethylbenzoic acid, 8.7 mg (72%) of the title compound were recovered.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21](COCC[Si](C)(C)C)[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3NC4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3CCC)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(CCc3ccccc3)c2c1=O
Agent: CCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(CCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
Reaction was carried out in the same manner as in Example 6-(c) except for using 364 mg (0.641 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-phenethyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 21-(b) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-5-(2-trimethylsilylethoxymethyl)-3-propyl-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the solid was collected by filtration from the reaction suspension and washed with 1,4-dioxane. To the obtained solid were added methanol and 28% aqueous ammonia, and the mixture was stirred at room temperature for 16 hours. Then, water was added to the solution, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain 224 mg of the title compound as a white solid. (Yield: 80%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:23])[C:13](=[O:22])[CH2:14][N:15]2[CH2:20][CH2:19]N(C)[CH2:17][CH2:16]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].ClCC(N(C1C=CC([N+]([O-])=O)=C(OC)C=1)C)=[O:27].N1CCOCC1.CN1CCNCC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:23])[C:13](=[O:22])[CH2:14][N:15]2[CH2:20][CH2:19][O:27][CH2:17][CH2:16]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N(C)C(=O)CCl)ccc1[N+](=O)[O-]
Reactant: COc1cc(N(C)C(=O)CN2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: CN1CCNCC1
Solvent: C1COCCN1
Product: COc1cc(N(C)C(=O)CN2CCOCC2)ccc1[N+](=O)[O-]

Procedure:
N-(3-Methoxy-4-nitro-phenyl)-N-methyl-2-morpholin-4-yl-acetamide was prepared in an analogous fashion to N-(3-Methoxy-4-nitro-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-acetamide of Example 471a by treating the in situ generated 2-Chloro-N-(3-methoxy-4-nitro-phenyl)-N-methyl-acetamide with morpholine rather than 1-methyl piperazine. After workup the crude product was pumped under high vacuum to remove majority of morpholine, as some carried along in organic phase after extraction. Small residual amounts were separated after subsequent reduction via trituration with Et2O. (1.19 g, 73%). LC/MS (E/I+) 310.11 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:11][C:12]1[CH:13]=[C:14]([NH:18][NH2:19])[CH:15]=[CH:16][CH:17]=1>CC(O)=O.CCO.O>[Cl:11][C:12]1[CH:13]=[C:14]([NH:18][N:19]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][NH2:1])[CH:15]=[CH:16][CH:17]=1
Reactant: NNc1cccc(Cl)c1
Reactant: NCC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: NCC(=NNc1cccc(Cl)c1)c1ccccc1
Yield: 86.1 %

Procedure:
A mixture of 3.12 g 2-aminoacetophenone and 3.29 g 3-chlorophenylhydrazine in 4 ml HOAc and 20 ml EtOH was refluxed for one hour. The cooled reaction mixture was diluted with water and the precipitate was collected, washed with water, and dried to give 5.16 g solid. Recrystallization from methanol gave 2.12 g solid, m.p. 131°-134° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9]N)[CH:6]=[CH:7][CH:8]=1.Br[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C.Cl.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>C(O)C>[Cl:2][C:3]1[C:4]2[C:31]3[CH2:30][N:29]([CH3:28])[CH2:34][CH2:33][C:32]=3[N:9]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:5]=2[CH:6]=[CH:7][CH:8]=1.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[C:31]3[CH2:30][N:29]([CH3:28])[CH2:34][CH2:33][C:32]=3[N:9]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:5]=2[CH:4]=1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1cccc(Cl)c1
Reactant: BrCCC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3c(Cl)cccc3n2CCC2CCCCC2)C1
Product: CN1CCc2c(c3ccc(Cl)cc3n2CCC2CCCCC2)C1

Procedure:
Preparation of the title compounds was carried out according to General Method 8. 3-Chlorophenylhydrazine hydrochloride (5 g, 27.9 mmol), 1-bromo-2-cyclohexylethane (4.37 ml, 27.9 mmol), triethyl amine (11.66 ml, 83.7 mmol) and N-methyl-4-piperidone hydrochloride (4 g, 27.9 mmol) were combined in ethanol (30 ml) to obtain 9-chloro-5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 7-chloro-5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole after on purification on silica gel (230-400 mesh) chromatography eluting with acetone-hexane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv.) in anhydrous THF.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N([CH2:44][CH3:45])CC)C>CN(C)C=O.C(OCC)(=O)C>[C:15]([O:14][C:12]([NH:11][CH2:10][C:3]1[CH:4]=[N:5][N:6]([CH2:7][CH2:8][O:9][C:25]([C:45]2[CH:44]=[CH:37][CH:32]=[CH:33][CH:34]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:2]=1[NH:1][C:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCN(CC)CC
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1cnn(CCO)c1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-4-(tert-butoxycarbonylaminomethyl)-1-(2-hydroxyethyl)-1H-pyrazole (243 g) in N,N-dimethylformamide (1.82 L) was added triphenylmethyl chloride (581 g), triethylamine (452 ml) and N,N-dimethylaminopyridine (9.91 g) successively. The reaction mixture was stirred at 70° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (twice) and brine, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography to give 4-(tert-butoxycarbonylaminomethyl)-5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazole, which was crystallized from diisopropyl ether/hexane (1:2). The resulting crystals were collected by filtration on a glass filter, washed with diisopropyl ether/hexane (1:2) and dried in vacuo to give the objective compound (480 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](O)(=[O:20])=[O:19])=[CH:14][CH:13]=1.CS(OCCCCOS(C)(=O)=O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Br:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:3]=1
Reactant: Brc1cccc2c1OCC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CS(=O)(=O)OCCCCOS(C)(=O)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2cc(Br)c3c(c2)CCO3)cc1
Yield: 113.2 %

Procedure:
7-Bromo-1,2-dihydrobenzofuran (64 mg, 0.3 mmol; Intermediate 77) and para-toluenesulfonic acid monohydrate (62 mg, 0.3 mmol) were mixed and then a 1:10 mixture (by weight) of methanesulfonic and phosphorous pentoxide (1 mL) was added. The resultant mixture was stirred over night at room temperature and was then poured onto ice/water. The obtained crystalline material was filtered and dried to give 120 mg of the title product. 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 3.33 (t, 2H), 4.73 (t, 2H), 7.29 (d, 2H), 7.65 (d, 1H), 7.79 (d, 2H), 7.89 (d, 1H); GC-MS (EI+) for C15H13BrSO3 m/z 354 (M+H)+.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)SC)#[N:2].[CH2:21]([NH2:23])[CH3:22]>>[N:16]1[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[NH:13][C:12]=1[CH2:11][S:10][CH2:9][CH2:8][NH:7][C:4]([NH:3][C:1]#[N:2])=[N:23][CH2:21][CH3:22]
Reactant: CCN
Reactant: CSC(=NCCSCc1nc2ccccc2[nH]1)NC#N
Product: CCN=C(NC#N)NCCSCc1nc2ccccc2[nH]1

Procedure:
Reacting N-cyano-N'-[2-(2-benzimidazolylmethylthio)ethyl]-S-methylisothiourea with ethylamine by the procedure of Example 4 gives N-[2-(2-benzimidazolylmethylthio)ethyl]-N'-cyano-N"-ethylguanidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-6-methoxy-6-oxohexanoic acid (23.5 g, 85 mmol) in anhydrous THF (100 mL) was added Et3N (14.2 mL, 102 mmol, 1.2 equiv.). The solution was cooled down to 0° C. and isobutyl chloroformate (12.2 mL, 93.5 mmol, 1.1 equiv.) was added dropwise. The solution was stirred for 30 min. The precipitate was filtered off. The filtrate was cooled down to 0° C. and a suspension of sodium borohydride (6.5 g, 170 mmol, 2 equiv.) in H2O (3 mL) was added in one portion. The reaction was stirred for 1 h, and quenched with saturated NH4Cl. THF was removed. The residue was dissolved into EtOAc (400 mL) and extracted with saturated NH4Cl twice. The organic layers were combined, dried and concentrated. The residue was purified on silica gel column (hexanes/EtOAc 1:1) to give (S)-methyl 5-(tert-butoxycarbonylamino)-6-hydroxyhexanoate (20 g, 90%) as a colorless oil. LRMS (M−Boc+H+) m/z 162.1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:11][N:10]=[C:9](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)(=O)=O.[NH3:30]>O1CCOCC1>[C:22]1(/[CH:21]=[CH:20]/[C:9]2[N:8]=[C:7]([NH2:30])[C:12]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Oc1nc(/C=C/c2ccccc2)ncc1OC1CCCCO1)C(F)(F)F
Reactant: N
Solvent: C1COCCO1
Product: Nc1nc(/C=C/c2ccccc2)ncc1OC1CCCCO1
Yield: 63 %

Procedure:
Crude 2-[(E)-2-phenylethenyl]-5-(tetrahydro-2H-pyran-2-yloxy)-4-pyrimidinyl trifluoromethanesulfonate (6.8 mmol) was reacted with a 0.5M solution of ammonia in 1,4-dioxane (136 mL) in a pressure bottle at 60° C. for 24 h. The reaction was concentrated under vacuum, the residue was taken up in DCM and washed with water, saturated aq. NaHCO3, and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica gel) using a MeOH/DCM gradient to yield the desired compound as a tan solid (1.28 g, 63% for two steps).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH2:3][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Product: CC(C)(CN1CCCC1)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with pyrrolidine to provide the title compound: H1 NMR (400 MHz, CDCl3) 1.56 (s, 6H), 1.61 (m, 4H), 2.35 (m, 4H), 2.70 (m, 4H), 7.60 (s,1H), 7.92 (s, 1H); MS m/z 239.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:26][CH:23]1[CH2:25][CH2:24]1)=[O:9]
Reactant: NC1CC1
Reactant: Cc1ccc(Cl)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)cc1C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a toluene solution (1 M) of 5-chloro-2-methylbenzoic acid (1 eq.) and DMF (1.2 eq.) was added at 0° C. oxalyl chloride (1.2 eq.) dropwise over 1 h. The resulting solution was stirred at 0° C. for 2 h before the volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane (1 M), cooled to 0° C. and added sequentially cyclopropylamine (1.5 eq.) and Hunig's base (2 eq.) dropwise. The resulting suspension was stirred at RT for 18 h. The reaction was quenched with 1 N aq. HCl and extracted with dichloromethane. The combined organic extracts were dried over MgSO4, filtered and the filtrate concentrated in vacuo to ˜1/3 in volume. The resulting white suspension was added an equivalent volume of hexanes and the title compound was isolated via vacuum filtration.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:15][CH2:14][N:13](C#N)[CH2:12][CH2:11]2)=[N:2]1.[OH-].[Na+]>OS(O)(=O)=O>[N:10]1([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: N#CN1CCN(c2n[nH]c3ccccc23)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(N3CCNCC3)n[nH]c2c1
Yield: 73 %

Procedure:
A mixture of 4-(1H-indazol-3-yl)-1-piperazinecarbonitrile (8.0 g, 40 mmol) and 25% H2SO4 (100 ml) was stirred at reflux for 4.5 hours. The reaction was cooled in an ice bath and made basic by the dropwise addition of ,50% NaOH. The basic solution was extracted with ethyl acetate. The ethyl acetate was washed with H2O, dried with MgSO4, and concentrated to afford 5.2 g (73% of the desired compound, as a solid. The solid was recrystallized twice from toluene to afford 3.0 g of 3-(1-piperazinyl)-1H-indazole, m.p.=153°-155° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[S:20][CH:21]=[CH:22][N:23]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: Brc1nccs1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nccs3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 2-bromo-1,3-thiazole (commercially available).