Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1.C(O)(C)C>O1CCCC1.O>[CH3:3][C:4]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][N:16]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: CC1([C@H]2CC[C@@H](O)CC2)CC1
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CC1([C@H]2CC[C@@H](Oc3ncnc4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.32 g (10.8 mmol) of sodium hydride (80% dispersion in mineral oil) was added to a solution of 1.7 g (7.9 mmol) of cis-4-(1-methylcyclopropyl)cyclohexanol in 20 ml of tetrahydrofuran, and the mixture was heated under reflux for 3 hours. It was then cooled to room temperature, 1.2 g (7.2 mmol) of 4-chloroquinazoline dissolved in 5 ml of tetrahydrofuran were added, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, isopropanol was added to the reaction solution, which was subsequently stirred for 15 minutes and poured into water, after which extraction was carried out with diethyl ether. The organic phase was dried and concentrated. The residue was purified by chromatography on silica gel with petroleum ether/ethyl acetate 3:1. 1.2 g (62% of theory) were obtained of a colorless oil, which gradually solidified.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O.[NH2:40][C:41]1([C:62]([NH2:64])=[O:63])[CH2:46][CH2:45][N:44]([S:47](/[CH:50]=[CH:51]/[C:52]2[C:57]([CH3:58])=[CH:56][C:55]([NH:59][CH3:60])=[CH:54][C:53]=2[CH3:61])(=[O:49])=[O:48])[CH2:43][CH2:42]1.C(N(C(C)C)CC)(C)C.CC(C)([O-])C.[K+]>CN(C=O)C.C(O)C>[CH3:58][C:57]1[CH:56]=[C:55]([NH:59][CH3:60])[CH:54]=[C:53]([CH3:61])[C:52]=1/[CH:51]=[CH:50]/[S:47]([N:44]1[CH2:43][CH2:42][C:41]2([N:40]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:39])[NH:64][C:62]2=[O:63])[CH2:46][CH2:45]1)(=[O:49])=[O:48]
Reactant: CNc1cc(C)c(/C=C/S(=O)(=O)N2CCC(N)(C(N)=O)CC2)c(C)c1
Reactant: O=C(O)CCCCCCCCCCCO
Agent: CC(C)(C)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(C)c(/C=C/S(=O)(=O)N2CCC3(CC2)N=C(CCCCCCCCCCCO)NC3=O)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.9 %

Procedure:
HATU (57 mg, 0.149 mmol) was added to a solution of 12-hydroxy-dodecanoic acid (33 mg, 0.149 mol), 4-amino-1-[(E)-2-(2,6-dimethyl-4-methylamino-phenyl)-ethenesulfonyl]-piperidine-4-carboxylic amide (50 mg, 0.136 mmol) and diisopropylethylamine (71 μL, 0.47 mmol) in DMF (1.3 ml) at 0° C., and the mixture was stirred at room temperature for 1.5 hours. Ethanol (2.6 ml) and potassium t-butoxide (76 mg, 0.678 mmol) were added to the reaction mixture, and the mixture was heated with stirring at 70° C. for three hours. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution, and water was then added, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 8-[(E)-2-(2,6-dimethyl-4-methylamino-phenyl)-ethenesulfonyl]-2-(11-hydroxy-undecyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (58.7 mg, 79%).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH:6]([N:16]([CH3:27])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[CH:6]([N:16]([CH3:27])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:7][C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3]1=[O:4]
Reactant: COc1ccc(CC(N(C)S(=O)(=O)c2ccc(C)cc2)C(C)(C)C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(=O)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a cooled (with ice water) and stirred solution of 256 g of 2,2-dimethyl-4-(p-methoxyphenyl)-3-(N-methyl-p-toluenesulfonamido)butyryl chloride in 1500 ml of dry benzene 195 g of aluminium chloride is added rather rapidly. The mixture is stirred at room temperature for an additional 25 minutes and then poured on to a mixture of ice and 950 ml of concentrated hydrochloric acid. After stirring the mixture at room temperature for 30 minutes the organic layer is separated whereas the aqueous layer is shaken twice with benzene. The combined organic solutions are washed twice with water and again twice with an aqueous solution of potassium carbonate whereupon, after drying, the whole is concentrated in vacuo. The residue is taken up in ether which brings about the crystallization of the title product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[OH:24][C:25]([CH3:30])([CH3:29])[C:26](O)=O>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][CH2:26][C:25]([OH:24])([CH3:30])[CH3:29])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: CC(C)(O)CNc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (50 mg) was reacted with 2-hydroxyisobutyric acid via General Procedure I to give N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxy-2-methylpropanamine. 62 mg of the crude N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxy-2-methylpropanamine was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 16.2 mg of 112. MS (Q1) 515 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:5]2[OH:26]>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:5]2[OH:26]
Reactant: Cc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C2(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)O)C(=O)C2(C)C
Yield: 89.3 %

Procedure:
1,1-Dimethylethyl N-((6-methyl-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (255 mg, 709 μmol) was dissolved in TFA (3 mL) at ambient temperature for 30 minutes. The reaction mixture was then concentrated, precipitated with hexanes, filtered, and dried in a vacuum oven to give the title compound (192 mg) as a white solid. MS (m/z)=304 (M+H)+. Calculated for C16H17NO5 303.11.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@H:64]([NH:67][C:68]([C@@H:70]3[CH2:73][CH2:72][N:71]3[C:74]([O:76][CH2:77][C:78]3[CH:83]=[CH:82][C:81]([N+:84]([O-:86])=[O:85])=[CH:80][CH:79]=3)=[O:75])=[O:69])[CH2:63]2)=[O:61])[CH2:43]1>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=4)=[O:48])[C@H:44]([C:60]([N:62]4[CH2:66][CH2:65][C@H:64]([NH:67][C:68]([C@@H:70]5[CH2:73][CH2:72][N:71]5[C:74]([O:76][CH2:77][C:78]5[CH:83]=[CH:82][C:81]([N+:84]([O-:86])=[O:85])=[CH:80][CH:79]=5)=[O:75])=[O:69])[CH2:63]4)=[O:61])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(N[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)[C@@H]1CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)[C@@H]5CCN5C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 70.6 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (960 mg) and (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-[(2S)-1-(4-nitrobenzyloxycarbonyl)azetidin-2-ylcarbonylamino]pyrrolidin-1-ylcarbonyl]pyrrolidine (1.06 g), reaction and purification were carried out in a similar manner to that described in Example 1-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-[(2S)-1-(4-nitrobenzyloxycarbonyl)azetidin-2-ylcarbonylamino]pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (1.14 g) was obtained as a powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:11]([OH:13])=[O:12].[OH-].[Na+:23]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:11]([O-:13])=[O:12].[Na+:23]
Reactant: Cc1ccccc1NC(C(=O)O)c1c(Cl)ccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccccc1NC(C(=O)[O-])c1c(Cl)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8.62 parts of 2,3,6-trichloro-α-[(2-methylphenyl)amino]benzeneacetic acid, 25 parts of a sodium hydroxide solution 1 M in water and 100 parts of distilled water is stirred for 30 minutes at room temperature. The resulting solution is evaporated to dry, methylbenzene is added and evaporation is continued. The residue is suspended in 2,2'-oxybispropane. The product is filtered off and crystallized from acetonitrile, yielding 7 parts of sodium 2,3,6-trichloro-α-[(2-methylphenyl)amino]benzeneacetate; mp. 203.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:10][C:9]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1.C(O)(=O)C>C(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:10][C:11]2[N:12]([C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:15][N:14]=2)[N:13]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)cc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetohydrazide (124 mg, 0.24 mmol) and acetic acid (69 μL, 1.2 mmol) in ethanol (2.5 mL) in a vial was heated in a microwave oven at 180° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-70%) in hexanes to obtain 100 mg of the desired product with 96% purity. The product was crystallized from methanol (2 mL) to yield 42 mg of the pure product as a white solid. The mother liquid was concentrated. The obtained residue was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 70% to 100% B, 10 min gradient, 100% B hold for 4 min, (A=90% H2O, 10% MeOH and B=10% H2O, 90% MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) to afford additional 48 mg of the title compound as a white powder (90 mg in total, 75% yield). HPLC/MS (method A): retention time =4.08 min, (M+H)+=499.3.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH2:12]([N:19]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 140 °C

Procedure:
N-Benzylphthalimide is prepared as described in Example 2, starting with 10 g of phthalic anhydride, 7.3 cm3 of benzylamine and a catalytic amount of para-toluenesulfonic acid in 100 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 3 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is taken up in 100 cm3 of saturated aqueous sodium bicarbonate solution and the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 10.3 g of N-benzylphthalimide are thus obtained in the form of a white powder. (Rf=0.44, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17].I[CH2:19][CH3:20]>C(OCC)(=O)C.O>[CH2:19]([O:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[F:8])[CH:13]=[O:14])[CH3:20]
Reactant: O=Cc1ccc(F)c(O)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C=O)ccc1F
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Sodium hydride (171 mg) was added to a DMF (10 mL) solution of 4-fluoro-3-hydroxybenzaldehyde (300 mg) obtained above at room temperature, and the reaction solution was agitated for 30 minutes. Then, iodoethane (0.26 mL) was added dropwise to the reaction solution, and the reaction mixture was agitated at room temperature for 1 hour. After the reaction ended, water and ethyl acetate were added to the reaction solution under ice-cooling and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 5:1), and 250 mg (70%) 3-ethoxy-4-fluorobenzaldehyde was obtained. The physical properties of the compound are as follows.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:33])([F:32])[F:31])=[N:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)=[CH:10][C:9]=1[C:42]([N:44]1[CH2:48][CH2:47][CH:46]([N:49]([CH3:51])[CH3:50])[CH2:45]1)=[O:43])(C)(C)C>Cl(O)(=O)(=O)=O.C(O)(=O)C.SCC(O)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:33])([F:32])[F:31])=[N:21][NH:20][C:17]3=[N:18][CH:19]=2)=[CH:10][C:9]=1[C:42]([N:44]1[CH2:48][CH2:47][CH:46]([N:49]([CH3:51])[CH3:50])[CH2:45]1)=[O:43]
Reactant: CN(C)C1CCN(C(=O)c2cc(-c3cnc4c(c3)c(-c3ccccc3OC(F)(F)F)nn4COCC[Si](C)(C)C)ccc2NC(=O)OC(C)(C)C)C1
Agent: O=C(O)CS
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CN(C)C1CCN(C(=O)c2cc(-c3cnc4[nH]nc(-c5ccccc5OC(F)(F)F)c4c3)ccc2N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{2-(3-Dimethylaminopyrrolidine-1-carbonyl)-4-[3-(2-trifluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-carbamic acid tert-butyl ester (220 mg, 0.3 mmol) was dissolved in 1 ml of 5% v/v of 70% perchloric acid in glacial acetic acid containing 0.4 ml of mercaptoacetic acid and the resulting mixture stirred overnight at room temperature. The crude was filtered over a 0.45 μm PTFE syringe filter and directly purified by mass-triggered reverse phase HPLC to afford {2-amino-5 [3-(2-trifluoromethoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone. 1H NMR (500 MHz, DMSO-d6) δ 1.65 (m, 1H), 1.92-2.02 (m, 7H), 3.15-3.68 (m, 5H), 5.45 (s, 2H), 6.78 (d, 1H), 7.45 (m, 2H), 7.50-7.58 (m, 3H), 7.88 (d, 1H), 8.18 (s, 1H), 8.66 (s, 1H). MS: m/z 511.2 (M+H+).
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[C:7]([N+:21]([O-])=O)[CH:8]=[C:9]([N+:18]([O-])=O)[C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:5][C:4]1=[O:24].[Sn].Cl>C(O)C>[C:12]1([C:10]2[C:9]([NH2:18])=[CH:8][C:7]([NH2:21])=[C:6]3[C:11]=2[CH2:3][C:4](=[O:24])[NH:5]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CSC1C(=O)Nc2c([N+](=O)[O-])cc([N+](=O)[O-])c(-c3ccccc3)c21
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Nc1cc(N)c(-c2ccccc2)c2c1NC(=O)C2

Procedure:
A mixture of 4.9 grams (0.014 mole) of 3-methylthio-4-phenyl-5,7-dinitroindolin-2-one, 4.2 grams (0.035 mole) of tin powder, 10 milliliters of concentrated hydrochloric acid and 50 milliliters of ethanol are refluxed for 4 hours under nitrogen. The hot mixture is filtered and the filtrate concentrated to give a solid.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][N:58]5[CH2:63][CH2:62][NH:61][CH2:60][C@@H:59]5[CH3:64])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1>>[ClH:3].[ClH:1].[ClH:3].[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][N:58]5[CH2:63][CH2:62][N:61]([CH3:4])[CH2:60][C@@H:59]5[CH3:64])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:33][CH2:34]1
Reactant: Cc1cnc(NCCCN2CCNC[C@@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: Cc1cnc(NCCCN2CCN(C)C[C@@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from (S)-2{5-methyl-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 479 [M(free base)+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)COC1(c2ccc(Br)cc2)CCCC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To an ambient solution of Example 30B (200 mg, 0.668 mmol) in N,N-dimethylformamide (4 mL) was added iodomethahe (0.208 mL. 3.34 mmol) and potassium carbonate (184 mg, 1.34 mmol). The mixture was stirred at room temperature for 40 h, and then diluted with water (10 mL) and ethyl acetate (20 mL). The layers were separated, and the organic was washed with water (3×10 mL), brine (1×10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.67-1.72 (m, 2 H), 1.74-1.84 (m, 4 H), 2.10 (m, 2 H), 3.58 (s, 3 H), 3.67-3.70 (m, 2 H), 7.34-7.40 (m, 2 H), 7.51-7.57 (m, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C:21](=[N:23]O)[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].N>CO.O.[Ni].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH2:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=NO)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Ni]
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O
Product: C[C@H](N)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 0.03 h
Yield: 63.8 %

Procedure:
To a solution of 61E (3.6 g, 10.0 mmol) in methanol in a pressure vessel was added Raney Ni in water (˜0.2 g), 10% Pd/C (Degussa type, 200 mg), water (7.5 mL) and ammonia in methanol (2.0 M, 5 mL). The reaction vessel was carefully evacuated under vacuum until the solvent bubbled gently. Hydrogen gas was then introduced to a pressure of 70 psi and the reaction was stirred for 2 min). The reaction vessel was again carefully evacuated under vacuum until the solvent bubbled gently. Hydrogen gas was then introduced to a pressure of 70 psi and the reaction was stirred for 18 h at rt. The reaction was filtered through a pad of celite, taking care to keep the captured catalyst wet with methanol at all times. The celite pad was washed with methanol until the product could no longer be detected in the eluent (TLC, 5% MeOH in CH2Cl2, stain with ninhydrin and heat). Solvent was removed under vacuum and purification by flash chromatography (110 g ISCO silica gel cartridge, step gradient 0%-5%-10% MeOH in CH2Cl2) gave the title compound (2.2 g): MS (ES) m/z 345.35 [M+H]+
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Brc1cnc2ccc(NC3CCCCC3)nn12
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: COCCOC
Solvent: O
Product: NCc1ccc(-c2cnc3ccc(NC4CCCCC4)nn23)cc1
Temperature: 160 °C
Yield: 43.9 %

Procedure:
A mixture of 3-bromo-N-cyclohexylimidazo[1,2-b]pyridazin-6-amine (100 mg, 0.34 mmol), 4-(aminomethyl)phenylboronic acid hydrochloride (160 mg, 0.84 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (25 mg, 0.034 mmol), potassium phosphate (360 mg, 1.7 mmol), DME (1.5 mL) and H2O (0.5 mL) was heated in a sealed conical vessel at 160° C. for 360 s by microwave irradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic layers were concentrated under reduced pressure to afford an oil that was purified by reverse phase HPLC to afford [3-(4-aminomethyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-cyclohexylamine (48 mg, 44%) as a white solid: 1H NMR (400 MHz, MeOD-d4) δ ppm 8.29 (d, J=8.6 Hz, 2H), 7.82 (s, 1H), 7.63 (d, J=9.6 Hz, 1H), 7.54 (d, J=8.6 Hz, 2H), 6.72 (d, J=9.6 Hz, 1H), 4.13 (s, 2H), 3.70-3.78 (m, 1H), 2.19 (d, J=9.1 Hz, 2H), 1.83-1.93 (m, 2H), 1.70-1.76 (m, 1H), 1.42-1.54 (m, 2H), 1.29-1.40 (m, 3H); LCMS (ESI) m/e 322.2 [(M+H)+, calcd for C19H24N5 322.2].