Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.O=[C:12]1[C:17]([CH2:18][CH2:19][C:20]([O:22]CC)=O)=[CH:16][CH2:15][CH2:14][CH2:13]1.Cl>C1COCC1.CCOCC>[O:22]1[CH:12]2[C:17](=[CH:16][CH2:15][CH2:14][CH2:13]2)[CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)CCC1=CCCCC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=C2CCCOC2CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 48 mL diisobutylaluminum hydride (1.0 M in cyclohexane) was cooled to −78° C. and a solution of 2.335 g ethyl 3-(6-oxocyclohex-1-en-1-yl)propanoate in 48 mL THF was added. The reaction was warmed to 0° C. and stirred for one hour, then warmed to RT and stirred for one more hour. The reaction was not complete at this point, so 10 mL additional diisobutylaluminum hydride solution was added the reaction was and stirred at RT for two hours. The reaction was then cooled to −78° C. and then 25 mL 6 M HCl was added dropwise. After the addition was complete, the reaction was allowed to return to RT and was stirred overnight. The reaction was diluted with 200 mL Et2O then washed 2× with water, then with brine. The organic layer was dried over Na2SO4 then filtered, concentrated, and purified on silica gel to provide the title compound.
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[NH:5].C(OCC)C.[OH-].[Na+].[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH:24]=O>C(Cl)Cl.CCCCCC>[CH2:7]([NH:6][C:4]([NH:3][N:2]=[CH:24][C:23]1[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:22]=1[Cl:21])=[NH:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N=C(NN)NCc1ccccc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: N=C(NCc1ccccc1)NN=Cc1ccc(Cl)cc1Cl
Reaction time: 0.25 h

Procedure:
A 10.0 g. portion of 1-amino-3-benzylguanidine hydroiodide in a mixture of 100 ml. each of diethyl ether, hexane and methylene chloride is shaken with 10 ml. of 5N NaOH. A 5.98 g. portion of 2,4-dichlorobenzaldehyde is added and and the mixture is shaken for 15 minutes. The organic layer is washed with saturated aqueous sodium chloride, passed through hydrous sodium magnesium silicate and concentrated to dryness under reduced pressure. The residue is crystallized from methylene chloride-hexane, giving the desired product as cream colored crystals, m.p. 139°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.C[O-].[Na+]>CO>[Cl:11][C:12]1[CH:13]=[C:14](/[CH:15]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)\[C:7]#[N:8])[CH:17]=[CH:18][CH:19]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=Cc1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
Method B To a solution of 4-chlorobenzyl cyanide (Aldrich) (4.5 g, 30 mmol) and 3-chloro-benzaldehyde (Aldrich) (4 g, 29 mmol) in methanol (150 mL) was slowly added a methanolic solution (Aldrich, 25 wt. %) of sodium methoxide (10 mL, 44 mmol). The reaction mixture was heated and stirred at 50° C. for 3 h. The mixture became cloudy, and was cooled to room temperature and filtered. The white precipitate was washed with water, cold methanol, and then dried in vacuo to give the first batch of desired product (5.5 g). The filtrate was concentrated, diluted with water, neutralized by aqueous HCl solution to “pH” 7, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20, then 1:10) to give the second batch of the desired product (1.6 g). The two batches were combined to give (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile as a white powder (7.1 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](Br)=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[N:32][CH:33]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: COc1ccc(Br)cn1
Product: COc1ccc(C#Cc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)cn1

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and 2-methoxy-5-bromo-pyridine.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([C:9]1[CH:10]=[C:11]([C:17]#[N:18])[C:12](=[O:16])[NH:13][C:14]=1[CH3:15])(=[O:8])[CH3:7]>>[C:6]([C:9]1[CH:10]=[C:11]([C:17]([NH2:18])=[O:2])[C:12](=[O:16])[NH:13][C:14]=1[CH3:15])(=[O:8])[CH3:7]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Product: CC(=O)c1cc(C(N)=O)c(=O)[nH]c1C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To 100 grams of concentrated sulfuric acid is added 10 g (0.056 mole) of 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile. The mixture is stirred at 60° C. for 5 hours, cooled and then poured on 1 kg ice. The resulting solid is collected, washed with water and recrystallized from ethanol to give the title compound.
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[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][C:20]=1[N+:31]([O-:33])=[O:32].C(N(CC)CC)C>CN(C)C=O>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][C:20]=3[N+:31]([O-:33])=[O:32])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)ccc1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ccc(-c4ccccc4)cc3[N+](=O)[O-])cc12
Temperature: 110 °C
Yield: 24 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 4-bromo-3-nitrobiphenyl were used. Triethylamine was used as base, N,N-dimethylformamide was used as solvent, and the reaction was heated at 110° C. for 12 hours. Column chromatography afforded the title compound (24%) as a red amorphous solid: 1H NMR (CDCl3) δ 9.63 (br s, NH), 8.97 (br s, NH), 8.42 (d, J=2.2 Hz, 1 H), 7.56-7.25 (m, 9H), 7.08 (d, J=9.0 Hz, 2H), 3.50-3.32 (m, 2H), 2.95-2.79 (m, 2H), 2.59-2.52 (m, 1H), 2.53 (s, 3H), 2.05-1.71 (m, 4H); 13C NMR (CDCl3) δ 144.4, 138.8, 134.9, 134.5, 132.4, 131.1, 130.2, 129.7, 129.0, 127.3, 126.2, 124.7, 124.1, 120.8, 116.7, 115.9, 112.7, 112.0, 67.9, 57.4, 40.6, 31.2, 28.6, 21.9; FAB HRMS calculated for [C26H26N4O2.H]427.2136, found 427.2099.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1C#N.[CH:25]([Br:28])(Br)Br.N(OC(C)(C)C)=O>>[Br:28][C:25]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:20])([F:22])[F:21])[C:3]=1[C:2]#[N:1]
Reactant: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Product: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Temperature: 50 °C

Procedure:
A stirred mixture of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.89 g) and bromoform (13 ml) was treated with tert-butyl nitrite (2.26 ml) at room temperature. After 15 minutes the mixture was heated to 50° C. for 1 hour, and evaporated in vacuo to yield a red oil. This was purified by chromatography on silica (Merck, 40-230 mesh, 0.7 kg cm-2) eluting with a mixture of dichloromethane and petroleum ether (1:2) to furnish 5-bromo-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole as a fawn solid m.p. 85°-87° C. (3.7 g).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:7])[CH3:6])C.[AlH4-].[Li+].O1CCCC1>C(OCC)C>[C:10]([NH:9][O:8][C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)(C)ONC(=O)OC(C)(C)C
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NOC(C)(C)CO
Temperature: 0 °C
Reaction time: 5 h
Yield: 99.5 %

Procedure:
To a solution of 2-(N-Boc-aminooxy)isobutyric acid ethyl ester (2.35 g, 9.5 mmol) in anhydrous ethyl ether (100 mL) at 0° C. under nitrogen was added 1.0 M lithiumtetrahydroaluminate in tetrahydrofuran (17.1 mL, 17 mmol), and the reaction mixture stirred at 0° C. for 5 hours. The reaction mixture was quenched with water (25 mL) and allowed to warm to room temperature. The suspension was filtered and the residue washed with diethyl ether and layers separated. The organic extract was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid (1.94 g, 99%). 1H NMR (CDCl3, 400 MHz) 3.40 (s, 2H), 1.50 (s, 9H), 1.20 (s, 6H).
Reaction SMILES: [F:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:4].[CH:12](O)=[O:13]>C1(C)C=CC=CC=1>[F:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]=[O:13])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CC(CF)c1ccc(N)cc1
Reactant: O=CO
Solvent: Cc1ccccc1
Product: CC(CF)c1ccc(NC=O)cc1

Procedure:
A solution of 20 g (0.13 Mol) of 4(1-fluoromethyl-ethyl)benzeneamine and 6 g (0.13 Mol) of 98% formic acid in 150 ml of dry toluene is boiled under reflux. When 2.5 ml of water have separated in the water trap, an additional 6 g of formic acid are added and refluxing is continued until no more water and formic acid separate.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[NH2:57][C@@H:58]1[C:84](=[O:85])[N:60]2[C:61]([C:72]([O:74][CH2:75][C:76]3[CH:81]=[CH:80][C:79]([O:82][CH3:83])=[CH:78][CH:77]=3)=[O:73])=[C:62]([S:65]/[CH:66]=[CH:67]\[C:68]([O:70][CH3:71])=[O:69])[CH2:63][S:64][C@H:59]12>CN(C)C=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])/[C:27]([NH:57][C@@H:58]2[C:84](=[O:85])[N:60]3[C:61]([C:72]([O:74][CH2:75][C:76]4[CH:77]=[CH:78][C:79]([O:82][CH3:83])=[CH:80][CH:81]=4)=[O:73])=[C:62]([S:65]/[CH:66]=[CH:67]\[C:68]([O:70][CH3:71])=[O:69])[CH2:63][S:64][C@H:59]23)=[O:28])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)/C=C\SC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: COc1ccc(CO/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c(OC)c1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C\SC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](NC(=O)/C(=N\OCc3ccc(OC)cc3OC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a solution of 531 mg (0.92 mM) of 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2,4-dimethoxybenzyloxyimino]acetic acid in 10 ml of N,N-dimethylformamide was added 124 mg (0.96 mM) of diisopropylethylamine. To the cooled (-50° C.) mixture was added 105 mg (0.92 mm) of methanesulfonyl chloride, and the mixture was stirred for 30 minutes. Then, 200 mg (0.46 mM) of 4-methoxybenzyl 7β-amino-3-[(Z)-2-methoxycarbonylvinylthio]-3-cephem-4-carboxylate and 60 mg (0.46 mM) of diisopropylethylamine were added at the same temperature, and the mixture was stirred for 30 minutes. After the reaction, 30 ml of water was added, the mixture was extracted with 50 ml of ethyl acetate, and the extract was washed with 30 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel column (eluent; ethyl acetate:benzene=1:4) to give 270 mg of 4-methoxybenzyl 7β-{2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2,4-dimethoxybenzyloxyimino]acetamido}-3-[(Z)-2-methoxycarbonylvinylthio]-3-cephem-4-carboxylate.
Reaction SMILES: C([N:8]([CH2:26][C:27]([C:29]1[C:37]2[S:36][C:35](=[O:38])[NH:34][C:33]=2[C:32]([OH:39])=[CH:31][CH:30]=1)=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[OH:39][C:32]1[C:33]2[NH:34][C:35](=[O:38])[S:36][C:37]=2[C:29]([C:27](=[O:28])[CH2:26][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:30][CH:31]=1
Reactant: O=C(CN(CCCCCCOCCCCc1ccccc1)Cc1ccccc1)c1ccc(O)c2[nH]c(=O)sc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(CNCCCCCCOCCCCc1ccccc1)c1ccc(O)c2[nH]c(=O)sc12
Reaction time: 20 h
Yield: 10.8 %

Procedure:
A solution of 7-({benzyl[6-(4-phenylbutoxy)hexyl]amino}acetyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one (100 mg) in dry ethanol (10 ml) and acetic acid (0.5 ml) was added to 10% Pd/C catalyst (40 mg) and stirred under hydrogen for 20 h. The catalyst was collected by filtration through celite and the filtrate evaporated in vacuo. The residue was purified on SCX and then silica SPE cartridge, eluting with a stepped gradient of 1-10% methanol-dichloromethane mixtures, to give the title compound (9 mg). LCMS RT=2.81 min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].[OH-].[Li+].C(OCC)(=O)C>CS(C)=O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)c1ccc(N)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)c1ccc(Nc2cc(F)ccc2[N+](=O)[O-])c(C#N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Heat a solution of 2-amino-5-isopropyl-benzonitrile (1.21 g, 7.55 mmol) with 2,4-difluoro-1-nitro-benzene (1.20 g, 7.55 mmol) and lithium hydroxide (0.54 g, 22.66 mmol) in DMSO (15 ml) to 70° C. for 18 hours. Cool the reaction to ambient temperature and then pour into approximately 200 ml of ice water and stir for one hour. The title compound precipitates and is colleted by filtration. Purify the solid via flash chromatography eluting with a 95% hexanes: 5% ethyl acetate mobile phase to obtain 0.372 g (1.24 mmol, 16% yield) of the title compound as an orange amorphous solid: Mass Spectrum (m/e): 298 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([O:31]C)=[O:30])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1Cl)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:35]>>[C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([OH:31])=[O:30])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1[OH:35])(=[O:17])=[O:16])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O
Reactant: COC(=O)C(CCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O)C(=O)O
Yield: 75.7 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-[5-(tert-butoxycarbonylamino)-5-methoxycarbonylpentyl]-2,6-dichloro-3-nitrobenzenesulfonamide (1.2 g, 2.33 mmol), 60% NaH (379 mg, 9.32mmol) and water (84 μL, 4.66 mmol) were reacted to form the desired product (850 mg, 76%). 1H NMR (MeOD-d4): δ 8.05 (d, 1H), 7.22 (d, 1H), 4.00 (m, 1H), 3.01 (t, 2H), 1.72 (m, 2H), 1.50-1.65 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[OH-].[K+].Cl[CH2:13][CH2:14][CH2:15][Si:16]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:18].[Cl-].[K+].[SiH4]>CN(C)C=O.C(O)C>[CH3:1][C:2]1([CH3:9])[N:6]([CH2:13][CH2:14][CH2:15][Si:16]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:18])[C:5](=[O:7])[NH:4][C:3]1=[O:8]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CC1(C)NC(=O)NC1=O
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CO[Si](CCCN1C(=O)NC(=O)C1(C)C)(OC)OC
Temperature: 95 °C

Procedure:
A mixture containing 12.8 g (0.1 mole) 5,5-dimethylhydantoin, 5.6 g (0.1 mole) potassium hydroxide and 100 cc ethanol was heated to the boiling point until a clear solution was obtained. The ethanol was then evaporated under reduced pressure to isolate the solid, anhydrous salt. The salt was combined with 100 cc of dry N,N-dimethylformamide and the resultant mixture was heated at 50° C. until a clear solution formed. A 19.8 g (0.1 mole) portion of chloropropyl trimethoxysilane was then added dropwise to the aforementioned salt solution under a nitrogen atmosphere with stirring. The temperature of the reaction mixture increased slightly during the addition, which is indicative of an exothermic reaction, and a white precipitate (potassium chloride) began to form when the silane addition was begun. Following completion of the addition the reaction mixture was heated at 95° C. for three hours. Analysis by vapor phase chromatography of the liquid phase demonstrated that the initial chloropropyl trimethoxysilane had been converted to a product exhibiting a high retention time. The reaction mixture was then cooled and filtered, following which the liquid phase was distilled to remove the N,N-dimethylformamide. A second fraction was collected at a temperature of 194° C. and a pressure of 4 mm of mercury and subsequently solidified to a white solid. Analysis by vapor phase chromatography indicated that this material was 98% pure and contained a trace amount of the initial hydantoin. The infra-red spectrum of the material was consistent with the proposed structure ##STR7## The product was found to contain 9.74% by weight of silicon and 9.92% nitrogen. The calculated values for the expected product are 9.64% silicon and 9.66% nitrogen.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].F[C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[C:24]#[N:25]>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:22]([O:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7]3)=[C:23]([CH:26]=1)[C:24]#[N:25]
Reactant: N#Cc1cc(F)ccc1F
Reactant: CC(C)Cn1ncc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Temperature: 110 °C
Yield: 80.8 %

Procedure:
To a solution of 1-isobutyl-1H-indazol-5-ol (2.33 g, 12.2 mmol) and K2CO3 (2.03 g, 14.7 mmol) in DMF (75 mL) was added 2,5-difluorobenzonitrile (1.87 g. 13.5 mmol). The mixture was heated to 110° C. for 18 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with 1N HCl, filtered, and concentrated under reduced pressure. The residue was chromatographed on Biotage eluting with hexanes/ether (5:2) to afford 3.05 g of pale yellow oil (81% yield).
Reaction SMILES: [NH3:1].CC(O)C.[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[C:20]([C:21]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23](SC)[N:22]=3)=[CH:19][C:18]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:33][CH2:32]3)=[CH:17][N:16]=2)=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[C:20]([C:21]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:1])[N:22]=3)=[CH:19][C:18]([CH2:30][N:31]3[CH2:32][CH2:33][N:34]([S:37]([CH3:40])(=[O:38])=[O:39])[CH2:35][CH2:36]3)=[CH:17][N:16]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: CC(C)O
Product: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 90 °C
Yield: 56.3 %

Procedure:
2 M NH3 in 2-propanol (2.00 mL, 92 mmol) was added to N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (221 mg, 0.428 mmol) and the mixture was sealed and heated at 90° C. overnight. After cooling, the reaction mixture was concentrated, adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (DCM to 10% MeOH in DCM) followed by washing of the isolated solid with MeOH to give 4-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (117 mg, 0.241 mmol, 56.3% yield) as a yellow solid. LCMS (API-ES) m/z 486 (M+H); 1H NMR (400 MHz, d6-DMSO) δ 11.76 (br. s., 1H) 8.71 (br. s., 1H) 8.55 (br. s., 1H) 8.03-8.28 (m, 2H) 7.87 (br. s., 1H) 7.73 (br. s., 1H) 6.82 (d, J=7.63 Hz, 1H) 3.84 (br. s., 3H) 3.48 (br. s., 2H) 3.11 (br. s., 4H) 2.87 (br. s., 3H) 2.52-2.58 (m, 3H) 2.44 (br. s., 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1Br.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH3:9][C:5]1[CH:4]=[C:3]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[C:2]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[CH:7][C:6]=1[CH3:8]
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: Cc1cc(Br)c(Br)cc1C
Product: Cc1cc(Nc2ccc(-c3ccccc3)cc2)c(Nc2ccc(-c3ccccc3)cc2)cc1C
Yield: 75.8 %

Procedure:
The synthesis is carried out in accordance with the general procedure in accordance with Example 2 from 63.3 g (240 mmol) of 1,2-dibromo-4,5-dimethylbenzene and 85.4 g (505 mmol) of 4-aminobiphenyl. The precipitated solid is recrystallised from toluene/acetonitrile (5:1), and the residue is washed with MeOH, giving 80.3 g (182 mmol) of a crystalline solid. The overall yield is 76%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH2:22][N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:25]=4[CH3:24])[CH2:33][CH2:34]3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4C)CC3)nn2-c2ccccc2)cc1

Procedure:
117 mg (93%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245 mmol), 1-(2,3-dimethylphenyl)piperazine (47 mg, 0.245 mmol), DIPEA (0.064 mL, 0.368 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).