Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=[O:8])=CC=1.[C:12]1([N:18]2[C:26]3[CH2:25][CH2:24][CH2:23][C:22](=[CH:27][CH2:28][N+:29]4[CH:34]=[CH:33]C=[CH:31][CH:30]=4)[C:21]=3[CH:20]=[N:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCOCC1>C(#N)C.C(OCC)(=O)C>[N:29]1([CH2:28]/[CH:27]=[C:22]2/[C:21]3[CH:20]=[N:19][N:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:26]=3[CH2:25][CH2:24][CH2:23]/2)[CH2:34][CH2:33][O:8][CH2:31][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: C(C[n+]1ccccc1)=C1CCCc2c1cnn2-c1ccccc1
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C(\CN1CCOCC1)=C1\CCCc2c1cnn2-c1ccccc1
Yield: 57.1 %

Procedure:
A mixture of 1-[2-(1-phenyl-1,5,6,7-tetrahydro-indazol-4-ylidene)-ethyl]-pyridinium toluene-4-sulfonate (290 mg, 0.63 mmol) and morpholin (180 mg, 1.5 mmol) in 15 mL of acetonitrile is refluxed during 4 hours, following the reaction by TLC. The solvent is next evaporated, the crude is diluted in ethyl acetate and washed three times with water. Then the organic phase is evaporated under reduced pressure. The crude thus obtained is purified by silica gel chromatography giving (E)-4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethylidene)-1-phenyl-1H-indazole (110 mg, 0.36 mmol, 57%, beige solid, m.p=114-116° C.).
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][CH2:6][C@@H:7]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:15])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH2:31](Br)[CH:32]=[CH2:33]>CN(C)C=O>[CH2:33]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C@H:7]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:15])[CH2:6][O:5][CH2:4][O:3][CH2:1][CH3:2])[CH:32]=[CH2:31]
Reactant: CCOCOC[C@H](CCC(=O)O)NC(=O)c1ccc(I)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)CC[C@@H](COCOCC)NC(=O)c1ccc(I)cc1
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in Example 2 (4.11 g) in dimethylformamide (DMF; 20 ml), potassium carbonate (1.62 g), sodium iodide (small amount) and allyl bromide (5 ml) were added. The mixture was vigorously stirred overnight. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with hexane to give the title compound having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21]([N+]([O-])=O)[CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CCOC(=O)c1ccc(Cl)c(O)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(Cl)c2)c1
Yield: 76.6 %

Procedure:
Using the method of Example 3, Step A, ethyl 4-chloro-3-hydroxybenzoate (0.759 g, 3.78 mmol), 60% sodium hydride in mineral oil (151 mg, 3.78 mmol), and 2-chloro-4-nitropyridine (0.600 g, 3.78 mmol) were reacted to provide ethyl 4-chloro-3-(2-chloropyridin-4-yloxy)benzoate (0.904 g, 76% yield) as a white solid. 1H NMR (CDCl3) δ 8.27 (d, 1H), 7.96 (d, 1H), 7.84 (s, 1H), 7.60 (d, 1H), 6.77 (s, 1H), 6.76 (d, 1H), 4.39 (quartet, 2H), 1.41 (t, 2H).
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.Cl.C(N(CC)CC)C.C1(C)C(C)=CC=CC=1.Cl[C:22]1[N:23]=[N:24][C:25]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=12>O>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:25]2[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[C:22]3[N:23]([CH:1]=[N:3][N:4]=3)[N:24]=2)=[CH:33][CH:34]=1
Reactant: COc1ccc(-c2nnc(Cl)c3cnccc23)cc1
Reactant: NNC=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2nn3cnnc3c3cnccc23)cc1
Yield: 75.2 %

Procedure:
240 mg (4.0 mmol) of formohydrazide and 551 mg (4.0 mmol) of triethylamine hydrochloride were added to a xylene solution (10 ml) of 543 mg (2.0 mmol) of 4-chloro-1-(4-methoxyphenyl)-pyrido[3,4-d]pyridazine, and then stirred under reflux for 2 hours. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 417 mg of a crude product of 6-(4-methoxyphenyl)-pyrido[3,4-d][1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:7]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 100 °C
Yield: 52.1 %

Procedure:
To a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (5 g, 26 mmol,) in DMSO (50 ml) was added tert-butyl 4-aminopiperidine-1-carboxylate (5.3 g, 26.5 mmol, 1 eq.) and potassium carbonate (7.3 g, 52.8 mmol, 2 eq.). The resulting solution was stirred with heating overnight at 100° C. (oil bath). The resulting solution was diluted with of ethyl acetate (300 ml) and washed with sodium chloride (sat., 300 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with ethyl acetate to afford tert-butyl 4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate as a white powder (5 g, 51%). (ES, m/z):[M+H]+ 370.1.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]([NH2:19])=[O:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.N1CCCCC1>C(O)C>[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)[C:3]=2[C:17]([NH2:19])=[O:18])=[CH:23][CH:22]=1
Reactant: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N=Cc1ccc(O)cc1
Yield: 47 %

Procedure:
5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 100 mL of ethanol and 4-hydroxybenzaldehyde (12.945 g, 2.00 eq.) and piperidine (0.25 eq.) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-hydroxybenzylidene)amino)-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (9.00 g, 47% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:7][CH2:6]2.[C:17]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.C1COCC1.O.CN(C=O)C>[C:17]([NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH2:9][CH:8]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:7][CH2:6]3)=[O:31])=[CH:33][CH:34]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2)cc1
Reactant: CN(C)CC1CCc2cc(N)ccc2C1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)CC1CCc2cc(NC(=O)c3ccc(NC(=O)c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.4 %

Procedure:
6-Amino-2-(N,N-dimethylamino)methyltetralin hydrochloride (139 mg), 4-benzoylaminobenzoic acid (121 mg), WSCD (0.13 ml), HOBt (92 mg), triethylamine (0.14 ml) and DMAP (61 mg) were added to DMF (4 ml). After the reaction mixture was shaken at room temperature for 20 hours using a shaker, the reaction mixture was poured into water, and extraction was conducted using ethyl acetate-THF (1:1). The organic layer was washed with water, saturated sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried, and then concentrated. The resulting crude crystal was washed with hexane, to give the titled compound (181 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13]CC)=[O:12])[O:7][C:6]=2[CH:5]=[C:4]([C:16]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:21]=[CH:20][CH:19]=2)=[O:17])[C:3]=1[Cl:29].O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([OH:13])=[O:12])[O:7][C:6]=2[CH:5]=[C:4]([C:16]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:21]=[CH:20][CH:19]=2)=[O:17])[C:3]=1[Cl:29]
Reactant: CCOC(=O)C1Oc2cc(C(=O)c3ccnn3-c3ccccn3)c(Cl)c(Cl)c2O1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cc2c(c(Cl)c1Cl)OC(C(=O)O)O2)c1ccnn1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
1.5 g of ethyl 4,5-dichloro-6-(1-[2-pyridyl]-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylate are dissolved in a mixture of 18 ml of tetrahydrofuran and 2 ml of water. 177 mg of lithium hydroxide monohydrate are added to the solution and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated under reduced pressure to remove tetrahydrofuran. Water and 1N hydrochloric acid are added to the residue, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated under reduced pressure to remove solvent. The residue is recrystallized from ethyl acetate-n-hexane to give 1.35 g of 4,5-dichloro-6-[1-(2-pyridyl)-5-pyrazolylcarbonyl]-1,3-benzodioxole-2-carboxylic acid. Yield: 96%
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[Cl:21].C(OC([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=O)(C)(C)C.C(C1C=C(NC(=O)C2C=CC(N3CCNCC3)=C(F)C=2)C=CC=1)(C)(C)C>>[C:15]([C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:3]([Cl:21])[CH:4]=2)[CH:14]=[CH:13][CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(Cl)c2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(Cl)c2)c1

Procedure:
N-(3-tert-Butyl-phenyl)-3-chloro-4-piperazin-1-yl-benzamide was synthesized from 4-bromo-N-(3-tert-butyl-phenyl)-3-chloro-benzamide and piperazine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of N-(3-tert-butyl-phenyl)-3-fluoro-4-piperazin-1-yl-benzamide above. LCMS calcd for C21H26ClN3O (m/e) 371, obsd 372 (M+H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C@H:22]([C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)[CH3:23])[CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][C:11]=1[Cl:21])([CH3:4])([CH3:3])[CH3:2].[C:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:35]([O:34][C:32]([N:39]1[CH2:44][CH2:43][N:42]([C:27]2[CH:28]=[CH:29][C:24]([C@@H:22]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:31])[CH2:8][CH2:9][C:10]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][C:11]=3[Cl:21])[CH3:23])=[CH:25][CH:26]=2)[CH2:41][CH2:40]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COc1cc(CCN(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(Br)cc2)c(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(CCN(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of [(S)-1-(4-bromo-phenyl)-ethyl]-[2-(2-chloro-5-methoxy-4-nitro-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.66 g, 1.17 mmol), N-Boc piperazine (0.44 g, 2.34 mmol), cesium carbonate (0.96 g, 2.92 mmol) and devphos (46.1 mg, 0.117 mmol) in 1,4-dioxane (5 mL) was degassed with argon. Pd2(dba)3 (0.054 g, 0.058 mmol) was added and the mixture heated to reflux for 3 hours under an argon atmosphere. The mixture was allowed to cool to room temperature, diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 20% EtOAc in hexane to give the title compound (0.33 g, 46%).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21](O)=[O:22].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: Nc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccnc(N)c1)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a mixture of (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (300 mg, 1.17 mmol, Amine-1, single enantiomer), 2-aminoisonicotinic acid (161 mg, 1.17 mmol), and N,N-diisopropylethylamine (0.82 mL, 4.68 mmol) in N,N-dimethylformamide (12 mL) is added HBTU (665 mg, 1.75 mmol) at room temperature. After stirring at room temperature for 1 hour, the mixture is poured onto water (20 mL), and the mixture is extracted with ethyl acetate (20 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with dichloromethane/methanol (10:1) to give 252 mg (63% yield) of the title compound as a slight brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]=O)[N:11]=1.[CH3:30][NH:31][CH3:32].Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(CC)CC)C>ClCCCl>[CH3:30][N:31]([CH3:32])[CH2:28][CH2:27][CH2:26][N:12]1[C:13]2=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=[C:18]2[C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[N:11]1
Reactant: Cc1cccc(C)c1Nc1nn(CCC=O)c2nc(Nc3ccccc3)ncc12
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(C)c1Nc1nn(CCCN(C)C)c2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 66 mg (0.2 mmol) of crude 3-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propanal 36 (Example 4, Step A) and 28 mg (0.3 mmol) of dimethylamine•HCl in 7 mL of 1,2-dichloroethane was treated sequentially with 60 mg (95%, 0.3 mmol) of NaBH(OAc)3 and 75 μl (0.5 mmol) of triethylamine. The resulting brown slurry was stirred at room temperature for 17 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (CH2Cl2:MeOH, 44:6 grading to CH2Cl2:MeOH, 4:1) to give the title compound 38. 1H-NMR (CD3OD) δ 2.06-2.14 (m, 2H), 2.28 (s, 6H), 2.49 (s, 6H), 2.72 (t, J=7.3 Hz, 2H), 4.19 (t, J=6.3 Hz, 2H), 7.01 (t, J=7.4 Hz, 1H), 7.12-7.19 (m, 3H), 7.31 (t, J=8.0 Hz, 2H), 7.75 (dd, J=8.6 Hz, 0.9 Hz, 2H), 8.27 (s, 1H). Mass Spectrum (ESI) m/e=416.1 (M+1).
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[CH:8]1([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N1C=CC=CC=1.O>C(Cl)Cl>[CH:8]1([C:14]2[CH:15]=[CH:16][C:17]([NH:18][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:19][CH:20]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C(=O)Nc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chloro(oxo)acetate (1.88 mL) was added to a stirred solution of 4-cyclohexylaniline (2980 mg) and pyridine (1.80 mL) in DCM (100 mL) at 0° C. After the addition was complete allowed to warm to ambient temperature and stirred for 16 hours. Water (50 mL) added. Extracted with DCM (2×75 mL). The organics were combined washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to give methyl [(4-cyclohexylphenyl)amino](oxo)acetate (4133 mg) as a solid; 1H NMR δ 10.66 (1H, s), 7.60 (2H, d), 7.19 (2H, d), 3.84 (3H, s), 2.50 (1H+DMSO, m), 1.84-2.65 (5H, m), 1.46-1.14 (5H, m); MS m/e M−H− 260.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][C:17](O)=[O:18])=[O:14])=[CH:11][C:10]=1[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:33][CH2:32][C@@H:31]2[CH2:34][C@H:28]1[C:29](=[O:42])[N:30]2C(OC(C)(C)C)=O.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CCOC(C)=O.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][C:17](=[O:18])[NH:26][C@H:27]2[CH2:33][CH2:32][C@@H:31]3[CH2:34][C@H:28]2[C:29](=[O:42])[NH:30]3)=[O:14])=[CH:11][C:10]=1[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N
Reactant: CC(C)(C)c1cc(C(=O)NCC(=O)O)ccc1OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)NCC(=O)N[C@H]2CC[C@@H]3C[C@H]2C(=O)N3)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.6 %

Procedure:
To a solution of 2-(4-(benzyloxy)-3-tert-butylbenzamido)acetic acid (418 mg, 1.22 mmol) in anhyd DMF (8 mL) was added (1R,2S,5R)-tert-butyl 2-amino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (287 mg, 1.11 mmol), BOP reagent (738 mg, 1.67 mmol), and N-methylmorpholine (366 μL, 3.34 mmol). The mixture was stirred at room temperature for 12 h under nitrogen atmosphere and then diluted with EtOAc (250 mL). The organic layer was washed with water (100 mL), 0.1 N HCl (100 mL), satd NaHCO3 (100 mL), and brine (50 mL), dried (Na2SO4), and concentrated in vacuo. 4-(benzyloxy)-3-tert-butyl-N-(2-oxo-2-((1R,2S,5R)-7-oxo-6-aza-bicyclo[3.2.1]octan-2-ylamino)ethyl)benzamide (713 mg, quant.) was isolated as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.81-6.93 (m, 8H), 6.69 (s, 1H), 5.15 (s. 1H); 5.16 (s, 1H), 4.13-4.06 (m, 4H), 3.20-2.80 (m, 2H), 2.40-1.30 (m, 6H), 1.52 (s, 9H), 1.42 (s, 9H); MS found: (M+H)+=564.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[CH2:24][O:25][CH3:26].[C:27](=O)([O-])[O-:28].[K+].[K+]>COCCOC.CO>[CH3:26][O:25][CH2:24][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:3]=1[CH2:2][O:28][CH3:27])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:23])[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]
Reactant: COCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: COCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1COC
Yield: 27.7 %

Procedure:
A mixture of 4-chloromethyl-8-(2,6-dichlorobenzoylamino)-3-methoxymethylquinoline (70 mg) and potassium carbonate (26 mg) in 1,2-dimethoxyethane and methanol was refluxed for 2 hours. After cooling, the mixture was partitioned between saturated ammonium chloride solution and dichloromethane, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography and crystallized from isopropyl alcohol to give 3,4-bis(methoxymethyl)-8-(2,6-dichlorobenzoylamino)quinoline (19.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][C:26]([C:28]1[S:37][C:36]2[S:35][CH2:34][CH2:33][NH:32][C:31](=[O:38])[C:30]=2[CH:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:23][CH2:24][CH2:25][C:26]([C:28]3[S:37][C:36]4[S:35][CH2:34][CH2:33][NH:32][C:31](=[O:38])[C:30]=4[CH:29]=3)=[O:27])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Reactant: O=C(CCCCl)c1cc2c(s1)SCCNC2=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CCCN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)c1cc2c(s1)SCCNC2=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 4.5 %

Procedure:
The mixture of 2.4 g of 4-(bis(4-chlorophenyl)methyl)piperazine, 2.0 g of 7-(4-chlorobutyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one, 1.9 g of potassium carbonate and 1.2g of potassium iodide in 15 ml of N,N-dimethylformamide and 15 ml of toluene was stirred at 60° C. for 5 hours. After the mixture was cooled in a water bath, water was added thereto. The precipitated crystals were filtered off and the filtrate was extracted with toluene. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and the resulting crystals were recrystallized from isopropyl alcohol-isopropyl ether to give 0.18 g of 7-(4-(4-(bis(4-chlorophenyl)-methyl)piperazin-1-yl)butyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one as white crystals, m.p. 185°-187° C. (decomposition).
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:21])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[N:15]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Temperature: 25 °C
Yield: 73.1 %

Procedure:
Dowtherm A (Fluka, 500 mL) was brought to boiling (250° C.) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distil over. The resulting solution was cooled to RT and diluted with hexanes (750 mL). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72 g, 73%).