Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[N:21]=[C:20]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH:29]C(OC(C)(C)C)=O)[C:19]([C:37]#[N:38])=[CH:18][C:14]=3[C:15]([NH2:17])=[O:16])[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1.C([O-])([O-])=[O:40].[K+].[K+].OO.O>CS(C)=O>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:15]([NH2:17])=[O:16])=[CH:18][C:19]([C:37]([NH2:38])=[O:40])=[C:20]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH2:29])[N:21]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Nc2cccc(-n3nccn3)c2)c(C(N)=O)cc1C#N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(C(N)=O)c(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Reaction time: 0.08 h
Yield: 38.3 %

Procedure:
To a solution of 2-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-6-((1R,2S)-2-tert-butyloxycarbonylaminocyclohexylamino)-5-cyanonicotinamide (50 mg, 0.12 mmol) in DMSO (1 mL) was added K2CO3 (200 mg, 1.45 mmol) and H2O2 (50% in H2O, 0.8 mL) at ambient temperature (caution: gas evolution). After stirring for 5 min, it was added water, the resulting precipitate was collected by filtration and was treated with TFA in DCM, 10 min later, the solution was concentrated and purified by preparative HPLC to give 2-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-6-((1R,2S)-2-aminocyclohexylamino)pyridine-3,5-dicarboxamide (20 mg). MS found for C26H33N9O4 as M+H, 436.4. λ=267.6, 312.8 nm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([CH2:16]O)[CH:12]=[N:13]2)=[CH:8][CH:7]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:16][C:11]1[CH:12]=[N:13][C:14]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH:15]=2
Reactant: OCc1cnc2cc(-c3cccs3)ccc2c1
Reactant: O=S(Cl)Cl
Product: ClCc1cnc2cc(-c3cccs3)ccc2c1
Yield: 77 %

Procedure:
In substantially the same manner as in Reference Example 73, 7-(2-thienyl)-3-quinolylmethanol was reacted with thionyl chloride to obtain 3-chloromethyl-7-(2-thienyl)quinoline. The yield was 77%. Recrystallization from ethyl acetate-hexane gave colorless leaflets, 120-121° C.
Reaction SMILES: [C:1]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br.Br[CH2:18][CH2:19][CH2:20][NH2:21].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:1]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6][N:7]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)C1(c2ccccc2)CCN(CCCN)CC1
Yield: 39.9 %

Procedure:
4-Acetyl-4-phenylpiperidine (1.53 g, 7.50 mmol, 1.00 equiv, Aldrich), 3-bromopropylamine hydrobromide (1.64 g, 7.50 mmol, 1.00 equiv) and potassium carbonate (1.24 g, 9.00 mmol, 1.20 equiv) were stirred in refluxing 1,4-dioxane (50 mL) for 12 hours. After removal of dioxane, water (50 mL) was added and the pH was adjusted to 11-12 by addition of 1 N aqueous NaOH. The mixture was extracted with CH2Cl2 (100 mL+3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (EtOAc-MeOH-Et3N 100:40:20) to give 780 mg (40%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: C[O:2][C:3]1([CH3:12])[O:9][CH:8]2[CH:5]([CH2:6][C:7]2([CH3:11])[CH3:10])O1.C[Si](C)(C)[Br:15]>C(Cl)Cl>[Br:15][C@@H:5]1[CH2:6][C:7]([CH3:11])([CH3:10])[C@H:8]1[O:9][C:3](=[O:2])[CH3:12]
Reactant: C[Si](C)(C)Br
Reactant: COC1(C)OC2CC(C)(C)C2O1
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](Br)CC1(C)C
Yield: 78.9 %

Procedure:
34.4 g (0.2 mol) of 3-methoxy-3,6,6-trimethyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 33.6 g (0.22 mol) of trimethylbromosilane in 150 ml of methylene chloride are heated to the reflux for 15 hours. Evaporation and fractional distillation of the residue in vacuo give 34.9 g (79%) of trans-1-bromo-2-acetoxy-3,3-dimethyl-cyclobutane. Boiling point14 87°-89°, nD20 1.4629.
Reaction SMILES: CCO.[C:4]1([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([O:20]CC3C=CC=CC=3)[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>[C].[Pd].C1COCC1>[O:20]=[C:12]1[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=[C:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:11]1
Reactant: [H][H]
Reactant: COC(=O)c1cc(OCc2ccccc2)nc(-c2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1

Procedure:
In a nitrogen atmosphere, 10% palladium-carbon (3.2 g) was added to an EtOH (50 mL)-THF (5 mL) mixed solution of methyl 2-phenyl-6-benzyloxypyridine-4-carboxylate (5.3 g), and in a hydrogen atmosphere, this was stirred at room temperature for 9 hours. The reaction liquid was filtered through Celite, concentrated under reduced pressure, and a mixed solution of hexane/ethyl acetate=2/1 was added thereto. The precipitate was taken out through filtration, washed with that solution, and dried to obtain the title compound as a white powder. The filtrate was concentrated, and the residue was purified through silica gel column chromatography (from hexane/ethyl acetate to chloroform/methanol), and combined with the previous powder to obtain the title compound as a white powder.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OCc1ccc2ccccc2c1
Product: N=C(OCc1ccc2ccccc2c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-hydroxymethylnaphthalene, there is obtained 2-naphthylmethyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 378 (19), 237 (15), 194 (90), 141 (100), 115 (53);
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][S:8][N:9]=2.Br[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[N:14]([CH3:16])[CH3:15]>>[N:9]1[S:8][N:7]=[C:6]2[CH:10]=[C:2]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[N:14]([CH3:16])[CH3:15])[CH:3]=[CH:4][C:5]=12
Reactant: CN(C)c1ccccc1Br
Reactant: Brc1ccc2nsnc2c1
Product: CN(C)c1ccccc1-c1ccc2nsnc2c1

Procedure:
Starting from 5-bromo-benzo[1,2,5]thiadiazole and 2-bromo-N,N-dimethylaniline. Orange resin. MS(ES+): 256 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([O:12]C)=O)[C:7]([NH:14][C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:23]=[N:24][N:25]([CH3:31])[C:26]=1[C:27]([NH:29][CH3:30])=[O:28]>>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:21][C:22]3[CH:23]=[N:24][N:25]([CH3:31])[C:26]=3[C:27](=[O:28])[NH:29][CH3:30])=[O:12])[C:7]([NH:14][C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1nc(C2CC2)cnc1Nc1cnccn1
Reactant: CNC(=O)c1c(N)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(C3CC3)cnc2Nc2cnccn2)cnn1C

Procedure:
According to the procedure described in step 2 of example 14, methyl 6-cyclopropyl-3-(pyrazin-2-ylamino)pyrazine-2-carboxylate was reacted with 4-amino-N,1-dimethyl-1H-pyrazole-5-carboxamide to give the title compound. Yellow solid.
Reaction SMILES: Cl[C:2]1[N:19]=[N:18][C:5]2[CH2:6][CH2:7][N:8]3[C:16]4[CH:15]=[CH:14][CH:13]=[C:12]([F:17])[C:11]=4[CH:10]=[C:9]3[C:4]=2[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B(O)O)=[CH:36][C:30]=3[C:31]=2[C:32](=[O:35])[NH:33][CH3:34])=[CH:23][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[F:17][C:12]1[C:11]2[CH:10]=[C:9]3[C:4]4[CH:3]=[C:2]([C:37]5[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]6[O:28][C:27]([C:24]7[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=7)=[C:31]([C:32]([NH:33][CH3:34])=[O:35])[C:30]=6[CH:36]=5)[N:19]=[N:18][C:5]=4[CH2:6][CH2:7][N:8]3[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B(O)O)cc12
Reactant: Fc1cccc2c1cc1n2CCc2nnc(Cl)cc2-1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cc4c(nn3)CCn3c-4cc4c(F)cccc43)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 13.2 %

Procedure:
To a degassed solution of 2-chloro-11-fluoro-5,6-dihydropyridazino[4′,3′:3,4]pyrido[1,2-a]indole (100 mg, 0.37 mmol), (2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)boronic acid (169 mg, 0.4 mmol) and K3PO4 (155 mg, 0.73 mmol) in DMF (3 mL) was added Pd(dtbpf)Cl2 (5 mg) under N2. Then the mixture was stirred at 100° C. for 3 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O and dried over Na2SO4. After being concentrated, the residue was purified by prep-HPLC to give the product of 5-(11-fluoro-5,6-dihydropyridazino[4′,3′:3,4]pyrido[1,2-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 13%). 1H-NMR (CDCl3, 400 MHz) δ 8.11 (d, J=9.0 Hz, 2H), 8.00 (dd, J=5.6, 8.8 Hz, 2H), 7.66 (s, 1H), 7.25 (s, 1H), 7.15˜7.23 (m, 4H), 6.81 (dd, J=7.6, 9.6 Hz, 1H), 6.17 (d, J=4.0 Hz, 1H), 4.47 (t, J=6.4 Hz, 2H), 3.67 (t, J=6.4 Hz, 2H), 3.21 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.97 (s, 3H). MS (M+H)+: 614.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5](Br)[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2].[C:17]([NH2:20])(=[S:19])[CH3:18]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[S:19][C:17]([CH3:18])=[N:20][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])=[O:16])[CH3:2]
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)c1ccccc1C
Solvent: CCO
Product: CCOC(=O)c1sc(C)nc1-c1ccccc1C
Yield: 33.5 %

Procedure:
A stirred mixture of 2-bromo-3-oxo-3-o-tolyl-propionic acid ethyl ester (2.74 g, 9.60 mmol, 1.0 equiv) and thioacetamide (0.76 g, 10.1 mmol, 1.05 equiv) in ethanol (30 mL) was heated to reflux for 4 hours. The cooled mixture was filtered and concentrated under vacuum. The residue was partitioned between ethyl acetate and water and the organic phase was separated and then washed with saturated aqueous sodium chloride solution. The collected organic was dried over magnesium sulphate, filtered, and concentrated under vacuum. The resultant residue was purified by flash column chromatography on silica gel (gradient: 0 to 20% ethyl acetate in pentane) to afford 0.84 g (34%) of 2-methyl-4-o-tolyl-thiazole-5-carboxylic acid ethyl ester as an oil. LCMS (ESI) m+H=261.9; 1H NMR (400 MHz, CDCl3) δ: 7.31-7.18 (m, 4H), 4.16 (q, 2H), 2.76 (s, 3H), 2.18 (s, 3H), 1.14 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].C1C=CC2N(O)N=NC=2C=1.[NH:19]([C:21]1[N:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)[NH2:20].CCOP(O)N(C(C)C)C(C)C>C(Cl)Cl.C1(N=C=NC2CCCCC2)CCCCC1.CCN=C=NCCCN(C)C.Cl.CO.C([O-])(O)=O.[Na+]>[F:1][C:2]([F:8])([F:7])[CH2:3][C:4]([N:19]([C:21]1[N:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)[NH2:20])=[O:5]
Reactant: O=C(O)CC(F)(F)F
Reactant: NNc1ccc(-c2ccc(Oc3ccccc3)cc2)nn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CCOP(O)N(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: NN(C(=O)CC(F)(F)F)c1ccc(-c2ccc(Oc3ccccc3)cc2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,3,3-trifluoropropionic acid (2.07 mmole) in DCM (10 mL), was added EDCI HCl (3.02 mmole) and HOBt (2.07 mmole). The solution was stirred at RT for 0.5 hour followed by addition of 3-hydrazinyl-6-(4-phenoxyphenyl)pyridazine A, prepared as disclosed in Example 3, (2.07 mmole) in 30 mL of DCM and EDIPA ((7.24 mmole). The coupling reaction will also work with 1,3-dicyclohexylcarbodiimide and DCM as a solvent or EDCI HCl and methanol as a solvent. The resulting reaction mixture was stirred at RT overnight. The mixture was diluted with saturated aqueous NaHCO3. The organic extract was washed with H2O and dried over Na2SO4 and then evaporated in vacuo. The crude product was purified with prep TLC eluting with 5% methanol and dichloromethane mixture to give B.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.[Br:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[O:39][C:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[C:37]([C:47]1[CH:52]=[CH:51][C:50]([C:53]3([NH:57]S(C(C)(C)C)=O)[CH2:56][O:55][CH2:54]3)=[CH:49][CH:48]=1)[C:36]2=[O:64]>>[NH2:57][C:53]1([C:50]2[CH:51]=[CH:52][C:47]([C:37]3[C:36](=[O:64])[C:35]4[C:40](=[C:31]([Br:30])[CH:32]=[CH:33][CH:34]=4)[O:39][C:38]=3[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:48][CH:49]=2)[CH2:56][O:55][CH2:54]1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)COC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)COC1
Yield: 34 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, 2-methyl-propane-2-sulfinic acid {3-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-oxetan-3-yl}-amide was reacted to give the title compound as a white solid (16 mg, 34%). 1H NMR (400 MHz, DMSO-d6): δ 8.18 (dd, J=7.8 and 1.6 Hz, 1H), 8.11 (dd, J=8.2 and 1.9 Hz, 1H), 7.54 (d, J=8.7 Hz, 2H), 7.50-7.34 (m, 6H), 7.23 (d, J=8.5, 2H), 4.71 (d, J=6.1 Hz, 2H), 4.67 (d, J=6.1 Hz, 2H), 3.32 (s, 2H). LCMS (Method E): RT=3.67 min, [M+H]+=448/450.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: C1=COCCC1
Reactant: OCCCCCCCBr
Product: BrCCCCCCCOC1CCCCO1

Procedure:
7-Bromoheptanol will be treated with dihydropyrane in the presence of acid to give 1-O-(tetrahydropyran-2-yl)-7-bromoheptanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[CH2:9][CH2:10][OH:11].[H-].[Na+].[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[CH2:9][CH2:10][O:11][C:26]([N:23]1[CH2:24][CH2:25][N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21][CH2:22]1)=[O:27]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Reactant: CN1CCN(C)C(CCO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C)C(CCOC(=O)N2CCN(c3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.3 %

Procedure:
2-(1,4-Dimethylpiperazin-2-yl)ethanol (703 mg, 4.44 mmol) was dissolved in anhydrous THF (20 mL) and the stirred solution cooled to 0° C. before NaH (60% dispersion in mineral oil; 550 mg, 13.8 mmol) was added. The suspension was left to stir for 10 minutes. 4-Nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 1.89 g, 5.77 mmol) was added to the reaction mixture, which was left to stir at room temperature for 3 hours. After this time the reaction was terminated by cooling the mixture to 0° C. and cautiously quenching with saturated aqueous NaHCO3 solution (50 mL). The THF was removed in vacuo and transferred to a separating funnel where the organic product was extracted with EtOAc (3×75 mL). The combined organic extracts were collected together and washed with saturated aqueous NaHCO3 solution (3×75 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give a crude yellow slurry. The crude residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 15% (over 70 min) to 100% (over 5 min) MeOH in water with 1% formic acid). De-salting (using K2CO3 in DCM), filtration and concentration in vacuo afforded 4-phenylpiperazine-1-carboxylic acid 2-(1,4-dimethylpiperazin-2-yl)ethyl ester (236 mg, 13%) as a dark yellow oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].CO.[CH2:17]1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromomethyl-3-nitrobenzoic acid (2.6 g, 10 mmol), MeOH (320 mg, 10 mmol) and DMAP (122 mg, 1 mmol) in methylene chloride (40 mL) was added DCC (2.06 g, 10 mmol) and the resulting mixture was stirred at ambient temperature for 2 h. The resulting precipitate was filtered and the filtrate evaporated under reduced pressure. The resulting oil was filtered through a plug of silica gel using methylene chloride as eluent. The solvent was removed under reduced pressure to give 4-bromomethyl-3-nitrobenzoic acid methyl ester as a pale-yellow oil.
Reaction SMILES: C([O-])(=O)C.[CH3:5][O:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][P+:12]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.CO.[P:38](=[O:42])([OH:41])([OH:40])[OH:39]>O>[P:38]([O-:42])([O-:41])([O-:40])=[O:39].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][P+:12]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:34][CH:35]=1.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][P+:12]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:34][CH:35]=1.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][P+:12]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:34][CH:35]=1
Reactant: O=P(O)(O)O
Agent: CC(=O)[O-]
Agent: COc1ccc(C[P+](c2ccc(C)cc2)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: O
Solvent: CO
Product: O=P([O-])([O-])[O-]

Procedure:
Into a 2 oz. (59 mL) bottle is placed 1.38 gm of 4-methoxybenzyl-tri-p-tolylphosphonium acetate.acetic acid complex followed by the addition of 1.75 gms of methanol. To another 2 oz. (59 mL) bottle is added 2.2 gms of water and 3.4 gms of 85% phosphoric acid and the contents mixed completely. To the first 2 oz. bottle is placed 0.56 gm of the phosphoric acid solution and the contents mixed completely.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([CH3:8])[CH3:7].CN1CCN(C)C1=O.O.C(O[CH:28](OCC)[N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[N:34][N+:35]([O-:37])=[O:36])C>>[CH:6]([C:9]1[CH:15]=[CH:14][C:12]([N:13]=[CH:28][N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[N:34][N+:35]([O-:37])=[O:36])=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: CC(C)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CC(C)c1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 41.6 %

Procedure:
0.05 g of concentrated sulfuric acid was dropped in a mixture of 5.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 2.48 g of p-isopropylaniline and 2 ml of 1,3-dimethyl-2-imidazolidinone at 110° C., followed by agitation at the same temperature for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and evaporated. Ether was added to the resultant oily residue and the resultant crystals were separated by filtration and dried to obtain 2.1 g of 1-(4-isopropylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:20]([F:22])[F:21])=[C:14]([CH:19]=1)[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:20]([F:21])[F:22])=[C:14]([CH:19]=1)[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(C(F)F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Treat a solution of methyl 5-(tert-butoxycarbonylaminomethyl)-2-(difluoromethyl)benzoate (1.43 g, 4.54 mmol, 1.0 equiv) in 1,4-dioxane (20 mL) with sodium hydroxide (5 N aqueous, 1.81 mL, 9.07 mmol, 2.0 equiv), and stir the mixture at room temperature overnight. Concentrate under reduced pressure, and adjust the pH to 4 with aqueous HCl. Extract with EtOAc (2×40 mL), and wash the combined organic extracts with saturated aqueous NaCl, separate, and dry the organic phase over Na2SO4, filter, and concentrate under reduced pressure to give the title compound (1.21 g, 88%). MS (m/z) 319 (M+18).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7][OH:8]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A mixture of [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (5.0 g, 18.3 mmol) and MnO2 (2.4 g, 27.5 mmol) in chloroform (110 mL) are heated to reflux for 48 hrs, cooled to room temperature, filtered through celite. Concentration gave 5 gram of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=1)[NH2:17])([O-:13])=[O:12].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:17][C:16]1[CH:18]=[C:19]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=1)=[O:6]
Reactant: Nc1cc(Oc2cccnc2)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cc(Oc2cccnc2)cc([N+](=O)[O-])c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
3-Chlorobenzoyl chloride (79 mg, 0.45 mmol, 1.05 eq), 4-dimethylaminopyridine (55 mg, 0.45 mmol, 1.05 eq) and 3-nitro-5-(pyridin-3-yloxy)aniline (0.1 g, 0.43 mmol, 1 eq) were dissolved in CH2Cl2 (5 mL) and stirred at rt for 18 h. Water was added and the organic layer separated, dried (MgSO4), filtered, and concentrated in vacuo to afford 140 mg (88%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.58 (t, J=1.9 Hz, 1H), 8.53 (d, J=2.8 Hz, 1H), 8.50 (dd, J=4.6, 1.0 Hz, 1H), 8.01 (t, J=1.8 Hz, 1H), 7.91-7.87 (m, 2H), 7.70-7.65 (m, 2H), 7.60-7.56 (m, 2H), 7.53 (dd, J=8.4, 4.7 Hz, 1H); ES-MS [M+1]+: 370.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:11]/[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: Cn1cc(C=O)c2ccccc21
Product: COc1ccc(/C(C#N)=C/c2cn(C)c3ccccc23)cc1OC
Yield: 73 %

Procedure:
1-Methylindole-3-carboxaldehyde (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (223 mg) through Method A (production step 2), to thereby yield the target product (yield: 292 mg, 73%).