Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[C:15]([F:35])=[CH:16][C:17]([O:27][C:28]2[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[C:18]([CH:26]=1)[C:19](N(CC)CC)=[O:20]>C1COCC1>[Br:13][C:14]1[CH:26]=[C:18]2[C:17](=[CH:16][C:15]=1[F:35])[O:27][C:28]1[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][C:33]=1[C:19]2=[O:20]
Reactant: CCN(CC)C(=O)c1cc(Br)c(F)cc1Oc1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=c1c2cc(Cl)ncc2oc2cc(F)c(Br)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (3.14 mL, 7.84 mmol) was added to a solution of diisopropylamine (1.341 mL, 9.41 mmol) in THF (40 mL) at −78° C. The resulting solution was stirred at 0° C. for 15 minutes before being added dropwise via cannula to a solution of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethyl-4-fluorobenzamide (2.1 g, 5.23 mmol) in THF (40.0 mL) cooled to −78° C. under positive pressure. The resulting solution was stirred 3 hours at −78° C. before being quenched with saturated ammonium chloride (100 mL). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with saturated aqueous NH4Cl, water, saturated aqueous NaCl, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by dissolving in a minimal amount of CH2Cl2 and filtering through a pad of silica gel by eluting with 1:10 EtOAc in hexane, to provide 7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-c]pyridin-5-one as a off-white solid. MS m/z=330.0 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[OH:11])=[CH:15][C:14]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1ccc(O)c(C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 70.4 %

Procedure:
Using 5-methylsalicylic acid and 4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[H][H]>[Pd].O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:12])=[O:13]
Reactant: [H][H]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(N)c(S(N)(=O)=O)c1

Procedure:
A mixture of 2-amino-5-nitrobezenesulfonamide (10 g, 46.08 mmol), 10% palladium on charcoal (˜1 g) in tetrahydrofuran (250 mL) was hydrogenated for 26 h at 25° C. under 1 atmosphere of hydrogen gas via balloon. The mixture was then filtered through Celite, washed with tetrahydrofuran, and the solvent removed in vacuo to afford the desired product. The catalyst/Celite mixture was slurried in methanol (400 mL) for 16 h, filtered and the solvent was removed in vacuo to afford a second batch of the desired product, 2,5-diaminobenzenesulfonamide (combined: 7.79 g, 41.65 mmol, 90.4% yield) as a light-brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 4.54 (2H, bs), 4.98 (2H, bs), 6.55-6.60 (2H, m), 6.87 (1H, d, J=2.2 Hz), 6.99 (2H, bs). LC-MS (ESI) calcd for C6H9N3O2S 187.04, found 188.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:33])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:34]>CN(C)C=O.CO.O.NN>[NH2:1][C:2]1[C:7]2[C:8](=[O:33])[CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=3)[O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[F:34]
Reactant: Nc1c(F)ccc2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)cc3)cc(=O)c12
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: NCCCNc1ccc(-c2cc(=O)c3c(N)c(F)ccc3o2)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
4.78 g of Compound 15 was dissolved in 200 ml of a mixed solvent of dimethylformamide and methanol (1:1), 5.07 ml of hydrazine monohydrate was added and the mixture was stirred at 50-60° C. for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol :aqueous ammonia=9:1:1) to give Compound 16 which was dissolved in ethanol, a 5.5N hydrochloric acid- isopropylalcohol solution was added, isopropyl ether was added, and the precipitated crystals were collected by filtration to give 2.69 g (64%) of hydrochloride of Compound 16.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8].IC.[C:15](=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.C(OCC)(=O)C>[CH3:15][O:8][C:7](=[O:9])/[CH:6]=[CH:5]/[C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)/C=C/c1cccc(F)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1cccc(F)c1
Temperature: 65 °C
Yield: 87.6 %

Procedure:
To a mixture of trans-3-fluorocinnamic acid (50 g, 300 mmol) and iodomethane (300 mL) in acetone (1 L) was added portion wise cesium carbonate (147 g, 450 mmol, 1.5 equivalents), and the mixture was heated at 65° C. for 1.5 hours in a sealed reaction vessel. Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate (1 L), filtered through a pad of silica gel, and concentrated to give 47.33 g (87%) of trans-3-fluorocinnamic acid methyl ester as a colorless oil. MS (ES) m/z 180.0 (M+•).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:9]([C:16](OCC)=[O:17])=[C:10]([CH2:14][CH3:15])[CH:11]=[N:12][CH:13]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[CH2:16][OH:17]
Reactant: CCOC(=O)c1c(Cl)cncc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cncc(Cl)c1CO
Reaction time: 1 h
Yield: 88 %

Procedure:
To a suspension of lithium aluminum hydride (LAH, 0.920 g, 24.24 mmol) in anhydrous THF (20 mL) at 0° C. was added dropwise a solution of ethyl 5-chloro-3-ethylpyridine-4-carboxylate (2.59 g, 12.12 mmol) in THF (30 mL). After stirring for 1 hour, the reaction mixture was slowly quenched with 15% aqueous NaOH and then water. Ethyl acetate was added, and the mixture was stirred for 10 minutes. The white precipitate was filtered off and washed with ethyl acetate (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to provide (3-chloro-5-ethylpyridin-4-yl)methanol as a thick oil (1.83 g, 88% yield) and used for the next step without any further purification; M+166.5.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2CCO[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[CH:53]([OH:56])[CH2:52][CH2:51]1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][CH:53]([OH:56])[CH2:52][CH2:51]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: OC1CCNCC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCC(O)CC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and piperidin-4-ol and isolated as light-yellow gum (12.6 mg, 67%). MS(m/e): 401.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:16](Cl)(=O)=O)[CH:12]=2)[O:7][CH2:6]1.COC(=O)C=C1C(=O)C2C(=CC=C(SCC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)C=2)OC1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([SH:16])[CH:12]=2)[O:7][CH2:6]1
Reactant: COC(=O)CC1COc2ccc(S(=O)(=O)Cl)cc2C1=O
Agent: COC(=O)C=C1COc2ccc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)cc2C1=O
Product: COC(=O)CC1COc2ccc(S)cc2C1=O

Procedure:
Compound 20D was prepared according to the method of example 1C utilizing compound 20C. Compound 20D was prepared in 75% yield. MS: 251 (M−1)+. Preparation of 6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-4-oxo-chroman-3-ylidene-acetic acid methyl ester (Compound 20E)
Reaction SMILES: [C:1](/[C:4](/[N:7]([CH2:13][CH3:14])[C:8](=O)[CH2:9][CH2:10][CH3:11])=[CH:5]\[NH2:6])(=[O:3])[CH3:2].[OH-].[Na+].[NH4+].[Cl-]>CCO>[CH2:13]([N:7]1[C:4]([C:1](=[O:3])[CH3:2])=[CH:5][N:6]=[C:8]1[CH2:9][CH2:10][CH3:11])[CH3:14]
Reactant: CCCC(=O)N(CC)/C(=C/N)C(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CCCc1ncc(C(C)=O)n1CC
Reaction time: 48 h
Yield: 99.1 %

Procedure:
A solution of N-[(E)-1-acetyl-2-aminoethenyl]-N-ethylbutanamide (Method 11; 33.9 g, 171 mM) and NaOH (8.2 g, 205 mM) in EtOH (400 ml) was heated under reflux for 4 hours. NH4Cl (11.9 g, 222 mM) was added to the hot solution, which was allowed to cool and stir for 48 hours. The reaction mixture was filtered and the solution was evaporated. The residue was taken into ether and filtered again. The solution was evaporated to give the title compound as a yellow oil (30.55 g, 74%). NMR (300 Mz, DMS0-d6): 0.92 (t, 3H), 1.17 (t, 3H), 1.70 (sext, 2H), 2.37 (s, 3H), 2.64 (t, 2H), 4.23 (q, 2H), 7.83 (s, 1H); m/z 181.
Reaction SMILES: OCCN.Cl.C1([CH:12]2[CH2:22][N:15]3[C:16]([CH3:21])=[N:17][C:18]([Cl:20])=[CH:19][C:14]3=[N:13]2)C=CC=CC=1>>[CH3:21][C:16]1[N:15]2[CH2:22][CH2:12][N:13]=[C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=1
Reactant: CC1=NC(Cl)=CC2=NC(c3ccccc3)CN12
Agent: Cl
Solvent: NCCO
Product: CC1=NC(Cl)=CC2=NCCN12

Procedure:
By substituting α-phenyl-β-hydroxyethylamine for β-hydroxyethylamine in the above procedure, 2-phenyl-5-methyl-7-chloro-2,3-dihydroimidazo[1,2-c]pyrimidine hydrochloride was prepared decomposing about 150° C. after recrystallization from an ethanol-ethyl acetate ether solvent mixture.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1
Temperature: 90 °C
Yield: 74.4 %

Procedure:
To a stirring solution of p-fluorobenzaldehyde (6.15 mmol, 0.763 g) in dimethylformamide (20.5 mL) was added cesium carbonate (4.1 mmol, 1.33 g) and 38 (4.1 mmol, 0.819 g). This solution was heated to 90° C. and monitored with TLC. When complete, the reaction mixture was cooled to room temperature and filtered through a fritted funnel. The filtrate was then diluted with ethyl acetate (200 mL) and extracted with eight 15 mL portions of water and one 10 mL portion of brine. The organic layer was dried over magnesium sulfate, evaporated to dryness and purified with flash chromatography to yield 0.930 g (3.05 mmol) of the title product. 1H NMR (500 MHz, CDCl3) δ 9.93 (s, 1H), 7.85 (d, J=8.6, 2H), 7.55-7.22 (m, 6H), 7.07 (d, J=8.7, 2H), 6.86 (d, J=8.3, 1H), 6.71 (dd, J=5.2, 10.7, 2H), 5.06 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 190.79, 162.93, 160.50, 156.39, 131.94, 130.61, 128.66, 128.15, 127.52, 117.78, 112.66, 111.44, 107.25, 70.18.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]([CH2:5][CH2:4][CH2:3][C:2]([OH:25])=[O:1])([C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:13])([CH3:17])([CH3:18])[CH3:16]
Reactant: COC(=O)C1(CCCC=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COC(=O)C1(CCCC(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-(4-oxobut-1-yl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylate (23.0 g, 0.0734 mol) from Step C in acetone (775 mL) at room temperature was added Jones reagent (28.2 mL, 2.6M) via syringe. After 5 min, the reaction mixture was concentrated. The residue was taken up in water and diethyl ether and extracted three times with diethyl ether. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (23.4 g) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]2[CH2:17][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:24][CH2:23]1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]([OH:16])[CH2:17][NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:24][CH2:23]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Product: O[C@@H](CNCC1CCN(CCC(F)(F)F)CC1)COc1ccc(OCc2ccccc2)cc1
Yield: 3.8 %

Procedure:
Prepared from 2-(S)-(4-benzyloxy-phenoxymethyl)-oxirane (0.40 g, 1.57 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.329 g, 1.57 mmol) according to the procedure used for Example 2 to provide 0.0280 g of product as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:14])=[CH:15][CH:16]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cn2nccc2Br)cc1
Reactant: C1CCNC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(c1ccc(Cn2nccc2Br)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
4-((5-bromo-1H-pyrazol-1-yl)methyl)benzoic acid (200 mg, 0.71 mmol), pyrrolidine (61 mg, 0.85 mmol) and EDC-HOBt (452 mg, 2 mmol) were combined in CH2Cl2 and stirred for 4 h at room temperature. The mixture was evaporated in vacuuo and the residue dissolved in ethyl acetate and washed with water. The separated organic layer was dried and concentrated affording the product as an oil (231 mg, yield 99%), which was used in next step without further purification. LCMS (m/z): 334.2 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:9][CH2:8]1.O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:26][C:25]1[C:3]2[C:2](=[CH:24][CH:23]=[CH:22][C:4]=2[O:5][CH2:6][CH:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:11][CH2:12]2)[N:1]=[C:28]([CH3:35])[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: N#Cc1c(N)cccc1OCC1CCC(NC(=O)c2ccncc2)CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCC(NC(=O)c4ccncc4)CC3)c2c1N

Procedure:
Prepared as in Example 2a from N-(4-((3-Amino-2-cyanophenoxy)methyl)cyclohexyl)-isonicotinamide (Example 108b) and ethyl 3-oxobutanoate as a yellow solid (25%). MS 463 (MH+).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[OH:10])=[CH:15][CH:14]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccccc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccc2OC)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1.5 g of o-anisaldehyde are dissolved in THF and cooled to 0° C. 24.2 ml of 4-methoxyphenylmagnesium bromide (0.5 M in THF) are added to the mixture. The reaction solution is stirred at room temperature overnight and then poured into a 20% NH4Cl solution and extracted with ethyl acetate. 2.63 g of the product are obtained, and this can be employed without further purification.C15H16O3 (244.29) MS (ESI+) 227.05 (M−OH)+
Reaction SMILES: C(OC([N:8]([CH2:16][C@H:17]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[O:25][CH2:26][CH2:27][O:28][C:20]=12)[CH3:18])C(=O)OC(C)(C)C)=O)(C)(C)C.[ClH:29].CC(O)C>CCO>[ClH:29].[ClH:29].[O:28]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][C:19]=2[C@H:17]([CH3:18])[CH2:16][NH2:8])[O:25][CH2:26][CH2:27]1
Reactant: C[C@H](CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1ccnc2c1OCCO2
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: C[C@H](CN)c1ccnc2c1OCCO2
Reaction time: 16 h
Yield: 100 %

Procedure:
As shown in step 7-iv of Scheme 7, (S)-tert-butyl N-tert-butoxycarbonyl-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl]carbamate (7.74 g, 39.8 mmol) was dissolved in EtOH, HCl in IPA (60 mL of 4 M solution, 240 mmol) was added and the reaction mixture was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure to a minimum volume, Et2O was added, and the resulting suspension stirred for 16 hours. The solid was collected by filtration and dried under high vacuum to provide (S)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propan-1-amine, dihydrochloride as a yellowish solid (Compound 2025, 10.55 g, 100% yield): 1H NMR (300 MHz, CDCl3) δ 7.80 (d, 1H), 7.10 (d, 1H), 4.50 (m, 2H), 4.40 (m, 2H), 3.40 (m, 1H), 3.00 (m, 2H), 1.25 (d, 3H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[O:4]1[CH2:8][CH2:7][O:6][CH:5]1[CH2:9][CH2:10]Br>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[O:4]1[CH2:8][CH2:7][O:6][CH:5]1[CH2:9][CH2:10][C:1]#[N:2]
Reactant: [C-]#N
Reactant: BrCCC1OCCO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CCCC1OCCO1
Temperature: 90 °C
Yield: 88 %

Procedure:
58.8 g (1.2 mol) of sodium cyanide and 22.28 g (0.12 mol) of benzyltrimethylammonium chloride are dissolved in 360 ml of water. Thereafter 181.03 g (1.0 mol) of 2-[1,3]-dioxolan-2-yl-1-bromoethane are added dropwise and the reaction mixture is heated at 90° C. After six hours it is cooled, diluted with 400 ml of water and subjected to extraction with ether. Drying over magnesium sulfate and evaporation of the solvent give 111.85 g of 3-[1,3]-dioxolan-2-yl-propionitrile as a reddish oil which is used without further purification in the next stage of the reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([O-])=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([N:24]3[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][OH:17])[CH2:22][CH2:23]3)=[CH:28][CH:29]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([N:24]3[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][OH:17])[CH2:26][CH2:25]3)=[CH:35][CH:34]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C([O-])c1ccc(N2CCN(CCCO)CC2)cc1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCN(CCCO)CC4)cc3)cc2)cc1)c1ccc(N2CCN(CCCO)CC2)cc1

Procedure:
Compound 318 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-(4-(3-hydroxypropyl)piperazino)benzoate. [M+H]+ calcd for C41H48N6O5: 705.37; found: 705.19.
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.[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([Cl:51])=[CH:49][N:48]=[C:47]([NH:52][CH2:53][CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][NH:59][CH2:58][C@H:57]4[CH3:62])[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35]>>[ClH:3].[ClH:51].[ClH:1].[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([Cl:51])=[CH:49][N:48]=[C:47]([NH:52][CH2:53][CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][N:59]([CH3:4])[CH2:58][C@H:57]4[CH3:62])[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35]
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCNC[C@H]4C)ncc3Cl)cc12
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)C[C@H]4C)ncc3Cl)cc12

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 (R)-2-{5-chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 473 (35Cl) and 475 (37Cl) [M+H].
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=[N:17][OH:18])=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2n[nH]cc2C=NO)o1
Temperature: 0 °C
Yield: 97 %

Procedure:
Stir together 18 g of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde, 6.95 of hydroxylamine hydrochloride and 8.2 g of sodium acetate in 70 ml of water for 1.5 hours at 70° C. Cool the resulting admixture slowly to 0° C. Separate the formed precipitate by vacuum filtration and wash the residue with several portions of ice-cold water to obtain a 97% yield of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehydeoxime [m.p. 233° to 235° C (with decomposition)].
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:35])([C:19]([F:34])([F:33])[C:20]([F:32])([F:31])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH2:5][CH2:6][CH2:7]C1C=C(C)C=CC=1S([O-])(=O)=O>O1CCCC1>[CH3:1][NH:2][CH2:7][CH2:6][CH2:5][C:4]([F:3])([F:35])[C:19]([F:33])([F:34])[C:20]([F:31])([F:32])[C:21]([F:29])([F:30])[C:22]([F:27])([F:28])[C:23]([F:26])([F:25])[F:24]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 83.7 %

Procedure:
4.44 g of methylamine is condensed in a solution of 3.86 g of 4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-nonyltosylate in 10 ml of absolute tetrahydrofuran at −20° C., and it is stirred in a pressure vessel at room temperature. After the pressure vessel was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. The reaction solution is taken up in dichloromethane, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 2.38 g of methyl-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-nonyl)-amine is obtained as a crude product.