Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=4)[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)[CH:19]=4)[CH2:14]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCC1
Reactant: O=C(CN1CCc2cc(O)ccc2C1)N1CCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCc2cc(OC3CCCC3)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinolin-6-ol (145 mg, 0.44 mmol) in DMF (10.0 ml) is added 1-bromo-cyclopentane (72 mg, 0.48 mmol), and K2CO3 (60 mg, 0.44 mmol). The resulting mixture is stirred at 50° C. overnight. Water (10.0 ml) is added to quench the reaction, and the mixture is extracted with DCM (10 ml×3). The combined organic phase is dried over sodium sulfate, and the solvent is removed under reduced pressure to give a residue that is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 6.84-6.94 (1H, m), 6.60-6.70 (2H, m), 4.68-4.74 (1H, m), 3.60-3.74 (6H, m), 3.36 (2H, s), 2.62-2.86 (5H, m), 2.22-2.34 (4H, m), 1.56˜2.10 (14H, m); MS (+VE) m/z 398.3 (M++1).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][C@@H:10]2[CH2:15][O:16][CH2:17][C@@H:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]2[CH2:15][O:16][CH2:17][C@@H:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CO[C@@H]2COC[C@H]2N1Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(CN2CCO[C@@H]3COC[C@H]32)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of trans-4-benzyltetrahydro-2H-furo[3,4-b][1,4]oxazin-3(4H)-one (3.1 g, 13.2 mmol) in THF (35 mL) at 0° C. was added BH3:THF (1.0 M in THF; 39.7 mL, 39.7 mmol). The reaction mixture was stirred at 0° C. for 16 hours. The reaction was quenched with aqueous 1 N NaOH solution, adjusting to pH 13, and extracted with EtOAc (100 mL). The organic extract was washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford trans-4-benzylhexahydro-2H-furo[3,4-b][1,4]oxazine. 1H NMR (400 MHz, CDCl3) δ 7.29-7.31 (m, 5H), 3.96 (t, J=7.2 Hz, 1H), 3.92 (ddd, J=11.6, 3.6, 1.2 Hz, 1H), 3.86 (m, 1H), 3.67-3.77 (m, 2H), 3.52-3.66 (m, 3H), 3.45 (dd, J=12.0, 9.0 Hz, 1H), 3.34 (d, J=13.2 Hz, 1H), 2.71 (ddd, J=12.0, 2.8, 1.2 Hz, 1H), 2.42 (ddd, J=15.6, 8.8, 6.8 Hz, 1H). MS APCI calc'd for C13H17NO2 [M+H]+ 220. found 220.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.Cl.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-[(1-{[2,4-Bis(trifluoromethyl)phenyl]methyl}-1H-indol-5-yl)methylidene]-3-[3-(dimethylamino)propyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 238) and 3-(dimethylamino)propyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([N:22]([CH:19]([CH3:21])[CH3:20])[NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCc1cc(F)ccc1OC1CCCC1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1cc(F)ccc1OC1CCCC1
Yield: 29.9 %

Procedure:
A solution of 3-(2-cyclopentyloxy-5-fluoro-phenyl)-propionic acid (220 mg, 0.87 mmoles) and benzoic acid N′-isopropyl-hydrazide (130 mg, 0.73 mmoles) in DMF (5mL) was treated with diisopropylethylamine (0.32 mL, 1.81 mmoles), and PyBroP (507 mg, 1.09 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (90 mg, 30%). LC-MS m/e 413.32 (M+H+)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1>>[CH3:18][N:19]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: CNc1cccc(OC)c1
Product: COc1cccc(N(C)c2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Yield: 100 %

Procedure:
A mixture of 4-chloro-2-(2-pyridinyl)-6-trifluoromethyl-pyrimidine (180 mg, 0.693 mmol) and N-methyl-3-methoxyaniline (112 mg, 0.816 mmol) in 3 mL of solvent (ethanol:water=2:1) was refluxed for 20 h. The solvent was removed under reduced pressure and the residue was dissolved in 25 mL of ethyl acetate. The ethyl acetate solution was washed with 25 mL of 1M NaOH, and the aqueous layer was reextracted with ethyl acetate (25 mL). The combined organic extracts were washed with saturated NaCl and dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (40-45% ethyl acetate/hexanes) to give the title compound as an oil (250 mg, 0.693 mmol, 100%). 1H NMR (CDCl3): 8.86 (dd, J=0.6, 4.5 Hz, 1H), 8.50 (d, J=7.5 Hz, 1H), 7.85 (dt, J=1.8, 7.8 Hz, 1H), 7.42 (m, 2H), 6.95 (dd, J=1.8, 8.4 Hz, 1H), 6.86 (m, 1H), 6.82 (m. 1H), 3.85 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)OCO2

Procedure:
To a solution of 38 gms. of 1-nitro-3,4-methylenedioxybenzene in 75 mls. of absolute ethanol is added 1.5 gms. of 5% palladium on carbon. The resulting mixture is hydrogenated at approximately 4 atmospheres pressure of hydrogen and ambient temperature for 4 hours. The catalyst is removed by filtration and the filtrate concentrated to a syrup. Trituration of the syrup with petroleum ether (b.p. 30°-60°C.) causes solidification and recrystallization from the same solvent provides 1-amino-3,4-methylenedioxybenzene, m.p. 37°C.
Reaction SMILES: O.S(=O)(=O)(O)O.[F:7][C:8]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][C:9]=1[NH2:10].[C:16]1([C:22](O)([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[F:7][C:8]1[CH:14]=[CH:13][C:12]([S:15][C:22]([CH3:24])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])=[CH:11][C:9]=1[NH2:10]
Reactant: Nc1cc(S)ccc1F
Reactant: CC(C)(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Sc1ccc(F)c(N)c1)c1ccccc1
Temperature: 0 °C
Yield: 45.9 %

Procedure:
To a mixture of water (10 mL) and concentrated sulfuric acid (10 mL) were added 2-fluoro-5-mercaptoaniline (1.85 g) and a solution of 2-phenyl-2-propanol (1.76 g) in tetrahydrofuran (10 mL) successively at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1−3/1) to give the title compound (1.55 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[NH:5][C:4](=[O:13])[C:3]=1[C:14]1[NH:18][C:17]2[CH:19]=[C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:21]=[CH:22][C:16]=2[N:15]=1.[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32]>CN(C)C(=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[NH:5][C:4](=[O:13])[C:3]=1[C:14]1[NH:18][C:17]2[CH:19]=[C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:31](=[O:32])[C:30]([F:37])([F:36])[F:29])[CH2:25][CH2:24]3)[CH:21]=[CH:22][C:16]=2[N:15]=1
Reactant: Nc1c(-c2nc3ccc(N4CCNCC4)cc3[nH]2)c(=O)[nH]c2cccc(F)c12
Reactant: CCOC(=O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: Nc1c(-c2nc3ccc(N4CCN(C(=O)C(F)(F)F)CC4)cc3[nH]2)c(=O)[nH]c2cccc(F)c12
Temperature: 130 °C

Procedure:
4-Amino-5-fluoro-3-(6-piperazin-1-yl-1H-benzoimidazol-2-yl)-1H-quinolin-2-one was taken up in ethyl trifluoroacetate and N,N-dimethylacetamide (DMA). The resulting solution was heated at 130° C. in a sealed tube for 30 minutes. The reaction was cooled to room temperature and quenched by addition of saturated aqueous sodium bicarbonate followed by pouring the mixture into water. The resulting solid was collected by filtration and washed with diethyl ether to afford 4-amino-5-fluoro-3-{6-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-1H-benzoimidazol-2-yl}-1H-quinolin-2-one (Rt 2.63 minutes, MH+=457.1), which was immediately taken up in THF. Borane-THF complex (3.3 equivalents) was added and the reaction was stirred at room temperature overnight. After quenching the excess borane with water, the mixture was extracted into ethyl acetate, dried over magnesium sulfate, filtered and concentrated to a brown solid which was purified by reverse phase HPLC to yield the desired compound. MH+=461.1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CC(C)[C@@H](CS(N1CCN(C2N=CC(C3C=CC([C:60]([F:63])([F:62])[F:61])=CC=3)=CN=2)CC1)(=O)=O)C(O)=O>>[F:61][C:60]([F:63])([F:62])[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][C:11]([N:14]3[CH2:15][CH2:16][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:21])=[O:22])[CH2:18][CH2:19]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)NO
Yield: 35 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 3-methyl-2-(R)-{4-[5-(4-trifluoromethylphenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}butyric acid (0.086 g), to provide the title compound as a white solid (0.031 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]([NH2:5])=[O:12]
Reactant: Cc1cccc(Cl)c1C#N
Reactant: O=S(=O)(O)O
Product: Cc1cccc(Cl)c1C(N)=O

Procedure:
A solution of 2-chloro-6-methylbenzonitrile (2.0 g) in conc. sulphuric acid (10 mL) was heated at 100° C. for 3-4 h. The reaction mass was quenched in ice-water and the solid obtained was filtered. The precipitate was suck dried to afford 1.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.28 (s, 3H), 7.21-7.27 (m, 3H), 7.65 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][OH:10].C(N(CC)CC)C.[CH3:18][C:19]([CH3:26])([C:23](Cl)=[O:24])[C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:20](=[O:21])[C:19]([CH3:26])([CH3:18])[C:23](=[O:24])[O:10]1
Reactant: ONCc1ccccc1Cl
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)ON(Cc2ccccc2Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
To a stirred solution of 8.3 grams (0.053 mole) of N-(2-chlorophenylmethyl)hydroxylamine and 12.1 grams (0.12 mole) of triethylamine in 200 ml of dry toluene was added dropwise a solution of 9.0 grams (0.053 mole) of dimethylmalonyl chloride in 50 ml of dry toluene. The addition required approximately 30 minutes and caused a white precipitate to form. The reaction mixture was stirred at room temperature for about 16 hours. The white precipitate was collected by filtration and washed with toluene. The combined wash and filtrate was washed with two portions of water and one portion of an aqueous solution saturated with sodium chloride and then dried with sodium sulfate. The solution was filtered from the sodium sulfate, and the filtrate was concentrated under reduced pressure to a viscous liquid. The liquid was subjected to column chromatography on silica gel. Elution was accomplished with 15% ethyl acetate in hexane. The fractions showing product by thin layer chromatography were combined to give an oil, which was distilled under reduced pressure to give 4.0 grams of 2-[(2-chlorophenyl)methyl]-4,4-dimethylisoxazolidine-3,5-dione; bp 115° C./0.03 mm. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[Li]CCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:31]=[O:32])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 51.7 %

Procedure:
To a solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1.96 g, 6.05 mmol) in THF (75 mL) was a 2.5 M solution of n-BuLi in hexanes (3.2 mL, 7.9 mmol) at −78° C. The reaction mixture was then stirred at −78° C. for 45 minutes. DMF (0.94 mL, 12.1 mmol) was then added. The resulting mixture was stirred at −78° C. for 2 hours before being poured slowly onto ice. The mixture was then extracted three times with DCM. The combined extracts were washed with water, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (25% EtOAc in heptane) to give the title compound (1.1 g, 52%). LCMS: M+H+=352.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH3:12])(=[O:10])=[O:9].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][CH3:12])(=[O:10])=[O:9])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNS(=O)(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 45 °C
Reaction time: 15 h
Yield: 49.5 %

Procedure:
A mixture of 2-amino-N-methyl-benzenesulfonamide (2.93, 15.75 mmol), 2,4,5 trichloropyrimidine (2.9 g, 15.84 mmol) and K2CO3 (4.5 g, 32.6 mmol) in dry DMF (25 mL) was stirred at 45° C. for 15 h. The solvent was removed and the residue was taken in water and was extracted twice from ethylacetate. Combined organic was washed with water and brine. After drying solvent was removed. Upon triturating with ether and filtration gave the product 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide 7 as a white solid (2.6 g, 50%); 1H NMR (400 MHz, CDCl3) δ9.61 (s, 1H), 8.6 (d=12.89 Hz, 1H), 8.53 (s, 1H), 8.27 (s, 1H), 7.68 (m, 1H), 7.27 (m, 1H0, 1.66 (br s, 1H0, 2.66 (s, 3H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][CH:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:4]1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][CH:3]1[CH2:7][CH2:6][CH:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:4]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCC(C=O)C4)c3)ncnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCC(CO)C4)c3)ncnc21
Reaction time: 0.17 h

Procedure:
A solution of 3-(3-formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (50.0 mg, 0.108 mmol) in methanol (280 μL) was cooled to 0° C., then sodium tetrahydroborate (14 mg, 0.37 mmol) was added. The reaction was held at 0° C. for 10 minutes, at which point LCMS and TLC indicated complete reaction. The reaction was quenched by cautious addition of 1N HCl (3 drops) and methanol (1 mL), followed by addition of aqueous NaHCO3 and CHCl3. The phases were separated and the aqueous phase was washed with additional CHCl3. The combined organic phase was washed with sat'd NaCl, dried over MgSO4 and reduced to dryness. The residue was purified by column chromatography to obtain the product as a mixture of diastereomers (37.4 mg, 74%). 1H NMR (400 MHz, CDCl3): 8.84 (s, 1H), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.29 (m, 1H), 3.53 (m, 1H), 3.53 (t, 2H), 3.14 (m, 1H), 2.95 (m, 1H), 2.68 (m, 1H), 2.2-1.0 (m, 9H), 0.92 (t, 2H), −0.059 (s, 9H). MS (EI) m/z=467.2 (M′H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCOCC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2-morpholin-4-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine and 4-(2-chloroethyl)-morpholine hydrochloride following General Procedure H.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[P:11]([O-:16])([O:14]C)[O:12][CH3:13].C(N(CC)CC)C>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[PH:11](=[O:14])([O:16][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1)[O:12][CH3:13]
Reactant: COP([O-])OC
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CO[PH](=O)Oc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
1-Iodo-3-nitrobenzene (249 mg, 1 mmol) was dissolved in 10 mL of acetonitrile. Tetrakis(triphenylphosphine)palladium (58 mg, 3 mol %), dimethyl phosphite (0.138 ml, 1.5 mmol) and triethylamine (0.28 ml, 2 mmol) were added thereto and stirred at 70° C. overnight. After removing a solvent, the mixture was purified in accordance with the purification process A to obtain a mixture (0.222 g) of monomethyl (3-nitrophenyl) phosphonate and dimethyl ester. The obtained monomethyl phosphonate was dissolved in 10 mL of methanol. Pd/C in catalyst quantity was added thereto and stirred under hydrogen atmosphere overnight. After filtering out the catalyst, a solvent was removed to obtain a mixture of monomethyl (3-aminophenyl) phosphonate and dimethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:30]1[CH2:34][CH2:33][N:32]=[C:31]1[C:35]1[CH:47]=[CH:46][C:38]([CH2:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([N:43]3[CH2:44][CH2:45][CH:40]([CH2:39][C:38]4[CH:37]=[CH:36][C:35]([C:31]5[NH:32][CH2:33][CH2:34][N:30]=5)=[CH:47][CH:46]=4)[CH2:41][CH2:42]3)=[O:29])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: c1cc(C2=NCCN2)ccc1CC1CCNCC1
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)N1CCC(Cc2ccc(C3=NCCN3)cc2)CC1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 2c) and 4-[4-(4,5-dihydro-1H-imidazol-2-yl)-benzyl]-piperidine (Reference Example 6) according to the method described in Example 1e. MS (EI) 674.3 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH:32]=O>C1(C)C=CC=CC=1>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:11])=[O:12]
Reactant: NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=Cc1ccc2ccccc2c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCCCCNCc1ccc2ccccc2c1
Yield: 18.1 %

Procedure:
A mixture of N-(6-Aminohexyl)-2-nitrobenzenesulfonamide hydrochloride (0.67 g, 2.0 mmol) and 2-naphthaldehyde (0.32 g, 2.1 mmol) in 75 mL of toluene was refluxed using a Dean Stark trap for 20 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethanol (40 mL) and sodium borohyride (0.020 g,6.0 mmol) was added. After the reaction was complete (6 h), the solvent was evaporated and residue taken up in 30 mL of saturated sodium chloride solution and extracted with ethyl acetate(3×40mL), washed with saturated sodium chloride solution, dried over sodium sulfate and concetrated to afford an oil. The oil was flash chromatographed over silica gel to afford the titled compound (0.16 g, 37%) which was converted into hydrochloride salt (mp 169° C.).