Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrC1[CH:19]=[CH:20][CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[N:31]1CCCC1=O>O>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][C:20]1[CH:21]=[N:22][CH:23]=[N:31][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1S
Reactant: Brc1cccnc1
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1Sc1cncnc1
Temperature: 100 °C

Procedure:
A mixture of 2-(tert-butyl-dimethylsilanyloxymethyl)benzenethiol (5.6 g), 5-bromopyridine (4.6 g), cesium carbonate (11 g) and N-methylpyrrolidone (25 mL) was heated at 100° C. for 2 hours. The mixture was diluted with water and extracted with diethyl ether. The combined organic extract was washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound as a light brown oil (7.0 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17](B(O)O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:28]([OH:29])=[C:25]([O:26][CH3:27])[CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([C:22]([O:33][CH3:34])=[O:32])[CH:31]=[CH:30][C:28]=1[O:29][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B(O)O)cc2CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, Step 2) (500 mg, 1.72 mmol) was dissolved in dry dichloromethane (15 ml) and treated sequentially with methyl vanillate (313 mg, 1.72 mmol), molecular sieves (4 A, 1.0 g), copper acetate (467 mg, 2.58 mmol) and triethylamine (1.20 ml, 8.60 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane, filtered through celite and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic portion was dried under magnesium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of (0.1:9.9) to afford the title compound (240 mg). MS (ES+) m/e 328 [(M+H)—CO2tBu]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:52][N:53]1[CH:57]=[C:56](B2OC(C)(C)C(C)(C)O2)[CH:55]=[N:54]1>O.O1CCOCC1>[CH3:43][O:42][C:35]1[CH:34]=[C:33]([C:56]2[CH:55]=[N:54][N:53]([CH3:52])[CH:57]=2)[CH:38]=[CH:37][C:36]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnn(C)c2)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 90 °C
Reaction time: 0.58 h
Yield: 11.9 %

Procedure:
A vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE OOO) (71.96 mg, 0.151 mmol), (4-chloro-2-methoxyphenyl)boronic acid (31.0 mg, 0.166 mmol), Pd(AmPhos)2Cl2 (5.35 mg, 7.56 μmol), potassium phosphate (128 mg, 0.605 mmol), 1,4-dioxane (567 μl), and water (189 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 30 min h at 90° C. At this point, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62.9 mg, 0.302 mmol) and additional catalyst (about 3 mg) were added. The vial was resealed and heated in the microwave reactor for 1 h at 100° C. Additional portions of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62.9 mg, 0.302 mmol), potassium phosphate (128 mg, 0.605 mmol), and catalyst (about 3 mg) were added, and the vial was heated for 1 h at 100° C. in the microwave. The vial was heated for an additional 2 h at 110° C. The mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 35 min, the mixture was diluted with MeOH and filtered through diatomaceous earth. The filtrate was concentrated. The residue was purified by reverse-phase HPLC (25 to 70% CH3CN/H2O with 0.1% TFA). Fractions containing the desired product were combined in saturated aq. sodium bicarbonate solution with the aid of methanol. The mixture was extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give 1-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (8.5 mg, 0.018 mmol, 11.77% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.88 (br. s., 1H), 8.67 (d, J=5.7 Hz, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.29 (s, 1H), 8.06 (d, J=5.6 Hz, 1H), 8.01 (s, 1H), 7.89-7.74 (m, 2H), 7.38 (s, 1H), 7.34-7.24 (m, 3H), 6.87 (d, J=4.6 Hz, 1H), 3.91 (s, 3H), 3.71 (s, 3H); m/z (ESI) 478.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]([NH2:17])[CH3:16].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]([NH:17][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)(=[O:28])=[O:27])[CH3:16]
Reactant: CC(N)c1cc(F)ccc1-c1ccccc1F
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)NC(C)c2cc(F)ccc2-c2ccccc2F)cc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A stirred solution of 1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethylamine (0.26 g, 1.12 mmol) in dichloromethane (10 mL) was treated with 4-methoxybenzenesulfonyl chloride (0.23 g, 1.12 mmol), and pyridine (0.09 g, 1.12 mmol). The reaction was stirred at room temperature for twelve hours, diluted with dichloromethane, washed sequentially with a 1 N hydrochloric acid solution (2×) and a saturated, aqueous, sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and evaporated to a residue which, after crystallization from ethyl acetate-hexane, afforded the title compound (0.22 g, 0.53 mmol, 48%) as a racemic, homogeneous, colorless, crystalline solid, m.p. 182-184° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CC[N:33](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH2:33])=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc(N2N=C3c4ccc(C(N)=O)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.3 %

Procedure:
In a dried reaction flask, the crude 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (Compound 1) (0.43 g, about 0.967 mmol), DIEA (0.77 mL, 4.45 mmol) and HATU (2.154 g, 5.665 mmol) were added to a mixed solvent of DMF (3.65 mL) and dichloromethane (6.8 mL) Ammonia gas was passed thereto. The mixture was stirred at room temperature for 24 hr. Water and dichloromethane were added. The mixture was extracted with dichloromethane. The combined organic phase was washed with water and saturated salt water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to produce a crude yellow solid, which was then washed with methanol and ethyl ether respectively to produce a purified product (0.18 g) in 44.3% yield.
Reaction SMILES: C(O[BH-](O[C:11](=O)[CH3:12])OC(=O)C)(=O)C.[Na+].[CH2:15]1[O:24][C:23]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=2[O:16]1.[CH3:25][C:26]([CH3:28])=O.[OH-].[Na+]>C1COCC1.O.C(O)(=O)C>[CH:26]([N:20]([C:19]1[CH:21]=[CH:22][C:23]2[O:24][CH2:15][O:16][C:17]=2[CH:18]=1)[C:12]1[CH:11]=[CH:22][CH:23]=[CH:17][CH:18]=1)([CH3:28])[CH3:25]
Reactant: CC(C)=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(c1ccccc1)c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
Sodium triacetoxyborohydride (27.9 g, 134 mmol) is added poRTionwise over 45 minutes to a 0° C. solution of 3,4-methylenedioxy aniline (13.8 g, 101 mmol) in THF (100 mL), acetone (7.82 mL, 106 mmol) and acetic acid (5.9 mL) and the resultant mixture is allowed to attain RT overnight. The reaction mixture is cooled to 0° C. and then water (50 mL) is added slowly followed by 50% aqueous sodium hydroxide solution (20 mL) and the resultant mixture stirred for 1.5 h. The organics were removed and the residual aqueous phase diluted with water (30 mL) and extracted into ethyl acetate (3×50 mL). The combined organics were washed with water (2×100 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo to afford crude N-Isopropyl-N-(3,4-methylenedioxy-phenyl) aniline (12.0 g) as a dark oil which is used without further purification. 1H NMR (300 MHz, CDCl3) δ6.72 (d, 1H, J=8.3), 6.43 (s, 1H), 6.29 (s, br, 1H), 5.91 (s, 2H), 3.53 (m, 1H, J=6.8), 1.17 (m, 6H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[N:18]#[C:19][NH2:20].[Na]>>[O:15]1[CH2:16][CH2:17][CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:2]3[O:1][C:19]([NH2:20])=[N:18][CH2:3]3)=[CH:7][CH:8]=2)[CH2:13][CH2:14]1
Reactant: c1cc(C2CCOCC2)ccc1OCC1CO1
Reactant: N#CN
Agent: [Na]
Product: NC1=NCC(COc2ccc(C3CCOCC3)cc2)O1

Procedure:
The title compound was prepared from 4-(4-oxiranylmethoxy-phenyl)-tetrahydropyran and sodium hydrogen cyanamide according to the procedures employed for the preparation of the compound in Step 2 of Example 1.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([NH:19][C:20]([NH2:22])=[S:21])[S:16][C:17]=3[CH3:18])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([S:32](N)(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C(C)=CC=CC=1>C(OCC)(=O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]=[C:15]([NH:19][C:20]([NH:22][S:32]([C:28]4[C:29]([CH3:31])=[CH:30][C:25]([O:24][CH3:23])=[CH:26][C:27]=4[CH3:36])(=[O:34])=[O:33])=[S:21])[S:16][C:17]=3[CH3:18])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C)c(S(N)(=O)=O)c(C)c1
Reactant: Cc1sc(NC(N)=S)nc1-c1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)NC(=S)Nc2nc(-c3ccc(C4CCCCC4)cc3)c(C)s2)c(C)c1
Yield: 55.7 %

Procedure:
A mixture of N-[4-(4-cyclohexylphenyl)-5-methyl-2-thiazolyl]thiourea (1.00 g), 4-methoxy-2,6-dimethylphenylsulfonamide (1.30 g), potassium carbonate (500 mg) and xylene (40 ml) was refiuxed with heating for 2 hours. After ethyl acetate (200 ml) was added, the mixture was washed with 2 N-hydrochloric acid and water and dried (magnesium sulfate), after which the solvent was distilled off. The residue was subjected to silica gel chromatography and eluted with methanol-chloroform (5:95, v/v) to yield a crystal of 1-[4-(4-cyclohexylphenyl)-5-methyl-2-thiazolyl]-3-(4-methoxy-2,6-dimethylphenylsulfonyl)-2-thiourea (890 mg, yield 56%). This product was recrystallized from dichloromethane-methanol to yield a colorless prismatic crystal.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
69.1 g (0.5 mol) of para-hydroxybenzoic acid were first dissolved in 200 ml of water and 300 ml of isopropanol and this solution was adjusted to a pH of 10.5 at 20 to 25° C. using 87.4 g of NaOH solution (32% strength by weight aqueous solution, 0.7 mol). Metered into this solution then at a pH of 10.5, over the course of three hours, were 88.3 g (0.5 mol) of nonanoyl chloride. The pH was held at 10.5 using 40.5 g of NaOH solution (32% strength by weight aqueous solution, 0.324 mol), and the temperature was held at 20 to 25° C. The batch was stirred for one hour thereafter. Subsequently the reaction mixture was adjusted to a pH of 7 at 20 to 25° C. using 5.3 g of HCl solution (32% strength by weight aqueous solution) and adjusted to a pH of 1.5 to 3 at 65 to 70° C. using 60 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to room temperature (25° C.) and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 121.3 g (87.2% of theory). According to HPLC and NMR measurement, the product was free from nonanoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1(C)C=CC(S([CH2:21][N+:22]#[C-:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[O:11][CH:23]=[N:22][CH:21]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1ccc(-c2cnco2)cc1F
Yield: 434.7 %

Procedure:
To a 100 mL round-bottom flask was added 2-fluoro-4-formylbenzonitrile 37 (1.00 g, 6.7 mmol), methanol (25 mL), p-toluene sulfonylmethyl isocyanide (1.44 g, 7.37 mmol), followed by potassium carbonate (1.195 g, 8.64 mmol). The reaction mixture was stirred at reflux for about 1.5 hour and followed by TLC. The solvent was then evaporated and saturated aq.NaHCO3 was added. The resultant suspension was extracted with CH2Cl2 (2×20 mL). Combined organic layers were washed with brine, dried (anhydrous Na2SO4), and concentrated to leave a yellow solid. Crude product was further purified by MPLC (Biotage) silica column chromatography (Acetone/hexane as an eluent) to afford 2-fluoro-4-(oxazol-5-yl)benzonitrile 38 (5.48 g, 79% yield). MS (ES) m/z 189 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3F)=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][C:31]([CH2:32][NH2:33])=[C:26]2[CH:25]=[N:24]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([C:14]3[C:15]([NH:33][CH2:32][C:31]4[CH:30]=[CH:29][N:28]=[C:27]5[NH:23][N:24]=[CH:25][C:26]=45)=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:21])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2cc(NC(=O)c3cccnc3F)ccc21
Reactant: NCc1ccnc2[nH]ncc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(C)CCNc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ncc34)ccc21
Temperature: 120 °C

Procedure:
N-(4,4-Dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoro-nicotinamide (60 mg, 0.201 mmol) was dissolved in NMP (0.5 mL), then C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (36 mg, 0.243 mmol) and DIEA (70 μL, 0.401 mmol) were added. The mixture was heated at 120° C. overnight. Additional C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (14 mg, 0.094 mmol) and DIEA (35 μL, 0.200 mmol) were added and the mixture was heated at 120° C. overnight. The mixture was partitioned between water and EtOAc. The mixture was diluted with EtOAc then washed with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification was achieved by preparative TLC (10% MeOH/CH2Cl2) to give N-(4,4-dimethyl-1,2,3,4-tetrahydro-7-quinolinyl)-2-((1H-pyrazolo[3,4-b]pyridin-4-ylmethyl)amino)-3-pyridinecarboxamide as a yellow solid. MS m/e 428.2(M+H)+. Calc'd for C24H25N7O—427.51.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[O:11]=[C:3]1[NH:4][C:5]2[CH:10]=[C:9]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:8]=[CH:7][C:6]=2[S:1][CH2:2]1
Reactant: O=C1CSc2ccccc2N1
Reactant: O=S(=O)(O)Cl
Product: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered 4H benzo[1,4]thiazin-3-one (7.0g) was added cautiously, portionwise (over 20 minutes), to chlorosulfonic acid (15 mL), cooled in ice. After 1 hour, the blue solution was allowed to warm to room temperature and it was heated at 45° C. for 2 hours, cooled and poured into ice. The solid was collected, washed with water, and hexane, and dried in vacuo, to give a white solid (7.0 g): LC-MS (ES) m/e 263 (M)+.
Reaction SMILES: [F:1][C:2]([N+:9]([O-:11])=[O:10])([N+:6]([O-:8])=[O:7])[CH2:3][CH2:4][OH:5].[F:12][S:13]([F:20])=[C:14](O)[C:15]([F:18])([F:17])[F:16]>>[F:12][S:13]([F:20])=[C:14]([O:5][CH2:4][CH2:3][C:2]([F:1])([N+:9]([O-:11])=[O:10])[N+:6]([O-:8])=[O:7])[C:15]([F:18])([F:17])[F:16]
Reactant: OC(=S(F)F)C(F)(F)F
Reactant: O=[N+]([O-])C(F)(CCO)[N+](=O)[O-]
Product: O=[N+]([O-])C(F)(CCOC(=S(F)F)C(F)(F)F)[N+](=O)[O-]
Yield: 83 %

Procedure:
Using a method similar to example 12, 3-fluoro-3,3-dinitropropanol and pentafluorothioacetic acid were reacted to form 3-fluoro-3,3-dinitropropyl pentafluorothioacetate (83% yield) mp 28° C.;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.Br[CH2:14][C@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOCC>[Si:18]([O:17][CH2:16][C@@H:15]([CH3:25])[CH2:14][N:7]1[C:6]2[CH:12]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: Cc1ccc2c(c1)NC(=O)CO2
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)N(C[C@H](C)CO[Si](C)(C)C(C)(C)C)C(=O)CO2
Temperature: 50 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
A dry 50 mL r-flask was charged with 6-Methyl-4H-benzo[1,4]oxazin-3-one (0.59 g, 3.6 mmol), (R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (1.0 g, 3.6 mmol), Cs2CO3 (2.9 g, 8.9 mmol) and 10 mL of dry DMF. The mixture was stirred at 50° C. overnight (15 h) and dissolved in ether (50 mL) washed with water (20 mL) and the water phase was extracted with ether (20 mL). The combined organic phases were then washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and the resulting oil was purified by flash chromatography (SiO2; Heptane/EtOAc 85:15) to yield the title compound as an oil (1.1 g, 88%). 1H NMR (CDCl3) δ 6.87 (d, J=1.6 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.72 (dm, J=8.0 Hz, 1H), 4.5 (bars, 2H), 3.93 (dd, J=8.8, 14.0 Hz, 1H), 3.81 (dd, J=5.6, 14.0 Hz, 1H), 3.53 (dd, J=4.8, 10.2 Hz, 1H), 3.41 (dd J=7.2, 10.2 Hz, 1H), 2.25 (s, 3H), 2.18 (m, 1H), 0.87 (s, 9H), 0.83 (d, J=6.8 Hz, 3H), 0.01 (s, 6H); 13C NMR (CDCl3) δ 170.5, 148.9, 137.8, 129.6, 122.2, 121.6, 73.3, 71.6, 49.0, 39.7, 31.5, 26.6, 23.8, 20.1, 0.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12](=O)[CH2:13][C:14]#[N:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O.[NH2:18][NH2:19].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(O)C.O>[CH3:1][C:2]1[C:3]([C:12]2[CH:13]=[C:14]([NH2:15])[NH:19][N:18]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2ccccc2nc1C(=O)CC#N
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1nc2ccccc2nc1-c1cc(N)[nH]n1
Temperature: 25 °C

Procedure:
A suspension of 3-(3-methylquinoxalin-2-yl)-3-oxopropanenitrile (45.8 g, 217 mmol) and hydrazine monohydrate (15.8 mL, 325 mmol) in acetic acid (109 mL) and ethanol (1083 mL) was refluxed for 17 h. After being cooled to ambient temperature, the reaction mixture was diluted with water (360 mL) and basified to pH 8 with sodium bicarbonate. The resulting precipitate was collected and washed with diisopropyl ether. The crude was diluted with methanol (1077 mL) and potassium carbonate (29.9 g), and then heated at 60° C. for 2 h. The precipitate was collected and washed with diisopropyl ether to give 3-(3-methylquinoxalin-2-yl)-1H-pyrazol-5-amine. MS (APCI): m/z 226 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:24]1COCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[CH3:24])=[CH:9][N:10]=2)[N:7]=1
Reactant: C1CCOC1
Reactant: O=C(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Product: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(7-fluoroquinolin-6-yl)methanone (2.93 g, 6.73 mmol) in THF (80 mL) was added MeMgl solution (3 M in THF, 4.48 mL, 13.45 mmol) and the resulting solution was stirred at reflux for 5 h. Then the reaction mixture was cooled to rt, quenched with water, washed with NH4Cl solution and extracted by DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 2.2 g (95%) of the title compound which was used to next step.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:19]([C:22]1[CH:23]=[C:24]([CH:37]=[CH:38][CH:39]=1)[CH:25]=[C:26]([C:34]([CH3:36])=O)[C:27]([O:29][CH2:30][CH:31]1[CH2:33][CH2:32]1)=[O:28])([O-:21])=[O:20].[NH3:40]>C(O)C>[CH3:36][C:34]1[NH:40][C:3]([CH3:5])=[C:2]([C:1]([O:7][CH2:8][CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:11])=[O:6])[CH:25]([C:24]2[CH:37]=[CH:38][CH:39]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:26]=1[C:27]([O:29][CH2:30][CH:31]1[CH2:33][CH2:32]1)=[O:28]
Reactant: CC(=O)CC(=O)OCCN(C)Cc1ccccc1
Reactant: N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCC1CC1
Solvent: CCO
Product: CC1=C(C(=O)OCCN(C)Cc2ccccc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC2CC2)=C(C)N1
Reaction time: 8 h
Yield: 42.1 %

Procedure:
A mixture of 4.0 g (16 mmol) of 2-(N-benzyl-N-methylamino)ethyl acetoacetate, 4.6 g (16 mmol) of cyclopropylmethyl 2-(3-nitrobenzylidene)acetoacetate, 1.12 ml of 28% aqueous ammonia and 40 ml of ethanol was stirred at the reflux temperature for 8 hours, and then the solvent was removed under reduced pressure. The residue was chromatographed on silica gel column to afford 3-cyclopropylmethyl 5-[2-(N-benzyl-N-methylamino)ethyl] 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (3.5 g, 42.1%) as yellow oil. Treatment of this oil with hydrochloric acid gave the corresponding salt.