Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)(=O)[CH3:9].Cl.[C:18]1([NH:24][NH:25]C2C=CC=CC=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>O.CCCCCC>[C:18]1([N:24]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:25]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:9])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(NNc2ccccc2)cc1
Reactant: Cc1ccccc1
Reactant: CC(=O)c1ccccn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: CC(=NN(c1ccccc1)c1ccccc1)c1ccccn1

Procedure:
A mixture of 120 ml toluene, 80 ml hexane, 24.2 g acetylpyridine, 24.2 g of diphenylhydrazine hydrochloride, and 30 g of anhydrous sodium acetate was stirred and heated at reflux in a flask equipped with a water separator until no more water was being collected (about 2 hours). The reaction mixture was filtered, and the filtrate was distilled under aspirator vacuum at 60° C. The residue was stirred with 100 ml of methanol with cooling to keep temprature between -10° and -20° C. The resulting solid was collected, washed with 100 ml of cold methanol, and was dried in vacuo to give 43 g of acetylpyridine diphenylhydrazone, mp 84° C. λmax in methanol is 358 nm; absorptivity is 6.7×103.
Reaction SMILES: N1C(C)=CC=CC=1C.[C:9]([S:12][CH:13]1[N:16]([CH:17](Cl)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:32])[CH2:14]1)(=[O:11])[CH3:10].[C:33]1([P:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCOCC1>[C:9]([S:12][CH:13]1[N:16]([C:17](=[P:39]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:32])[CH2:14]1)(=[O:11])[CH3:10]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: CC(=O)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
2,6-Lutidine (2.14 g., 20 mmole) was added to a solution of p-nitrobenzyl 2-(4-acetylthio-2-oxo-1-azetidinyl)-2-chloroacetate (5.9 g., 16 mmole) and triphenylphosphine (5.8 g., 22 mmole) in dioxane (80 ml.). The solution was kept at 55° for 18 hours and then concentrated on a rotary evaporator. The residue was partitioned between brine and ethyl acetate and the organic phase was washed with brine, dried and concentrated. The residue was purified by chromatography over silica gel (ethyl acetate:petroleum ether, 1:2 v/v) to give 4.64 g. (48%) of the title ester.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:28]=[C:29]([O:33][CH3:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4ccccc4OC)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12c and 3-bromoanisole
Reaction SMILES: [OH:1][CH:2]([CH2:20]O)[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9].[BrH:22].[C:23]([OH:26])(=O)[CH3:24].C(=O)(O)[O-].[Na+].C(=O)=O>>[C:23]([O:1][CH:2]([CH2:20][Br:22])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[N:10]([CH3:19])[C:8]1=[O:9])(=[O:26])[CH3:24]
Reactant: Br
Reactant: CC(=O)O
Reactant: Cn1cnc2c1c(=O)n(CCCCC(O)CO)c(=O)n2C
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Product: CC(=O)OC(CBr)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 96 %

Procedure:
To 1-(5,6-dihydroxyhexyl)-3,7-dimethylxanthine 1.0 g, 3.38 mmol) was added 30% hydrogen bromide-acetic acid (3.4 mL) over 30 seconds and then stirred for 2.5 hours until all of the solid dissolved. The solution was poured carefully over a mixture of sodium bicarbonate (12 g) and ice water (50 mL). After carbon dioxide evolution had subsided, the mixture was extracted with dichloromethane (3×25 mL). The combined extracts were dried over magnesium sulfate and the solvent evaporated under vacuum, yielding 1.3 g (3.24 mmol, 96%) 1-(5-Acetoxy-6-bromohexyl)-3,7-dimethylxanthine as a viscous oil, dissolved in methanol (5 mL). A 1M sodium methoxide in methanol solution (3.9 mL) was added over 30 seconds. After stirring for 20 minutes, the solution was reated with water (20 mL) and then extracted with dichloromethane (3×15 mL). The combined extracts were dried over magnesium sulfate and the solvents were evaporated under vacuum to yield 900 mg (3.24 mmol, 100% yield) 1-(5,6-Oxidohexyl)-3,7-dimethylxanthine as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])#[N:20].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[F:30][C:22]1[CH:23]=[C:24]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=2)[CH:25]=[CH:26][C:21]=1[C:19]#[N:20]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CNc1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 100 °C

Procedure:
4-Chloro-N-methyl-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]-2-pyrimidinamine (110 mg, 0.392 mmol) and (4-cyano-3-fluorophenyl)boronic acid (97 mg, 0.588 mmol) were dissolved in 1,4-dioxane (4 mL) in a 20 mL sealable vial. Saturated NaHCO3 solution (5 mL) was added, and N2 gas was bubbled through the mixture for 10 minutes. Then Pd(Ph3P)4 (371 mg, 0.321 mmol) was added, and N2 gas was bubbled through the mixture for an additional 5 minutes. The reaction vial was then capped and heated at 100° C. overnight. The reaction was diluted with water (10 mL) and then extracted with EtOAc (3×10 mL). Organic was then combined, dried over MgSO4, filtered and concentrated. The yellow oil was then purified on Biotage SNAP 10 g column with a gradient of 0 to 35% EtOAc in Hexane for 30 minutes to afford the title compouns (167 mg). LC-MS (ES) m/z=366 [M+H]+.
Reaction SMILES: C(C1SC(C2SC(NC(=O)C)=C(C)N=2)=CC=1)=O.[CH:18]([C:20]1[S:24][C:23]([C:25]2[S:29][C:28]([NH:30][C:31](=[O:33])[CH3:32])=[N:27][C:26]=2[CH3:34])=[CH:22][CH:21]=1)=O.Cl.[NH2:36][OH:37].N1C=CC=CC=1>C1COCC1.C(O)C>[OH:37][N:36]=[CH:18][C:20]1[S:24][C:23]([C:25]2[S:29][C:28]([NH:30][C:31](=[O:33])[CH3:32])=[N:27][C:26]=2[CH3:34])=[CH:22][CH:21]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C=O)s2)s1
Reactant: NO
Agent: CC(=O)Nc1sc(-c2ccc(C=O)s2)nc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Nc1nc(C)c(-c2ccc(C=NO)s2)s1
Temperature: 70 °C

Procedure:
N-[2-(5-Formyl-thiophen-2-yl)-4-methyl-thiazol-5-yl]-acetamide, Compound (1) (104 mg; 0.39 mmol; 1 eq.), is dissolved in a THF/Ethanol 1:1 mixture (10 ml) at room temperature. Hydroxylamine hydrochloride (275 mg; 3.9 mmol; 10 eq.) and pyridine (310 μl; 3.9 mmol; 10.0 eq.) are added and reaction mixture is heated at 70° C. for 30 minutes. Reaction mixture is cooled down to room temperature and solvents are evaporated. The crude material is dissolved in dichloromethane and filtrated through a small silica cartridge, affording Compound (14) as mixture of oxime isomers, a yellow solid (55 mg; 55%). 1H NMR (MeOH-d4, 300 MHz) δ 2.25 (s, 3H), 2.50 (s, 3H), 6.65 (s, 1H), 7.12 (d, J=6 Hz, 1H), 7.40 (d, J=6 Hz, 1H), 7.72 (s, 1H). M−(ESI): 280.36; M+(ESI): 282.40. HPLC, Rt: 2.64 min (purity: 87.8%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])[CH:8]=2)[N:3]=1.[C:27]1([Mg]Cl)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1COCC1>>[NH:21]=[C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]1[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:18]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[CH:10]2
Reactant: Cl[Mg]c1ccccc1
Reactant: Cc1cccc(C#N)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Solvent: C1CCOC1
Product: Cc1cccc(C(=N)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 60 °C

Procedure:
To a sealed vessel containing 2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylbenzonitrile (0.10 g, 0.290 mmol, prepared as in Example 14, Step 1) was added phenylmagnesium chloride, 2.0M solution in THF (0.58 mL, 1.161 mmol). The mixture was sonicated until all solids were in solution and then warmed vessel to 60° C. for 15 h. The reaction mixture was cooled to RT and divided into two portions. The imine solution was concentrated in vacuo. The residue was taken up in 2.5 mL MeOH and purified by HPLC (10-100% MeCN/H2O with 0.1% TFA modifier) to afford 6-(2-(imino(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:29])=[CH2:28])[C:19]=4[S:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Zn](CC)[CH2:31]C.ClCI>C(Cl)Cl>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]5([CH3:31])[CH2:29][CH2:28]5)[C:19]=4[S:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C=C(C)c1cccc2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)sc12
Reactant: CC[Zn]CC
Agent: ClCI
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4c(C5(C)CC5)cccc34)c(C)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
A solution of 8-(1-ethyl-propyl)-3-(7-isopropenyl-2-methyl-benzo[b]thiophen-3-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (97 mg, 0.24 mmol) in CH2Cl2 (5 mL) is cooled to 0° C., treated with 1.0 M Et2Zn (1.2 mL, 1.2 mmol) and ClCH2I (176 μL, 2.4 mmol). The reaction is stirred at 0° C. for 30 min, then at RT for 1 h. The reaction is cooled to 0° C., quenched with sat. NH4Cl (10 mL); diluted with H2O (15 mL); extracted with EtOAc (3×30 mL); dried with Na2SO4, filtered and concentrated. The crude material is subjected to the same condition to ensure the conversion is completed. Purification of the crude material using silica gel chromatography gives the title compound (12.4 mg, 0.03 mmol, 12%). 1H NMR (CDCl3): δ 0.80-0.84 (m, 2H), 0.92 (t, J=6.9 Hz, 6H), 0.97-1.11 (m, 2H), 1.51 (s, 3H), 1.79-1.94 (m, 4H), 2.41 (s, 3H), 2.43 (s, 3H), 2.46 (s, 3H), 3.22-3.54 (m, 1H), 6.69 (s, 1H), 7.07 (d, J=7.5 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.26 (d, J=7.5 Hz, 1H) ppm. ES-MS (m/z): calcd for C26H31N3S (M+H)+: 418.6. found: 418.3.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:34])[CH2:32]Br)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:32]([C:31](=[O:34])[C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:26][CH:27]=3)=[CH:7][C:6]=2[CH:9]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1cc2cc(Br)ccc2o1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
5-Bromosalicylaldehyde (2.9 g, 14.5 mmol), cesium carbonate (2.5 g, 7.7 mmol) and acetonitrile (40 ml) were combined and heated to reflux for 30 minutes. The mixture was cooled to 0° C. and a solution of 4'-benzyloxy-2-bromoacetophenone (J. Het. Chem., 2, 310 (1965)) (4.7 g, 15 mmol) in acetonitrile (20 ml) was added. The cooling bath was removed, the mixture stirred at room temperature for 2.5 hours and the precipitate collected (4.5 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([SH:14])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].Cl.CCOCC>O.[OH-].[Na+]>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[NH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1nc(SCc2ccccc2)n[nH]1
Reactant: CC(Br)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(Sc1nc(SCc2ccccc2)n[nH]1)C(=O)O
Reaction time: 8 h
Yield: 48.7 %

Procedure:
3-Benzylthio-5-mercapto-1,2,4-triazole (56 g) was added with stirring and cooling to a solution of sodium hydroxide (10.1 g) in water (150 ml). A cold solution of 2-bromopropionic acid (38.4 g) in aqueous sodium hydroxide (10 g in 50 ml water) was added dropwise with stirring. The mixture was stirred for a further 6 hours at room temperature and allowed to stand overnight. After acidification with concentrated hydrochloric acid (30 ml), the precipitated white sticky solid was taken into ether. The ether solution was washed with water, dried, and the volume reduced to about 200 ml. The product crystallised, and was isolated by filtration to give 36.1 g of desired product, mp 123°-124° C. Successive reductions of the mother liquors gave further product, giving a total yield of 60 g.
Reaction SMILES: [CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:15])[C@H:6]1[N:5]([CH3:16])[CH2:4][CH2:3]2.C([Li])CCC.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C(COC)OC>[CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([O:14][C:29]([NH:28][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:30])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:15])[C@H:6]1[N:5]([CH3:16])[CH2:4][CH2:3]2
Reactant: O=C=Nc1ccccc1
Reactant: CN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Product: CN1CC[C@@]2(C)c3cc(OC(=O)Nc4ccccc4)ccc3N(C)[C@@H]12
Reaction time: 0.17 h
Yield: 96456.5 %

Procedure:
Eseroline base (50 g, 0.229 mol) was dissolved in 400 mL anhydrous dimethoxyethane under an argon atmosphere. Catalytic amounts of 2.5 M n-butyl lithium in hexanes (6.4 mL, 16 mmol) were added within 1 minute and the solution stirred for 10 minutes. Phenyl isocyanate (27.269 g, 0.2286 mmol) was added over 32 minutes keeping the temperature between 20 and 23° C. The reaction solution was stirred at r.t. for 2 hours 20 minutes, then transferred to an addition funnel. The reaction solution was added over 49 minutes to mixture of DI water (630 mL) and dimethoxyethane (42 mL) under vigorous stirring. The obtained slurry was stirred for 30 minutes, then filtered via a Buchner funnel (Whatman #3 filterpaper). The solid residue was washed four times with DI water (100 mL each) and once with heptane (100 mL), then dried at 45° C. and >29 inches of vacuum for 9 hours. Phenserine base (74.4 g) was obtained as reddish solid in 96.2% yield and 95.1% purity.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:29][C:30]1[C:31]([OH:41])=[C:32]([S:37]([NH2:40])(=[O:39])=[O:38])[C:33]([Cl:36])=[CH:34][CH:35]=1>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:11]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:2]=2[Br:1])=[O:13])=[C:31]([OH:41])[C:32]=1[S:37]([NH2:40])(=[O:39])=[O:38]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: Nc1cccc(F)c1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(F)c2Br)c1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 17.7 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (42 mg, 0.0.22 mmol) in toluene (5 mL), triphosgene (26 mg, 0.09 mmol) and triethyl amine (0.04 mL, 0.26 mmol) were added. The reaction mixture was stirred at 80° C. for 4 hours. Then the reaction mixture was concentrated under reduced pressure and then it was added to 3-amino-6-chloro-2-hydroxybenzenesulfonamide (44 mg, 0.22 mmol) in DMF (1 mL), The reaction mixture was stirred at room temperature for 16 hours. Chromatography of the resulting liquid on silica gel (30%Ethyl acetate/Hexane) gave desired product (7 mg, 7%). EI-MS m/z 439.6 (M+).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[Cl:21])[C:3]=12.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:30]([C:33]1([S:36]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][N:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[Cl:21])[C:12]2=[O:22])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(Br)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(Br)cc3Cl)c3c(F)c4nnsc4cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (40 mg, 0.10 mmol) in DCM (5 mL) was added triethylamine (21 mg, 0.20 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (27 mg, 0.15 mmol) and DMAP (10 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (50 mg, 87.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.78-7.76 (d, 2H), 7.33 (m, 1H), 5.76-5.58 (m, 1H), 5.08 (m, 2H), 2.93-2.86 (m, 1H), 2.13-2.0 (m, 1H), 1.97-1.87 (m, 2H), 1.28-1.16 (m, 2H).
Reaction SMILES: C[CH2:2][N:3]([CH:7](C)C)[CH:4](C)C.[CH:10]1[CH:11]=[CH:12]C2N([OH:19])N=[N:16][C:14]=2[CH:15]=1>CN1CCCC1=O>[NH:16]1[CH2:12][CH2:11][CH2:10][CH2:15][CH2:14]1.[CH3:7][N:3]([CH:2]=[O:19])[CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: C1CCNCC1
Product: CN(C)C=O

Procedure:
125 ml of 2.6 g Bop/1-methyl-2-pyrrolidone +1.7 ml of DIEA +0.8 g of HOBt (15 hours, two times)
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][CH:47]=[C:21]23)[CH2:16][CH2:15]1>C(OCC)(=O)C>[OH:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:3][C:4](=[O:7])[O:5][N:41]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][CH:47]=[C:21]23)[CH2:18][CH2:19]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.70 g), sodium hydrogen carbonate (1.0 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.47 g) was added, and the mixture was stirred at 90° C. for 23 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.20 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([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])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)(O)[O-].[Na+].O>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>[C:40]1([C:2]2[CH:3]=[C:4]([CH:8]([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(-c5ccccc5)c4)c3)ncnc21
Temperature: 80 °C
Yield: 95.8 %

Procedure:
To a solution of 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (from Example 429) (60 mg, 0.0001 mol) in 1,4-dioxane (2 mL, 0.02 mol), phenylboronic acid (15 mg, 0.00012 mol) and sodium bicarbonate (30 mg, 0.0003 mol) in water (0.5 mL, 0.03 mol) were added. The resulting mixture was degassed using nitrogen. Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.00001 mol) was added and nitrogen was bubbled through the reaction again. The reaction was heated at 80° C. in oil bath for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (50 mg, 80%) as a crude product. MS (ES): 522 (M+1).