Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][C:9]#[CH:10])[CH:6]=[N:5][CH:4]=1.S(Cl)([Cl:13])=O>>[ClH:13].[Cl:13][CH2:2][C:3]1[N:7]([CH2:8][C:9]#[CH:10])[CH:6]=[N:5][CH:4]=1
Reactant: C#CCn1cncc1CO
Reactant: O=S(Cl)Cl
Product: C#CCn1cncc1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 5-hydroxymethyl-1-(2-propyn-1-yl)imidazole (8.0 g) was added by portions thionyl chloride (40 ml) at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in methanol, and then, the solvent was distilled off again under reduced pressure. The obtained solid was recrystalized from ethyl acetate, to give 5-chloromethyl-1-(2-propyn-1-yl)imidazole hydrochloride (9.8 g) as colorless crystals.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].C(Cl)(=O)C(Cl)=O.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.CN(C=O)C>[CH2:14]([O:6][C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: C#CCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CCCC(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 134.9 %

Procedure:
To a solution in dichloromethane (25 mL) containing a few drops DMF of 4-pentynoic acid (2.49 g, 23.4 mmol) was added oxalyl chloride (2.2 mL, 25 mmol). The reaction mixture was stirred for 1.5 hours and benzyl alcohol (3.9 mL, 38 mmol) was added via syringe. The reaction mixture was stirred for 6 hours and then was extracted with saturated aqueous sodium carbonate. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 4-pentynoic acid benzyl ester (5.94 g) as a yellow liquid.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][O:22][C:23](=O)[O:24]C>C1COCC1>[O:3]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]([C:23]([O:22][CH3:21])=[O:24])[C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)OC
Reactant: COC(=O)Cc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a suspension of NaH (1.02 g of 60% NaH in mineral oil washed with hexanes, 0.61 g, 25.6 mmol) in dry THF (30 mL) was added methyl (4-phenoxyphenyl)acetate (2.7 g, 11.1 mmol ) in dry THF (10 mL). The resulting mixture was stirred at room temperature for 30 minutes and then dimethylcarbonate (4.0 g, 3.75 mL, 44.4 mmol) was added . The reaction mixture was heated to reflux overnight and then cooled to room temperature, quenched with 1N HCl (60 mL), and extracted with ether (2×100 mL). The combined organic extracts were washed with water, then brine, dried (Na2SO4), concentrated, and purified using HPLC (porasil) eluted with 15% EtOAc/hexanes to give 2.56 g of dimethyl 2-(4-phenoxyphenyl)malonate as a white solid: 1H NMR (200 mHz, CDCl3) δ 7.39-6.92 (9H, m), 4.65 (1H, s), 3.75 (6H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:19].CC(C)([O-])C.[K+].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[C:21](\[O:20][CH2:18][CH3:19])/[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC(=O)OCC
Reactant: Cc1cc(C=O)ccc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)c(C)c1)OCC
Temperature: -20 °C
Yield: 24.8 %

Procedure:
4-(Benzyloxy)-3-methylbenzaldehyde (2.36 g; 10.2 mmole) and ethyl ethoxyacetate (1.62 g; 12.3 mmole) were dissolved in dry THF (10 ml) and cooled to −20° C. Potassium tert-butoxide (1.38 g; 12.3 mmole) dissolved in dry tetrahydrofuran (1 ml) was slowly added and the reaction was stirred over night at −20° C. The reaction was quenched with acetic acid (0.80 g; 13.3 mmole). The crude product was isolated, redissolved in toluene and refluxed overnight with p-toluenesulfonic acid (0.18 g; 1.0 mmole) in a Dean-Stark apparatus to separate the water. The solution was cooled, washed with sodium hydrogen carbonate, dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 10 μm, 50×500 mm) using acetronitrile (50-100%) in ammonium acetate buffer (pH 7) as mobile phase gave 0.86 g (25% yield) of ethyl (2Z)-3-[4-(benzyloxy)-3-methylphenyl]-2-ethoxyacrylate.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH:16]=[C:17]([CH2:19][CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21](O)=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][C:61]1[CH:62]=[CH:63][C:64]([NH2:67])=[N:65][CH:66]=1>CN(C=O)C.O>[CH3:1][N:2]([CH3:26])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:15]3[CH:16]=[C:17]([CH2:19][CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([NH:67][C:64]3[CH:63]=[CH:62][C:61]([CH3:60])=[CH:66][N:65]=3)=[O:22])[CH:11]=2)=[CH:24][CH:25]=1)=[O:4]
Reactant: Cc1ccc(N)nc1
Reactant: CCc1cc2c(Oc3ccc(C(=O)N(C)C)cc3)cc(C(=O)O)cc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(Oc3ccc(C(=O)N(C)C)cc3)cc(C(=O)Nc3ccc(C)cn3)cc2o1
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A solution of 4-{4-[(dimethylamino)carbonyl]phenoxy}-2-ethyl-1-benzofuran-6-carboxylic acid (400 mg, 1.13 mmol), HATU (671 mg, 1.70 mmol) and DIPEA (226 mg, 1.70 mmol) in DMF (20 mL) was stirred for 1 h. Then 5-methylpyridin-2-amine (146 mg, 2.26 mmol) was added. The resulting solution was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 1:1). The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via preparative HPLC to afford the desired compound (133.7 mg, 27%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.92 (bs, 1H), 8.25 (d, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 7.55 (d, 2H), 7.44-7.37 (m, 3H), 6.96 (d, 2H), 6.22 (s, 1H), 3.10-2.93 (d, 6H), 2.74 (q, 2H), 2.26 (s, 3H), 1.26 (t, 3H). LCMS m/z 444.40 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[N:10]=[CH:9]N(C(OC(C)(C)C)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:19]([N:22]([CH:26]([C:32](OCC)=O)[C:27](OCC)=O)[CH2:23]CC)CC>C1COCC1.CCOCC>[CH3:19][N:22]([CH3:23])[CH:26]1[CH2:32][C:7]2[C:11]3=[C:3]([CH:2]=[CH:9][N:10]3[CH2:27]1)[CH:4]=[CH:5][CH:6]=2
Reactant: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)C1Cc2cccc3ccn(c23)C1

Procedure:
This compound was prepared by following the procedure of Example 18, but substituting methyl 7-(bromomethyl)-1H-indole-1-carboxylate for t-butyl 4-(bromomethyl)-1H-benzimidazole-1-carboxylate and diethyl (dimethylamino)malonte for diethyl (dipropylamino)malonate. The bulk of the product was converted to the maleate salt, mp 114°-115° C. from THF/ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([OH:25])=[O:24].[OH:26]OS([O-])=O.[K+]>C1COCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])(=[O:26])=[O:19])=[CH:14][CH:13]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)=O)cc1
Reactant: O=S([O-])OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 24 h

Procedure:
To 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid (12.0 g, 33.66 mmol) in 140 ml THF is added gradually at 0° C. a solution of OXONE (12.47 g, 36.72 mmol) and tetrabutylammoniumhydrogensulfate (1.0 g, 1.62 mmol) in 35 ml H2O. The temperature of the reaction mixture is maintained in the range of 13°-23° C. After 24 h at room temperature, the THF phase is separated from the water phase and is dripped into water (280 ml, 40° C.). The suspension is stirred until it reaches room temperature. The yellow crystals of 5-fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid are filtered off and are washed with water (30 ml). 11.3 g, 30.29 mmol, 90% mp. 204°-206° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=O)[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O1CCCC1.C(O)C.[CH3:33][C:34]([CH3:44])=[CH:35][C:36]1[CH:37]=[CH:38][C:39]([CH:42]=O)=[N:40][CH:41]=1.C([N:47](CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:47][C:42]([C:39]4[CH:38]=[CH:37][C:36]([CH:35]=[C:34]([CH3:44])[CH3:33])=[CH:41][N:40]=4)=[CH:16][CH:15]=3)[CH2:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CC(C)=Cc1ccc(C=O)nc1
Reactant: CCN(CC)CC
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.20 g) in a mixed solvent of tetrahydrofuran (15 mL) and ethanol (15 mL) was deaerated, 5-(2-methylprop-1-en-1-yl)pyridine-2-carbaldehyde (0.666 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (93 mg) and triethylamine (0.192 mL) were added, and the mixture was stirred at 70° C. for 1.5 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in acetic acid (50 mL) was added ammonium acetate (2.65 g), and the mixture was stirred at 110° C. for 2 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-60:40, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (1.35 g, yield 80%) as colorless crystals. MS: 491 (MH+). melting point 114-116° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]2[N:26]([C@H:27]3[CH2:31][CH2:30][NH:29][CH2:28]3)[CH:25]=[N:24][N:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][C:33]([CH3:35])=O.[BH3-]C#N.[Na+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]2[N:26]([C@H:27]3[CH2:31][CH2:30][N:29]([CH:33]([CH3:35])[CH3:32])[CH2:28]3)[CH:25]=[N:24][N:23]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nncn2[C@H]2CCNC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CC[C@H](n2cnnc2-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of 4-tert-butyl-N-[4-chloro-2-((S)-4-pyrrolidin-3-yl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (200 mg, 0.43 mmol) in MeOH (5 MI) was added acetone (0.048 mL, 0.65 mmol) and then NaCNBH3 (0.054 g, 0.86 mmol). The reaction mixture was stirred at room temperature for 2 h, evaporated to dryness, adsorbed onto silica gel, and purified by automated normal-phase chromatography (50% MeOH in EtOAc) and then preparative HPLC (20→95% CH3CN in H2O with 0.1% TFA). The pure fractions were combined and lyophilized to obtain title compound as a powder: MS (ES) M+H expected 502.0, found 502.1.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=1)[NH:26][CH:25]=[CH:24]2.C([SiH](CC)CC)C>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:3]1[CH2:4][CH2:5][CH2:6][S:1][CH2:2]1
Reactant: O=C1CCCSC1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCCSC3)c[nH]c12
Temperature: 0 °C
Yield: 40.7 %

Procedure:
Dihydro-2H-thiopyran-3(4H)-one (0.217 g, 1.86 mmol) was dissolved in dichloromethane (23 mL) in an oven dried flask containing 3 Å molecular sieves and stirred under argon at 0° C. TMS-OTf (0.414 g, 1.86 mmol, 0.33 mL) was added slowly to the mixture over 10 min. Ethyl 5-bromo-1H-indole-7-carboxylate (0.5 g, 1.86 mmol) was dissolved in DCM (7 mL) and added to the reaction via syringe pump over 2 hours, after which it was stirred for 3 hours between 0 and 10° C. The reaction was cooled to 0° C. and triethylsilane (0.325 g, 0.44 mL, 2.8 mmol) was added all at once and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with a saturated sodium bicarbonate solution and extracted with DCM. The combined organics were washed with water. The combined aqueous layers were back-extracted with DCM. The combined organics were washed with brine, dried with MgSO4, and concentrated. The crude compound was purified on a Combiflash silica column with 5-25% EA/Hexane to give 0.279 g (40%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:27](O)=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[F:53][C:54]1[CH:55]=[C:56]([CH:59]=[CH:60][C:61]=1[O:62][C:63]([F:66])([F:65])[F:64])[CH2:57][NH2:58]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:27](=[O:28])[NH:58][CH2:57][C:56]2[CH:59]=[CH:60][C:61]([O:62][C:63]([F:64])([F:65])[F:66])=[C:54]([F:53])[CH:55]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)[C@@H](C(=O)O)C1
Reactant: NCc1ccc(OC(F)(F)F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)c(F)c2)C1
Yield: 95.7 %

Procedure:
To a solution of the compound (1.24 g) obtained in Example 1001, Step 1 in N,N-dimethylformamide (12 ml) were added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.65 g), 1-hydroxybenzotriazole hydrate (0.52 g) and the compound (0.59 g) obtained in Step 3. After stirring overnight at room temperature, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=4:96-6:94) to give the title compound (1.70 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[CH3:10][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 2,4,6-trichloro-1,3,5-triazine (20 g, 108 mmol, 1.0 equiv) in THF (8 mL) at −10° C., methylmagnesium bromide (45 ml, 135 mmol, 1.25 equiv) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 2 h. The mixture was poured onto ice-water and stirred for an additional hour. The product was extracted with ethyl acetate, washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure to afford 14 g of the title compound. The crude product was carried forward in the next step. MS (ES+): m/e 186.1 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C>[CH2:32]([N:15]1[C:14](=[O:17])[N:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[C:10]2=[N:16]1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCBr
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 31.4 %

Procedure:
To a stirring mixture of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.14 mmol) and K2CO3 (40 mg, 0.28 mmol) in DMF (0.47 mL) at 20° C. was added 4-bromobutane (40 mg, 0.28 mmol). The resulting reaction mixture was heated at 80° C. for 30 min. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature, diluted with water, and extracted twice with diethyl ether. The combined organic extract was washed with saturated aqueous NaHCO3 solution, then brine, then dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (18 mg, 0.044 mmol) as a light yellow solid. MS: [M+H]+=412.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)=[CH:9][CH:8]=1.[C:18]([O-:21])([O-])=O.[Na+].[Na+].BrBr.[CH3:26][OH:27]>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:26][O:27][CH:14]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:12][CH:11]=2)=[CH:17][CH:16]([O:21][CH3:18])[O:15]1
Reactant: CO
Reactant: O=C([O-])[O-]
Reactant: c1cnc(-c2ccc(-c3ccoc3)cc2)nc1
Agent: BrBr
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC1C=C(c2ccc(-c3ncccn3)cc2)C(OC)O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a slurry of 3-[4-(pyrimidin-2-yl)phenyl]furan and Na2CO3 (46 mg, 0.44 mmol) in methanol (0.8 mL) and benzene (0.8 mL) at −10° C. was added bromine (22 μL, 0.41 mmol) dropwise. The reaction mixture was stirred at −10° C. for 1 h, diluted with ethyl acetate, filtered, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 2:1 hexanes/ethyl acetate) gave 95 mg (75%) of the title compound. MS 285 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[C:16]2[CH:20]=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:20]([C:16]3[C:15]4[C:19](=[C:11]([CH3:10])[CH:12]=[CH:13][CH:14]=4)[NH:18][CH:17]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cccc2c(C=O)c[nH]c12
Reactant: Nc1cc(Br)cnc1N
Product: Cc1cccc2c(-c3nc4cc(Br)cnc4[nH]3)c[nH]c12

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 7-methylindole-3-carboxaldehyde.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]([CH3:15])=[C:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])[CH:5]=2)[CH2:3][CH2:2]1.ClS([N:35]=[C:36]=O)(=O)=O.CN(C)C=O>>[C:36]([C:5]1[C:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)(=[O:24])=[O:25])=[C:7]([CH3:15])[N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]=1[CH:1]1[CH2:3][CH2:2]1)#[N:35]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)Cn1c(C2CC2)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c1C1CC1
Yield: 5 %

Procedure:
General procedure II was followed using ethyl 2-(5-cyclopropyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (1.09 g, 2.53 mmol), chlorosulfonyl isocyanate (0.275 mL, 3.16 mmol) and N,N-dimethylformamide (0.196 mL, 2.53 mmol) to afford ethyl 2-(3-cyano-2-cyclopropyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (58.0 mg, 0.127 mmol, 5% yield) as a viscous oil. 1D-NOESY experiment was performed to confirm the drawn regioisomer (irradiation of methyl group and 1-2% interaction with both methylene groups).
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[C:22]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:21]([F:27])[C:20]([F:28])=[CH:19][CH:18]=1.[C:29](=[O:31])=[O:30]>C1COCC1.O>[Br:16][C:17]1[C:22]([Si:23]([CH3:24])([CH3:25])[CH3:26])=[C:21]([F:27])[C:20]([F:28])=[C:19]([CH:18]=1)[C:29]([OH:31])=[O:30]
Reactant: O=C=O
Reactant: C[Si](C)(C)c1c(Br)ccc(F)c1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(Br)cc(C(=O)O)c(F)c1F
Reaction time: 0.25 h

Procedure:
To a solution of n-BuLi (2.0 M in hexanes, 11.1 mL, 22.2 mmol) in anhydrous THF (17 mL) at −78° C. was added drop wise 2,2,6,6-tetramethylpiperidine (3.26 g, 22.1 mmol). After being stirred for 15 minutes, a solution of the product from step A (5.86 g, 22.1 mmol) in THF (20 mL) was added. The reaction mixture was stirred at −78° C. for 2 hours, then dry ice (100 g) was added. The mixture was allowed to stand at room temperature overnight, then it was diluted with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered, then concentrated to afford the title compound. The material was used directly in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 7.70 (d, J=4.4 Hz, 1H); 0.44 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16]C[CH2:14][CH2:13]1.C(=O)([O-])[O-:20].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:18][CH:12]3[CH2:17][CH2:16][O:20][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2ncc(Br)n2n1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cnc2ccc(NC3CCOCC3)nn12
Temperature: 40 °C
Yield: 74 %

Procedure:
A mixture of 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (1.1 g, 5.0 mmol), cyclohexylamine (0.86 mL, 7.5 mmol), cesium carbonate (3.3 g, 10 mmol), and DMF (10 mL) was maintained at 40° C. for 6 h, then cooled to RT and partitioned between ethyl acetate (100 mL) and H2O (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (4×40 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by flash chromatography (SiO2) to afford 3-bromo-N-(tetrahydro-pyran-4-yl)imidazo[1,2-b]pyridazin-6-amine (1.1 g, 73%) as a light yellow solid: 1H NMR (400 MHz, MeOD) δ 7.53 (d, J=9.6 Hz, 1H), 7.39 (s, 1H), 6.68 (d, J=9.9 Hz, 1H), 3.68-3.87 (m, 1H), 2.14 (dd, J=12.6, 3.3 Hz, 2H), 1.82 (dt, J=13.3, 3.7 Hz, 2H), 1.70 (dt, J=12.8, 3.7 Hz, 1H), 1.38-1.52 (m, 2H), 1.23-1.38 (m, 3H); LCMS (ESI) m/e 295.2 [(M+H)+, calcd for C12H15BrN4 295.1].