Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:18])=[C:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[S:30](Cl)(=[O:32])=[O:31])#[N:20]>N1C=CC=CC=1.C(Cl)Cl.C(Cl)Cl.CCOC(C)=O>[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[S:30]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:18])=[C:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)(=[O:32])=[O:31])#[N:20]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: COC(=O)Cc1c(C)c2ccc(N)cc2oc1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1c(C)c2ccc(NS(=O)(=O)c3ccc([N+](=O)[O-])cc3C#N)cc2oc1=O

Procedure:
Methyl 7-amino-4-methylcoumarin-3-acetate (compound 1 in FIG. 2) (34.0 mg, 0.14 mmol) synthesized in Example 1(1) was dissolved in pyridine/CH2Cl2 (1.4 ml, 1:1), 2-cyano-4-nitrobenzenesulfonyl chloride (CNS chloride; 63.8 mg, 0.26 mmol, 1.9 equivalents) dissolved in CH2Cl2 (0.5 ml) was added under cooling on ice, and the mixture was stirred. The next day, the disappearance of the starting materials was confirmed by TLC and the reaction mixture was diluted with EtOAc, and partitioned between saturated aqueous NaHCO3 solution and H2O. The organic layer was washed with saturated brine and dried over Na2SO4. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluate: 1% acetic acid-containing hexane:EtOAc=1:1) (compound 2a: 32.0 mg, 0.07 mmol, 51%).
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[O:23].BrCCC1CC1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:17](=[O:22])[C:16]2=[O:23]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: BrCCC1CC1
Agent: O=C1Nc2ccccc2C1=O
Product: CCOC(=O)CN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
Following the procedure as described in PREPARATION 2A, and making non-critical variations to replace isatin with 5-chloro-1H-indole-2,3-dione, and (2-bromoethyl)cyclopropane with ethyl 2-bromoacetate, the title compound was obtained (98%) as solid: 1H NMR (300 MHz, CDCl3) δ 7.60 (d, 1H), 7.54 (dd, 1H), 6.74 (d, 1H), 4.46 (s, 2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES+) m/z 268.6 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:6]=[CH:5][N:4]=1.S(Cl)([Cl:23])=O.[OH-].[Na+]>ClCCl>[Cl:23][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(-c2cc(CO)ncn2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(-c2cc(CCl)ncn2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
4-Hydroxymethyl-6-(3,4,5-trimethoxyphenyl)-pyrimidine (339 mg) was dissolved in dichloromethane (20 mL), and to the solution thionyl chloride (0.15 mL) was added dropwise under ice cooling, and the mixture was stirred for 1 hour. An aqueous solution of sodium hydroxide was added to the reaction mixture to neutralize it, and extraction was conducted with methylene chloride. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([C:14]([C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)=[O:15])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([C:5]1[O:6][C:7]2[C:13]([C@:14]([C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)([OH:15])[CH2:10][CH2:8][CH2:9][CH2:5][O:6][CH3:7])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc3cc(C(C)(C)C)oc23)C1
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc2cc(C(C)(C)C)oc12)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 195.5 %

Procedure:
A 50 mL three-necked flask was charged with (R)-tert-butyl 3-(2-tert-butylbenzofuran-7-carbonyl)piperidine-1-carboxylate (0.41 g, 1.08 mmol) and anhydrous THF (8 mL). The flask was evacuated and refilled with N2. The mixture was cooled with dry ice-acetone bath and the Grignard reagent derived from 1-chloro-4-methoxy-butane (5.4 mL, 2M) was added. The reaction mixture was allowed to slowly warm to rt while stirring overnight. The mixture was quenched with satd aq NH4Cl (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford (R)tert-butyl 3-((S)-1-(2-tert-butylbenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (0.5 g, 100%). 1H NMR:(CDCl3): 1.34 (s, 9H), 1.46 (s, 9H), 1.51 (m, 9H), 2.02 (m, 1H), 2.18 (m, 1H), 2.50 (m, 2)H, 2.67 (t, 1H), 3.23 (m, 5H), 3.99 (s, 1H), 4.43 (s, 1H), 6.35 (s, 1H), 7.16 (t, 1H), 7.23 (d, 1H), 7.39 (dd, 1H),
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][NH:13][CH3:14]>CCO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH3:14])[CH3:12])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CNC
Reactant: Cc1cc(C(=O)O)ccc1Br
Solvent: CCO
Product: Cc1cc(C(=O)N(C)C)ccc1Br
Yield: 65 %

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (n=about 2.7) (2.42 g, 7.53 mmol) was added to a mixture of 4-bromo-3-methylbenzoic acid (1.58 g, 7.37 mmol), EtOH (26 ml) and a 40% aqueous dimethylamine solution (0.75 ml, 7.4 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was then dissolved in ethyl acetate. The organic layer was washed with water, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 4-bromo-3,N,N-trimethyl-benzamide as a colorless solid (1.16 g, 65%).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:3]1.CC(C)=[O:21].O.[K+].[Br-]>[B-](F)(F)(F)F.[Ag+].CO>[OH:21][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:3]1
Reactant: CC(C)=O
Reactant: O=C(O)CCCCCCCCC1=CC(Br)CC1=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Agent: [Br-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCCC1=CC(O)CC1=O
Reaction time: 2 h

Procedure:
To a stirred solution of 57.2 g. of crude 4-bromo-2-(8-carboxyoctyl)cyclopent-2-en-1-one (Example 13) in 500 ml. of acetone and 325 ml. of water at 3° C. is added 44.1 g. (0.226 moles) of silver fluoborate during a 15-minute period. The mixture is stirred at 0°-3° C. for 2 hours and filtered. The filtrate is diluted with water, saturated with solid sodium chloride, and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Partition chromatography of the residue on Celite gives white crystals, m.p. 58°-66° C., λmax.MeOH = 223 mμ (7800); θmax (KBr) = 3340 (hydroxyl groups), 1705 (carbonyl groups), and 1625-1 (olefin group).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][C:7]2([CH3:14])[CH3:13].[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>CN(C)C=O.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>[CH3:16][O:15][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([CH:17]=[CH2:18])[CH:3]=1)[C:10](=[O:12])[CH2:9][CH2:8][C:7]2([CH3:14])[CH3:13]
Reactant: COc1cc(Br)c2c(c1)C(C)(C)CCC2=O
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cc(OC)cc2c1C(=O)CCC2(C)C
Temperature: 91 °C
Yield: 73.8 %

Procedure:
A solution of 8-bromo-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 154, 2.83 g, 10 mmol) and tributyl(vinyl)tin (3 mL, 10 mmol) in anhydrous N,N-dimethyl formamide (30 mL) was sparged with argon and treated with tetrakis(triphenylphosphine)palladium (0) (0.3 g, 0.26 mmol). The resulting reaction mixture was heated to 91° C. for two days at the end of which it was cooled to ambient temperature, diluted with water and extracted with diethyl ether (×2). The combined organic phase was washed with water (×1), and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated to a pale yellow oil. Flash chromatography using 15% ethyl acetate in hexane as the eluent afforded the title product (1.7 g, 73%) as a pale yellow oil.
Reaction SMILES: [N:1]#[C:2]Cl.[C:4]1([C:10]2[N:11]=[CH:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.CCOC(C)=O>C(#N)C>[C:4]1([C:10]2[N:11]=[C:12]([C:2]#[N:1])[N:13]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(Cn2cnc(-c3ccccc3)c2)cc1
Reactant: N#CCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1nc(-c2ccccc2)cn1Cc1ccccc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Under nitrogen, 2.0 g (0.0325 ml) cyanogen chloride was added to a 5° C. solution of 6.0 g (0.0256 mol) 4-phenyl-1-(phenylmethyl)-1H-imidazole in 100 ml acetonitrile/10 ml DMF. After 18 hour, the dark yellow reaction was warmed at 70° C. for 7 hours. After cooling, 4.5 ml (0.0325 mol) triethylamine was added and the reaction stirred overnight. The reaction was quenched with 300 ml saturated NaHCO3 and extracted into ethyl acetate (3×150 ml). After drying and concentration, a tan oil was obtained. Flash chromatography (500 ml silica gel, EtOAc) gave 3.7 g recovered starting material and 2.26 g of the desired product (84% based on recovered starting material) mp 95°-96° C. (cyclohexane).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:3].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OC(C)C)(C)C>CN(C)C=O.O>[CH3:3][C:2]([CH3:12])([C:4](=[O:11])[CH:5]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:1]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: BrCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)C(CCCCOc1ccccc1)n1cncn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 14.3 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one (cf. German Laid-Open Application DOS No. 2,638,470) in 20 ml of DMF is added dropwise, under a dry nitrogen atmosphere, to a stirred suspension of 2.3 g of sodium hydride in 20 ml of dimethylformamide (DMF), the reaction temperature being kept at 20°-30° C. by cooling; the mixture is subsequently stirred for 20 hours at room temperature. A solution of 19.5 g of 1-bromo-4-phenoxybutane in 20 ml of DMF is then added dropwise at 5°-10° C., with continued stirring, and whilst cooling with ice. After completion of the addition, stirring is continued for 10 hours at 5°-10° C., after which 200 ml of water are added and the mixture is extracted twice with 100 ml of methylene chloride at a time. The combined organic phases are extracted by shaking with water and dried over magnesium sulfate; removal of the solvent under reduced pressure gives an oil from which, on trituration with 20 ml of diisopropyl ether, 17 g of colorless crystals precipitate; melting point 59°-62° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)=O.B>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1ccc(NC(=O)CCCCCCCCCCBr)cc1
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCBr)cc1

Procedure:
A solution of 5 g. of ethyl 4-(11-bromoundecanamido)benzoate in 50 ml. of tetrahydrofuran is slowly added with stirring to 13 ml. of 1 M borane in tetrahydrofuran. The solution is poured into 50 ml. of dilute hydrochloric acid and the resulting mixture is filtered. The solid is crystallized from acetonitrile to yield ethyl 4-(11-bromoundecylamino)benzoate as a white, crystalline solid.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16](O)=[O:17]>S(=O)(=O)(O)O>[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:17]
Reactant: CCCCCCCCO
Reactant: O=C(O)c1cnccn1
Agent: O=S(=O)(O)O
Product: CCCCCCCCOC(=O)c1cnccn1
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A four-necked flask was charged with 426 g (3.271 mole) of 1-octanol, 100 g (0.806 mole) of pyrazinecarboxylic acid and 5.0 g (0.05 mole) of concentrated sulfuric acid and the internal temperature was maintained under stirring at 97°-100° C. for 8 hours. The reaction mixture was then cooled and transferred to a separatory funnel, in which it was washed with two portions, or a total of 330 g, of 8% aqueous solution of sodium carbonate. The oil layer which separated was washed with water and subjected to distillation under reduced pressure to give 168 g of octyl pyrazinecarboxylate. Yield: 88% (based on pyrazinecarboxylic acid).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH3:9][Mg+].[Br-]>C1COCC1.CCOCC>[Br:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[CH3:9])=[CH:5][N:6]=1
Reactant: C[Mg+]
Reactant: O=Cc1cnc(Br)s1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cnc(Br)s1
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 2-bromo-5-formylthiazole (100.6 mg, 0.524 mmol) in THF (5 mL) was added MeMgBr (175 μL of a 3M solution in Et2O, 0.524 mmol). After 30 minutes, additional MeMgBr (50 μL of a 3M solution in Et2O, 0.150 mmol) was added. After 30 more minutes, the reaction was quenched by pouring into saturated NH4Cl (20 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (25 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography (0 to 80% EtOAc/hexanes) afforded 1-(2-bromo-1,3-thiazol-5-yl)ethanol. Rf=0.13 (25% EtOAc/hexanes). LCMS=210.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.40 (s, 1H), 5.12 (q, J=6.4 Hz, 1H), 1.59 (d, J=6.4 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]3[CH:50]=[N:51][N:52]([CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[CH:53]=3)=[CH:45][C:41]=2[C:42](O)=[O:43])=[CH:34][CH:33]=1>CN(C)C=O>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]3[CH:50]=[N:51][N:52]([CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[CH:53]=3)=[CH:45][C:41]=2[C:42]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:43])=[CH:36][CH:37]=1
Reactant: O=C(O)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1
Reactant: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pyridinamine (26.5 mg, 0.28 mmol), 1-hydroxy-7-azabenzotriazole (30.7 mg, 0.23 mmol), EDC (43.3 mg, 0.23 mmol) and diisopropylethylamine (0.07 ml, 0.38 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-{1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl}benzoic acid (may be prepared as described in Description 114; 80 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml), and the reaction was stirred at room temperature overnight. The DMF was removed on a buchi. The residue was taken up into ethyl acetate (50 ml), washed with water (1×25 ml). The ethyl acetate layer was evaporated on a buchi under reduced pressure and the residue was purified using the MDAP to yield the title compound. 45 mg.
Reaction SMILES: [BrH:1].C(O)(=O)C.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=O)[CH2:14][S:15][C:16]#[N:17].O>C(O)(=O)C>[Br:1][C:16]1[S:15][CH:14]=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[Cl:6])[N:17]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccccc1Cl
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccccc1-c1csc(Br)n1
Temperature: 130 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A 25% hydrogen bromide/acetic acid (50 ml) solution was added to a solution of 2-(2-chlorophenyl)-2-oxoethyl thiocyanate (5.15 g, 24.3 mmol) in acetic acid (50 ml), and the mixture was stirred at 130° C. for 2 hours. Water (100 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 4.48 g (67.1%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:16])[CH:13]=[N+]=[N-])=[CH:4][CH:3]=1.[BrH:17].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:17][CH2:13][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Br:1])=[CH:3][CH:4]=1)=[O:16]
Reactant: Br
Reactant: [N-]=[N+]=CC(=O)c1ccc(Br)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc(Br)c2ccccc12
Reaction time: 0.25 h
Yield: 51 %

Procedure:
1-(4-Bromonaphthalen-1-yl)-2-diazoethanone (13.8 g) was dissolved in ethyl acetate (200 mL), and hydrobromic acid solution (8.4 mL, 5.7 M in acetic acid) was added at 0° C. Reaction mixture was stirred 15 minutes, NaHCO3 solution (100 mL) was added, and mixture was stirred 10 minutes. Ethyl acetate solution was extracted twice with NaHCO3 solution (50 mL), once with brine (50 mL), and evaporated under vacuum. The oil was dissolved in DCM and purified by chromatography (0-20% ethyl acetate:hexane), giving 2-bromo-1-(4-bromo-naphthalen-1-yl)-ethanone (6.67 g, 51%) as a tan solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][NH:7]1)=[O:5].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4]([C@H:6]1[N:7]2[C:12](=[O:17])[C:13]3[C:14]([C:15](=[O:16])[N:8]2[CH2:9][CH2:10][CH2:11]1)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:5]
Reactant: COC(=O)[C@@H]1CCCNN1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCn2c(=O)c3ccccc3c(=O)n21
Yield: 100 %

Procedure:
A solution of (S)-hexahydro-pyridazine-3-carboxylic acid methyl ester hydrochloride (Y. Nakamura, C. J Shin, Chem. Lett, 1991, 11, 1953-1956) (370 mg, 2.05 mmol), phthalic anhydride (318 mg, 2.15 mmol) and diisopropylethylamine (291 mg, 2.25 mmol) was heated in toluene (5 mL) for 2 h. The reaction mixture was then cooled and partitioned between ethyl acetate and dilute HCl. The organic phase was washed with saturated aq. NaHCO3, dried (MgSO4), filtered and evaporated. The residue was crystallised from hexane and filtered to afford the title compound as a white solid (562 mg, 82%): 1H NMR (400 MHz, CD3OD) δ 1.59 (1H, m), 1.96 (1H, m), 2.17 (1H, m), 2.55 (1H, m), 3.38 (1H, m), 3.70 (3H, s), 4.89 (1H, m), 5.74 (1H, m), 7.89 (2H, m), 8.16 (2H, m). 13C NMR (100 MHz, CD3OD) δ 21.2 (CH2), 25.7 (CH2), 46.0 (CH2), 53.8 (CH), 58.1 (CH3), 129.0 (CH), 129.1 (CH), 130.1 (C), 130.6 (C), 135.3 (CH), 135.7 (CH), 160.4 (C), 162.4 (C), 171.7 (C).
Reaction SMILES: Cl.[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2c(c3ccccc3n2-c2ccccc2)C1
Temperature: 120 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
A mixture of 1,1-diphenylhydrazine hydrochloride (0.365 g, 1.65 mmol) and 4-oxo-1-piperidinecarboxylic acid tert-butyl ester (0.329 g, 1.65 mmol) in pyridine (3 mL) was heated in a sealed tube at 120° C. with stirring for 3 h. The reaction mixture was subsequently cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed (SiO2/hexanes:ethyl acetate, 3:2) to give the title compound (0.214 g, 37%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 2H), 7.40 (m, 1H), 7.35 (m, 2H), 7.26 (m, 2H), 7.14 (m, 2H), 4.72 (s, 2H), 3.78 (s, 2H), 2.71 (s, 2H), 1.51 (s, 9H); LCMS: m/e 349 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([C@@H:33]([CH3:43])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:29][CH:28]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:27]1[CH:28]=[CH:29][C:30]([C@@H:33]([CH3:43])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:31][CH:32]=1
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1
Yield: 36.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (3.0 g, 9.26 mmol) was reacted with (R)-tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (5.2 g, 13.89 mmol) to afford the desired product (1.60 g, 35%) as a brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:12][O:13]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)OCCO2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: O=Cc1cc2c(cc1F)OCCO2

Procedure:
7-Fluoro-2,3-dihydrobenzo[1,4]dioxine-6-carboxaldehyde was prepared from 6-fluoro-2,3-dihydrobenzo[1,4]dioxine [V. Daukas et al Chemija, 1999, 10 (1), 59] by reaction of dichloromethyl methyl ether and titanium tetrachloride: LC-MS (ES) m/e 155 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[CH:12]1(P(C2CCCCC2)C2CCCCC2)[CH2:17]CCC[CH2:13]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11])([CH3:17])=[CH2:13]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: COc1ccc(C#N)nc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)c1nc(C#N)ccc1OC
Temperature: 130 °C

Procedure:
In a microwave vial, 6-bromo-5-methoxypyridine-2-carbonitrile (9-1 or 3-2, 200 mg, 0.94 mmol, 1.0 equiv), potassium trifluoro(isopropenyl)borate (Molander, Gary A., J. Am. Chem. Soc. Commun. 2003, 125, 11148-11149.) (347 mg, 2.35 mmol, 2.5 equiv), tricyclohexylphosphine (52.7 mg, 0.19 mmol, 0.2 equiv), palladium(II) acetate (21.1 mg, 0.09 mmol, 0.1 equiv), and tripotassium phosphate (697 mg, 3.29 mmol, 3.5 equiv) were suspended in toluene (10 mL) and water (0.5 mL). The reaction mixture was heated in a microwave reactor for 20 minutes at 130° C. and then filtered, rinsing with EtOAc. The filtrate was concentrated and the residue purified by normal phase column chromatography (15-40% EtOAc in hexanes) to afford the title compound (9-2). ESI+MS [M+H]+ C10H11N2O: 175.1 found, 175.2 required.