Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][C:18]#[CH:19].Cl[CH2:21][CH:22]=[N:23][OH:24].C(N(CC)CC)C>O1CCCC1>[CH3:21][C:22]1[CH:19]=[C:18]([CH2:17][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]2=[O:1])[O:24][N:23]=1
Reactant: ON=CCCl
Reactant: C#CCn1c(=O)c(C(=O)OCC)nc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2ccccc2n(Cc2cc(C)no2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.8 %

Procedure:
3.0 g (11.7 mmol) of ethyl 2-oxo-1-(2-propynyl)-1,2-dihydroquinoxaline-3-carboxylate and 3.28 g (35.1 mmol) of chloroacetaldoxime were dissolved in tetrahydrofuran (30 mL), and 3.55 g (35.1 mmol) of triethylamine was added dropwise at a temperature in the range of 0° C. to 5° C. The mixture was stirred for 3 days at room temperature. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of citric acid, dried over anhydrous sodium sulfate, and concentrated. The solid matter thus obtained was washed with diisopropyl ether, to obtain 3.4 g (yield: 93%) of ethyl 1-[(3-methylisoxazol-5-yl)methyl]-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as a white powder.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH2:10][C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Br)cc1

Procedure:
The title compound was prepared in the same manner as for intermediate 66 using sodium metal (0.404 g, 17.58 mmol), 1-(4-bromophenyl)ethanone (3.5 g, 17.58 mmol), and diethyl ethanedioate (2.384 mL, 17.58 mmol). The product was collected as 5.1 g (97%). LCMS E-S (M+H)=299.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22-1.37 (m, 3 H), 4.25 (d, J=6.57 Hz, 2 H), 7.72 (m, 2 H), 7.92 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:21][CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:19]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:18]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1[C:9](OC)=[O:10].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.Cl>C1COCC1>[OH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([NH:13][C:14]([CH:16]2[CH2:21][CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:19]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:18]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH2:17]2)=[O:15])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2ccc(C(=O)OC)c(OC)c2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2ccc(CO)c(OC)c2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 5 h
Yield: 100 %

Procedure:
N-(3-Methoxy-4-methoxycarbonylphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (70 mg, 0.06 mmol) was dissolved in dehydrated THF (1 ml), 1M DIBAL/toluene (0.2 ml, 0.012 mmol) was added dropwise, and the mixture was stirred for 5 hr. After completion of the reaction, 1N hydrochloric acid was added to quench the reaction, and the mixture was extracted with chloroform (5 ml) and washed with 1N hydrochloric acid (3 ml). The solvent was evaporated and the residue was precipitated with methanol (10 ml) and slurry-washed with acetonitrile (5 ml) and 1N hydrochloric acid (5 ml) to give N-(4-hydroxymethyl-3-methoxyphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (60 mg, 0.06 mmol, yield 100%).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH2:13][C@H:12]1[C@:7]2([NH2:18])[CH2:8][CH:9]=[CH:10][CH2:11]1.B(Br)(Br)Br>C(Cl)Cl>[NH2:18][C@@:7]12[CH2:8][CH:9]=[CH:10][CH2:11][C@@H:12]1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:4]([OH:3])=[CH:5][C:6]2=1
Reactant: COc1ccc2c(c1)[C@@]1(N)CC=CC[C@H]1CC2
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: N[C@@]12CC=CC[C@@H]1CCc1ccc(O)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
To a solution of the product from Example 128 (0.20 g) in CH2Cl2 (10 ml) was added BBr3 (2 ml of a 1.0M solution in CH2Cl2. The reaction was stirred at room temperature for 18 hours and quenched by the addition of water. Additional CH2Cl2 (10 ml) and 1N HCl (20 ml) was added. The aqueous phase was separated, and made basic (pH=10) by the addition of NaHCO3. The aqueous phase was extracted with EtOAc (5×10 ml). The combined organic phases were dried over MgSO4, filtered and concentrated. The residue was dissolved in 0.5N HCl and freeze dried to give the title compound as a white solid (90 mg, 41%), mp 156°-161° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:36]1[CH:41]=[CH:40][C:39]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:31])=[O:30])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH2:17][C:18]([F:19])([F:21])[F:20])=[CH:28][CH:27]=2)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Product: CC(C)(C)c1ccc(-c2ccc(OC(CCCC(F)(F)F)c3ccc(C(=O)NCCC(=O)O)cc3)cc2)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1 MS: 540.3 [M−H]−; Isomer 2 MS: 540.3 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.O>CN(C)C=O>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[N:4]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16]
Reactant: COc1ccc(N)c(F)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2C(=O)c3ccccc3C2=O)c(F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A suspension of 2-fluoro-4-methoxyaniline (2.22 g) and phthalic anhydride (2.33 g) in N,N-dimethylformamide (16 mL) was stirred at 120° C. for 1 hour. The reaction mixture was cooled to room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residual crystals were suspended in ethyl acetate (5 mL), and the suspension was stirred at room temperature for 10 minutes. To the suspension was added n-hexane (25 mL), and the crystals were collected by filtration. The collected crystals were dried under reduced pressure to give 3-fluoro-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)anisole (3.35 g). This material was suspended in 1,2-dichloroethane (12.4 mL). To the suspension was added chlorosulfonic acid (1.81 mL) in a dropwise manner under ice-cooling, and the mixture was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature. To the reaction mixture were added thionyl chloride (4.5 mL) and N,N-dimethylformamide (0.048 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. To the mixture was added water, and the organic layer was separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual crystals were suspended in ethyl acetate (10 mL). To the suspension was added n-hexane (30 mL), and the crystals were collected by filtration. The collected crystals were washed with n-hexane, and dried under reduced pressure to give the title compound (3.6 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>CC#N.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>[Br:14][C:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)c1ccncc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)C(C)(Br)c1ccncc1
Reaction time: 2 h

Procedure:
The above compounds were prepared according to the procedure reported in the literature: see D. Yang, J. Org. Chem. 2002, 67, 7429. MS: 258, 260 (M+1). To a solution of ethyl 2-(pyridin-4-yl)propanoate (5.3 g, 30 mmol), Mg(ClO4)2 (Aldrich, 2.0 g, 9.0 mmol) in CH3CN (60 mL) was added N-bromosuccinimide (Aldrich, 5.9 g, 33 mmol) at room temperature. After 2 h, the reaction mixture was diluted with ether (200 mL), and 10% Na2CO3. The organic phase was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography. Mass Spec. m/z+ion 258, 260 (M+1).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)([O:3][CH2:4][CH3:5])=[O:2].[K+].[Br-].O=P(Cl)(Cl)[Cl:22]>C(Cl)(Cl)Cl.CO>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:22])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Cl

Procedure:
3-Carbethoxy-4-hydroxy-7-methyl-1,8-naphthyridine (3.8 g; 0.016 M) was suspended in POCl3 (46 ml; 0.45 M) and the mixture heated at 70°-80° C. for 4 hr. The solution was concentrated in vacuo and the residue poured carefully onto crushed ice. The resulting solution was basified with 10% aq. NaOH to pH 6 and extracted with Et2O. The Et2O extracts were combined, washed with saturated brine and dried over anhydrous MgSO4. The drying agent was removed by filtration and the filtrate was decolourised by refluxing with charcoal, filtered through Kieselguhr and evaporated to dryness in vacuo to yield the product, 3.7 g. (92%), m.p. 92°-93° C. (dec.). An analytical sample was obtained by chromatography over silica gel using CHCl3 /MeOH (9:1) as eluent. m.p. 90°-91° C. (dec.) (Found: N, 11.36; C, 57.80; H, 4.66; Cl, 14.13%. C12H11ClN2O2 requires: N, 11.18; C, 57.48; H, 4.39; Cl, 14.17%), νmax (KBr) 1720, 1600, 1580, 1470, 1260, 1213, 1170, 1022, 810 cm-1, δ [(CD3)2SO] 1.39 (t), 4.4 (q), (CH3CH2), 2.74 (s) (CH3), 7.69 (d), 8.6 (d), 9.21 (s) (heterocyclic protons), m/e 250 (M+ ; 100%), 222 (41%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[C:8]([C:11]#[N:12])[C:5]2=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=[C:8]([C:11]#[N:12])[C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1c[nH]c2cc(Br)cnc12
Reactant: BrCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cn(CC2CCOCC2)c2cc(Br)cnc12
Temperature: 100 °C

Procedure:
To mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile (500 mg, 2.252 mmol) in N,N-dimethylformamide (4.5 mL) was added sodium hydride (60% dispersion in mineral oil) (59.4 mg, 2.477 mmol) followed by 4-(bromomethyl)tetrahydro-2H-pyran (444 mg, 2.477 mmol). The mixture was heated at 100° C. for 2 hours. The reaction was diluted with 50 mL of ethyl acetate and the organic mixture was washed with a solution of aqueous sodium bicarbonate (1×50 mL), water (1×50 mL), and brine (1×30 mL), dried over magnesium sulfate, filtered, concentrated, and purified by silica gel flash chromatography (Isco®, Redi-Sep® column) eluting with a gradient of 30-100% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:15][C:14]([F:16])([F:17])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:3][C:2]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reactant: C1COCCN1
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 75 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and morpholine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 75%; MS: m/z=419 (M+H).
Reaction SMILES: [N:1]12[CH2:8][C:5]([C:9]([O:11]CC)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.Cl.S(Cl)(Cl)=O.[NH3:19].ClCCl.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:1]12[CH2:8][C:5]([C:9]([NH2:19])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: CCOC(=O)C12CCCN(CC1)C2
Reactant: N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC(=O)C12CCCN(CC1)C2
Yield: 76 %

Procedure:
Ethyl 1-azabicyclo[3.2.1]oct-5-ylcarboxylate (E7, Example 7 hereinafter, 9.6 g, 0.053 mole) was treated with 8M hydrochloric acid (130 ml) and heated under reflux for 18h. The solution was concentrated in vacuo to give a white solid, which was treated with thionyl chloride (80 ml) and heated under reflux for 6h. The reaction mixture was concentrated in vacuo to leave a red semi-solid, which was suspended in dichloromethane (120 ml), cooled in an ice bath and treated with an excess of ammonia/dichloromethane solution. The mixture was stirred at room temperature for 1h, then treated with saturated potassium carbonate solution. The organic layer was separated and the aqueous was extracted with chloroform (3×70 ml). All the organics were combined, then dried (Na2SO4) and concentrated in vacuo to give the title compound (D20) as a brown solid (6.2 g, 76%), which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[NH:4][CH2:3]1.CC1N([C:26]([CH2:28][C:29]#[N:30])=[O:27])N=C(C)C=1.O1CCOCC1.C(=O)(O)[O-].[Na+]>O>[CH3:1][CH:2]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[N:4]([C:26](=[O:27])[CH2:28][C:29]#[N:30])[CH2:3]1
Reactant: CC1CNC12CCCN(c1ncnc3[nH]ccc13)C2
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1CN(C(=O)CC#N)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 21.3 %

Procedure:
An optically-active compound of 4-(3-methyl-1,6-diazaspiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (25 mg) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (32 mg) and 1,4-dioxane (750 μl), and the mixture was stirred at 100° C. for 3.5 hours. The mixture was cooled to room temperature. Thereto were added water and saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted with ethyl acetate five times, and the combined organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica-gel thin layer chromatography (eluent: chloroform/methanol=9/1). The resulting residue was purified by silica-gel thin layer chromatography (eluent: ethyl acetate/methanol=93/7) again. The resulting solid (8.0 mg) was slurry-washed with n-hexane/ethyl acetate solution to give the titled compound (6.7 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:19].[H-].[Na+].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[C:25]([F:31])[CH:24]=1>CN(C=O)C>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[C:5]3[CH:10]=[CH:9][C:8]([C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[C:13]#[N:14])=[CH:7][C:6]=3[N:2]([CH3:1])[C:3]2=[O:19])=[C:25]([F:31])[CH:24]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(Cc2ccc(Br)cc2F)c2ccc(-c3ccccc3C#N)cc21
Reaction time: 0.25 h

Procedure:
A solution of 2-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)benzonitrile (6-4, 20 mg, 0.08 mmol) in anhydrous DMF (1 ml) was charged with Sodium Hydride (6.42 mg, 0.16 mmol, 2.0 eq) and 4-Bromo-2-fluorobenzyl bromide (42.5 mg, 0.16 mmol, 2.0 eq). The resulting dark mixture was irradiated in a microwave at 200 deg C. for 15 min, then quenched with water, filtered and purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present) to afford the title compound, 2-[1-(4-bromo-2-fluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]benzonitrile (6-5), as an orange-tan solid-oil. LRMS m/z: Calc'd for C22H15BrFN3O (M+H) 436.0, found 435.9.
Reaction SMILES: [CH:1]([C:3]1[S:11][C:10]2[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[CH:4]=1)=O.[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:19]1([CH2:1][C:3]2[S:11][C:10]3[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=3[CH:4]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C=O)cc2C1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCc2sc(CN3CCC3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 2-formyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (0.3 g, 0.122 mmol) and azetidine (96 mg, 1.683 mmol) were dissolved in 1,2-dichloro-ethane (7 ml) and stirred at room temperature for 10 min. Sodium triacetoxyboro-hydride (0.331 g, 1.571 mmol) was added and the resulting mixture stirred at room temperature for 48 h. Saturated sodium hydrogen carbonate solution was added and the phases were separated. The aqueous phase was extracted with diethylether (3×) and the organics were washed with saturated sodium chloride solution (1×). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate/methanol, 10:1). Yield: 0.28 g (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[CH:17][C:18]([F:21])([F:20])[F:19].[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[C:17]([Br:22])[C:18]([F:21])([F:19])[F:20]
Reactant: Cc1cc(Cl)c(NN=CC(F)(F)F)cc1SCC(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cl)c(NN=C(Br)C(F)(F)F)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
3.6 g (10.3 mmol) of trifluoroacetaldehyde {2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}hydrazone was dissolved in 30 ml of N,N-dimethylformamide, and 2.0 g of N-bromosuccinimide was added at room temperature, followed by stirring at room temperature for 2 hours. The resulting reaction mixture was poured into water and extracted with toluene, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.1 g of N-{2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}trifluoroacetohydrazonoyl bromide.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:20][CH:19]=1
Reactant: COc1ccc(NN=C(Cl)C(C)=O)cc1
Reactant: CSc1ccc(S)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(NN=C(Sc2ccc(SC)cc2)C(C)=O)cc1

Procedure:
A suspension of 31.7 g (0.139 mol) of 1-chloro-1-[(4-methoxyphenyl)hydrazono]-2-propanone in 400 ml of ethanol was treated with 23.4 g of 4-methylthiothiophenol and 23.4 of triethylamine. The suspension was heated at reflux for 2 hours and cooled. The resultant suspension was filtered and the precipitate was washed with 1 portion of cold ethanol. The solids were dried in vacuo to yield 1-[(4-methylthiophenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, mp 124-127° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:13]([Mg]Br)[CH3:14]>>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:12])[CH2:13][CH3:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC[Mg]Br
Reactant: O=CC1CCC2(CC1)OCCO2
Product: CCC(O)C1CCC2(CC1)OCCO2

Procedure:
Reacting 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) with ethylmagnesium bromide as described in Example 2, Step A yielded the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:23])([CH3:22])[CH2:8][CH2:9][N:10]2[C:13]([NH:15][C:16]2[CH:21]=C[CH:19]=[CH:18][CH:17]=2)=[O:14])=[CH:5][CH:4]=1)#[N:2].[N:24]1C=CC=C(N=C=O)C=1>>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:22])([CH3:23])[CH2:8][CH2:9][N:10]2[C:13]([NH:15][C:16]2[CH:21]=[N:24][CH:19]=[CH:18][CH:17]=2)=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C=Nc1cccnc1
Reactant: CC1(C)CCN(C(=O)Nc2ccccc2)c2cc(C#N)ccc21
Product: CC1(C)CCN(C(=O)Nc2cccnc2)c2cc(C#N)ccc21

Procedure:
The title compound was prepared from 7-cyano-3,4-dihydro-4,4-dimethyl-1(2H)-quinoline (compound of example 1, part J) and 3-pyridylisocyanate by the same method as described in example 1, part K. The product was obtained as a colorless powder; m.p. 183°-185° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].Br.Br.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[OH:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCN(c2ccc(O)cc2)CC1
Temperature: 20 °C
Yield: 87.2 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 g), 4-(4-hydroxyphenyl)piperazine dihydrobromide (3.4 g) and sodium bicarbonate (1.3 g) in dimethylformamide (30 cc). The mixture is heated for 4 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5 - 1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (90 cc), 2-(2-[4-(4-hydroxyphenyl)-1-piperazin-Yl]ethyl}naphtho[1-,8-cd]isothiazole 1,1-dioxide (1.6 g) is obtained, m.p. 235° C.