Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[C:11]2[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:18]([C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[C:21]1=[O:28])[CH3:19].[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[CH2:18]([C:20]1([C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[O:35][C:2]2[CH:9]=[C:8]([CH:10]([OH:17])[C:11]3[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[C:21]1=[O:28])[CH3:19]
Reactant: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Reactant: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCC1(c2cccc(Oc3cc(C(O)c4cncn4C)ccc3C#N)c2)CCCCN(C)C1=O

Procedure:
2-Fluoro-4-[hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-benzonitrile (as described in Step E above) (0.162 g, 0.700 mmol), 3-ethyl-3-(3-hydroxy-phenyl)-1-methyl-azepan-2-one (0.173 g, 0.700 mmol) and KF.Al2O3 (0.208 g) and 18-Crown-6 (0.017 g, 0.064 mmol) were dissolved in anhydrous CH3CN (7 mL) and refluxed under Ar for 24 h. The reaction was filtered, concentrated and purified using SiO2 chromatography (1-3% MeOH/CH2Cl2).
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].S(=O)(=O)(O)O>>[CH2:16]([NH:20][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CN
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1F
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1NCC(C)C
Temperature: 25 °C
Reaction time: 192 h

Procedure:
2.0 g (9 mmol) of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid were dissolved in 26.5 ml (267 mmol) of isobutylamine. The mixture was heated at reflux with stirring for 8 days, cooled to RT, acidified with 10% strength sulfuric acid and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. This gave 2.4 g of a colorless solid of a purity of 98%.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:15]3[C:10]([CH:9]=[C:8]4[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]4)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Temperature: 25 °C

Procedure:
5.1 g (20 mmol) of 9-bromoanthracene, 3.6 g (20 mmol) of 4-tert-butylphenylboronic acid, and 244 mg (0.80 mmol) of tri(o-tolyl)phosphine were put into a 100-mL three-neck flask, and nitrogen substitution in the system was carried out. 20 mL of ethylene glycol dimethyl ether (DME) was added to this mixture, and the mixture was stirred under reduced pressure and degassed. After that, 45 mg (0.20 mmol) of palladium acetate(II) and 10 mL (2.0 mol/L) of a potassium carbonate solution were added. This reaction mixture was stirred at 80° C. for 3 hours under nitrogen gas stream. Then, the reaction mixture was cooled to the room temperature, and a solid that was precipitated was collected by suction filtration. The collected solid was dissolved in toluene, and the solution was subjected to suction filtration through Florisil, celite, and then alumina. The filtrate was condensed to obtain a solid, and the solid was recrystallized with ethanol, whereby 5.0 g of a white powdery solid, which was a target matter, was obtained with the yield of 81%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[O:22][CH2:21][CH2:20][CH2:19]3)O1.Br[C:28]1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][CH:35]=2)[S:30][C:29]=1[CH:37]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:43]([O:42][CH:37]([C:29]1[S:30][C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:36]2[C:28]=1[C:16]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][CH2:20][CH2:19][C:18]=2[CH:17]=1)[C:38]([O:40][CH3:41])=[O:39])([CH3:46])([CH3:44])[CH3:45]
Reactant: COC(=O)C(OC(C)(C)C)c1sc2ncccc2c1Br
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1sc2ncccc2c1-c1ccc2c(c1)CCCO2
Temperature: 110 °C
Yield: 46.7 %

Procedure:
Under a nitrogen atmosphere, sodium carbonate (16 mg, 0.15 mmol), water (1 mL), palladium tetrakis(triphenylphosphine) (27 mg, 0.02 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (40 mg, 0.15 mmol) were added to a solution of methyl 2-{3-bromothieno[2,3-b]pyridin-2-yl}-2-(tert-butoxy)acetate (14g) (55 mg, 0.15 mmol) in N,N-dimethylformamide (4 mL). The mixture was heated at 110° C. for 1 hour. The mixture was then cooled at room temperature, concentrated and water (20 mL) was added. The aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 90/10) to afford the desired product (14h) as a white solid (30 mg, 0.07 mmol, 49%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]3[O:33][C:34]([CH2:37]Cl)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(#N)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:23])=[O:24])=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Reactant: C1COCCN1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5CCOCC5)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Temperature: 80 °C
Yield: 96.1 %

Procedure:
N-(2-Chloro-5-{4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (50 mg, 0.084 mmol) and morpholine (0.015 ml, 0.169 mmol) were placed in acetonitrile (5 ml) and the mixture heated at 80° C. for 4 h. Further morpholine (150 was added and the reaction was continued to heat overnight. The mixture was cooled to room temperature and the mixture loaded onto an SCX (5 g) cartridge. The cartridge was washed with methanol and then eluted with 2M ammonia in methanol. The mixture was purified by chromatography on silica (20 g) cartridge eluting with 0-100% ethyl acetate in cyclohexane followed by 0-20% methanol to give the title compound (52 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1.C(OC)(OC)OC.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[BH4-].[Na+]>CO>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CN)cc2n1CCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
The compound (130 mg) obtained in Example 3-6 was dissolved in methanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and 2-imidazole carboxaldehyde (37.3 mg) and the whole was stirred for 1 hour. After having been cooled to 0° C., the solution was added with sodium borohydride (21.5 mg) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (64.0 mg) as a pale-yellow oily substance.
Reaction SMILES: C([N:9]1[C:14](=[O:15])[C:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][N:11]([CH2:22][CH2:23][CH2:24][Cl:25])[C:10]1=[O:26])(=O)C1C=CC=CC=1>N.CO>[Cl:25][CH2:24][CH2:23][CH2:22][N:11]1[CH:12]=[C:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:14](=[O:15])[NH:9][C:10]1=[O:26]
Reactant: O=C(c1ccccc1)n1c(=O)c(-c2cccnc2)cn(CCCCl)c1=O
Agent: N
Solvent: CO
Product: O=c1[nH]c(=O)n(CCCCl)cc1-c1cccnc1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
3-Benzoyl-1-(3-Chloro-propyl)-5-pyridin-3-yl-1H-pyrimidine-2,4-dione (Prep42, 90 mg, 0.24 mmol) was dissolved in a solution of 3% NH3 in MeOH (5 mL). The mixture was stirred at room temperature over night, the solvent was then evaporated under vacuum and the residue was passed over a SCX cartridge to give 42 mg of the title compound that was used in the next step without further purification (66% yield)
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]#[N:9])[CH:4]=[N:3][CH:2]=1.Br[CH:11](Br)[CH3:12].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:1]1[CH:6]=[C:5]([C:7]2([C:8]#[N:9])[CH2:12][CH2:11]2)[CH:4]=[N:3][CH:2]=1
Reactant: N#CCc1cncnc1
Reactant: CC(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#CC1(c2cncnc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.1 %

Procedure:
To a mixture of 2-(pyrimidin-5-yl)acetonitrile (104 mg, 0.873 mmol), dibromoethane (113 μL, 1.31 mmol) and tetrabutylammonium bromide (65 mg, 0.23 mmol) dissolved in toluene was added an aqueous solution of sodium hydroxide (50%, 500 mg in 0.5 mL of water, 12.5 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (2 mL), washed with water (0.5 mL×2) and brine (0.5 mL). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-80% ethyl acetate in heptanes) to afford 1-(pyrimidin-5-yl)cyclopropanecarbonitrile as a solid (28 mg, 22%). 1H NMR (500 MHz, CDCl3) δ 1.50-1.56 (m, 2H), 1.85-1.95 (m, 2H), 8.72 (s, 2H), 9.19 (s, 1H).
Reaction SMILES: C(C1C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC(CC)=CN=1)C.[CH2:22]([C@@H:24]1[C@H:32]([NH2:33])[C:28]2[CH:29]=[CH:30][S:31][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Br[C:35]1[C:40]([CH2:41][CH3:42])=[N:39][C:38]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=2[Cl:50])=[C:37]([CH2:51][CH3:52])[N:36]=1>>[Cl:50][C:44]1[CH:45]=[C:46]([Cl:49])[CH:47]=[CH:48][C:43]=1[C:38]1[N:39]=[C:40]([CH2:41][CH3:42])[C:35]([NH:33][C@@H:32]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH2:26][CH2:25][C@@H:24]2[CH2:22][CH3:23])=[N:36][C:37]=1[CH2:51][CH3:52]
Reactant: CC[C@H]1CCc2sccc2[C@H]1N
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Agent: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccsc2CC[C@@H]1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting cis-5-ethyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ; 7.50, 7.32, 7.08, 6.98, 5.77, 4.42, 2.99, 2.95, 2.62, 2.50, 1.98, 1.73, 1.39-1.18, 1.00; HRMS (FAB) calcd for C24H27Cl2N3S+H 460.1381, found 460.1376.
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=O)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[C:22]1([CH3:28])C=CC=CC=1>CN(C)C1C=CC=CC=1>[CH3:2][N:1]1[CH2:28][CH2:22][N:11]([C:10]2[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:11]=2)[CH2:5][CH2:6]1
Reactant: O=C1Nc2cccnc2Sc2ccccc21
Reactant: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3cccnc3Sc3ccccc32)CC1

Procedure:
3 g 5H, 6H-pyrido(2,3-b)benzo-1,4-thiazepine-6-one are refluxed with an excess of phosphorous oxychloride and 5 drops of N,N-dimethylaniline for 20 hours. The solution is taken up with anhydrous toluene and evaporated to dryness. The residue is taken up with 5 ml anhydrous toluene and an excess of N-methylpiperazine is added. This mixture is then refluxed for 2-4 hours. Once the reaction is terminated, the solvent is eliminated. The colored mass is taken up with chloroform and washed two times with water. The chloroformic phase is decolored with carbon and dried. After concentration into a small volume, the mixture is passed through a silica column (Woelm act III). The eluent phase is acetone. Once separated, the different phases containing the above mentioned product are evaporated to dryness. The residue is recrystallized in petrolein 100/140. The melting point is 134° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][CH:14]([CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)[CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1>ClCCl>[CH:13]([CH:14]([CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)[CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=[O:12]
Reactant: COC(=O)c1ccc(CCC(CO)CCc2ccc(C(=O)OC)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC(C=O)CCc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6.1 g (28.3 mmol) of pyridinium chlorochromate (PCC) are added to a solution of 8.73 g (23.6 mmol) of dimethyl 4,4′-[3-(hydroxymethyl)pentane-1,5-diyl]dibenzoate in 280 ml of dichloromethane, and the mixture is stirred at room temperature for 12 h. After the reaction has gone to completion, about 10 g of silica gel are added, and the solvent is removed to dryness under reduced pressure. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gives 7.08 g (19.22 mmol, 81.5% of theory) of a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([C:16]([O:18]CC)=[O:17])=[CH:4]1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([N:3]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)c2ccccc2)n(CC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1cc(C(=O)O)cc1C(=O)c1ccccc1

Procedure:
The entire batch of ethyl 1-ethyl-5-benzoylpyrrole-3-carboxylate from the preceding Example was taken up in 40 ml. of methanol and 20 ml. of 1N sodium hydroxide, and heated in an open flask on a steam bath for 1 hour. The aqueous residue was cooled, extracted with 20 ml. of ether, and made acidic with conc. hydrochloric acid. 1-Ethyl-5-benzoylpyrrole-3-carboxylic acid (585 mg., m.p. 157°-158° C., m/e 243) was recovered by filtration. For analysis, the product was recrystallized from acetone/hexane (380 mg., m.p. 158°-160° C.).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[N:5][CH:6]=[C:7](Br)[CH:8]=1.C([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[CH:21]=[C:20]1B(O)O)(OC(C)(C)C)=O>>[Cl:28][C:25]1[CH:26]=[C:27]2[C:22]([CH:21]=[C:20]([C:7]3[CH:6]=[N:5][CH:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:8]=3)[NH:19]2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Reactant: FC(F)(F)c1cncc(Br)c1
Product: FC(F)(F)c1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1

Procedure:
3-Trifluoromethyl-5-bromopyridine and N-Boc-6-chloro-indole-2-boronic acid are processed according to the procedure described in Example 91 to give 6-chloro-2-(5-trifluoromethyl-pyridin-3-yl)-1H-indole. (ESI) m/z 297.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:16](=[O:17])[N:15]([CH3:18])[C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=3[S:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:11]1([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16](=[O:17])[N:15]([CH3:18])[C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[S:12]1
Reactant: COc1ccc(C2Sc3ccccc3N(C)C2=O)cc1OC
Reactant: BrCCCCBr
Product: COc1ccc(C2(CCCCBr)Sc3ccccc3N(C)C2=O)cc1OC
Yield: 67.2 %

Procedure:
3,4-Dihydro-2-(3,4-dimethoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (5.0 g) and 1,4-dibromobutane (10.3 g) are treated by the similar method as in Example 12 to give 4.8 g (66.9%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9]N=C1CCCC1=O.[C:17]([O-:20])(O)=O.[Na+]>CC#N.OS(O)(=O)=O>[Cl:1][C:2]1[C:3]2[NH:9][C:3]3[C:17](=[O:20])[CH2:6][CH2:7][C:2]=3[C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C1CCCC1=NNc1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCc2c1[nH]c1c(Cl)cc(Cl)cc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-(2,4-dichlorophenyl)hydrazono)cyclopentanone (2.2 g, 8.59 mmol) in MeCN (10 mL), H2SO4 (1.4 mL, 1.8M solution) was added and the mixture stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature, basified with saturated NaHCO3 and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude title compound as an off-white solid (800 mg) which was used in the next step without purification.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC(S(O[C:22]2[C:23]([O:25][C@H:26]([CH3:32])[C:27]=2[C:28]([O:30][CH3:31])=[O:29])=[O:24])(=O)=O)=CC=1)([O-])=O>C(Cl)Cl>[CH2:1]([NH:8][C:22]1[C:23]([O:25][C@H:26]([CH3:32])[C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)C1=C(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O[C@@H]1C
Solvent: ClCCl
Product: COC(=O)C1=C(NCc2ccccc2)C(=O)O[C@@H]1C

Procedure:
At 0° C., 25.5 g of benzylamine are added dropwise within a period of 1 hour to a solution of 35.7 g of (R)-2-(4-nitrobenzenesulphonyloxy)-3-methoxycarbonyl-2-penten-4-olide in 250 ml of methylene chloride. The resulting benzylamine-p-nitrobenzenesulphonic acid salt is filtered off, and the filtrate is concentrated by evaporation, filtered over silica gel with toluene, and recrystallised from ether/petroleum ether. [α]D20 =+22° (3% in CHCl3), m.p. 68°-70° C., IR (CH2Cl2) 1752, 1678, 1632 cm-1.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].C[Si](C)(C)[O:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH2:16]>CCCCCC>[OH:6][CH2:14][C:15](=[O:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCCCCCCCCCC)O[Si](C)(C)C
Solvent: CCCCCC
Product: CCCCCCCCCCCC(=O)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
3-Chloroperoxybenzoic acid is added in one portion to a cooled (0° C.) solution of 2-trimethylsilyloxy-1-tridecene in hexane (200 mL). The ice bath is removed and the resulting slurry is stirred (4 hours, 25° C.). Ether (200 mL) and 1.5 N HCl (130 mL) are added and the resulting two-phase mixture is stirred vigorously (4.5 hours, 25° C.). The layers are separated and the organic layer is washed with saturated sodium bicarbonate (2×130 mL), washed with brine (1×130 mL), dried (MgSO4), and concentrated in vacuo. The residue is chromatographed on silica (90:10 hexane:ethyl acetate), and concentrated in vacuo. The resulting solid is washed with cold hexane and collected by filtration to yield 1.5 g (29%) of the title compound as white platelets, m.p. 52°-54° C.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:20]#[N:21])=[CH:15][CH:14]=1>CN(C=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:20]#[N:21])=[CH:15][CH:14]=1
Reactant: N#CC(c1ccc(F)cc1)c1cccnc1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCc1ccccc1)(c1ccc(F)cc1)c1cccnc1
Reaction time: 0.25 h
Yield: 78 %

Procedure:
In a 300 ml. 3 neck round bottomed flask under N2 was charged 0.9 g. of 60% NaH (1.5 eq., 0.0225 moles), washed 2 times with 15 ml hexanes, in 40 ml. DMF and 5.5 g. of 2-bromoethylbenzene (2.0 eq., 0.030 moles). This was followed by the addition of 3.18 g. of alpha-4-fluorophenyl-3-pyridylacetonitrile (1.0 eq., 0.015 moles) in 10 ml. DMF which resulted in an exotherm to 46° C. After 15 min. GLC analysis showed no unreacted nitrile. The reaction was quenched by the addition of 100 ml. water and then extracted with 250 ml. ether. The organic phase was washed twice with 100 mi. water, dried over MgSO4 and concentrated to give 5.0 g. of oil. The crude product was purified by flash chromatography with 2:3 EtOAc/hexane to give 3.7 g. of an oil (78.0 % yield).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14](=[O:32])[N:15]([CH2:17][CH2:18][O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[N:16]=2)=[CH:7][C:6]=1[Cl:33])=[N+]=[N-].O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>C1COCC1.CO>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14](=[O:32])[N:15]([CH2:17][CH2:18][O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[N:16]=2)=[CH:7][C:6]=1[Cl:33]
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(CN=[N+]=[N-])c(Cl)c4)ccc3=O)ccnc2c1
Agent: [Na+]
Agent: [S-2]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc2c(OCCn3nc(-c4ccc(CN)c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(4-(azidomethyl)-3-chlorophenyl)-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (400 mg, 864 μmol) in THF (8 mL), MeOH (1 mL), and water (1 mL) was added sodium sulfide, nonahydrate (540 mg, 6913 μmol) and stirred overnight at 40° C. The reaction was then partitioned between DCM and 5% NaHCO3. The organic layer was dried over MgSO4, concentrated, then purified on silica (40 g) eluting with 0>6% of NH3 in MeOH (2 M)/DCM. The product was further purified on RP-HPLC eluting with ACN/water (0.1% TFA). Desired fractions concentrated under reduced pressure then residue partitioned between DCM and NaOH (1 M). The organic was then dried over MgSO4 and concentrated under reduced pressure to provide a white solid. MS (ESI pos. ion) m/z: 437 (MH+); calc'd for C23H21ClN4O3: 436. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3 H) 3.99 (s, 2 H) 4.65 (t, J=5.38 Hz, 2 H) 4.80 (t, J=5.28 Hz, 2 H) 6.67 (d, J=5.48 Hz, 1 H) 6.98-7.09 (m, 2 H) 7.32 (d, J=2.35 Hz, 1 H) 7.48 (d, J=8.02 Hz, 1 H) 7.58 (dd, J=8.02, 1.76 Hz, 1 H) 7.64 (d, J=9.78 Hz, 1 H) 7.79 (d, J=1.76 Hz, 1 H) 8.02 (d, J=9.19 Hz, 1 H) 8.64 (d, J=5.28 Hz, 1 H)