Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>O1CCCC1>[Cl:16][C:17]1([C:20]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[O:21])[CH2:19][CH2:18]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)C1(Cl)CC1
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2(Cl)CC2)cc1
Temperature: 60 °C
Yield: 73.1 %

Procedure:
5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are dissolved in 100 ml of absolute tetrahydrofuran by stirring and heating to 60° C. The solution is allowed to cool to room temperature, 4.15 g (29.9 millimoles) of 1-chlorocyclopropanecarboxylic acid chloride are added dropwise and the reaction solution is then stirred for 6 hours at room temperature. It is then concentrated to half its volume and 200 ml of water are added. The precipitate which forms is filtered off, washed with water and recrystallized from methanol, giving 5.5 g (73% of theory) of 6-[p-(1-chlorocyclopropylcarbonylamino)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone as colorless crystals, of melting point 189°-190° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[S:57][CH:58]=[C:59]([CH2:61][S:62][C:63]3[C:68]([C:69]#[N:70])=[C:67]([C:71]4[CH:76]=[CH:75][C:74]([O:77][CH2:78][CH2:79]O)=[CH:73][CH:72]=4)[C:66]([C:81]#[N:82])=[C:65]([N:83]4[CH2:87][CH2:86][CH2:85][CH2:84]4)[N:64]=3)[N:60]=2)=[CH:52][CH:51]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([O:16][CH2:79][CH2:78][O:77][C:74]1[CH:73]=[CH:72][C:71]([C:67]2[C:66]([C:81]#[N:82])=[C:65]([N:83]3[CH2:84][CH2:85][CH2:86][CH2:87]3)[N:64]=[C:63]([S:62][CH2:61][C:59]3[N:60]=[C:56]([C:53]4[CH:52]=[CH:51][C:50]([Cl:49])=[CH:55][CH:54]=4)[S:57][CH:58]=3)[C:68]=2[C:69]#[N:70])=[CH:76][CH:75]=1)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCCC2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1

Procedure:
0.89 g (3.82 mmol) of N-(tert-butoxycarbonyl)-L-leucine were initially charged in 10 ml of DMF, and 0.81 g (4.18 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.80 g (5.23 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 1.13 g (8.71 mmol) of N,N-diisopropylethylamine were added. The mixture was stirred until a clear solution had been obtained. 1.00 g (1.74 mmol) of 2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)-6-(pyrrolidin-1-yl)pyridine-3,5-dicarbonitrile was then added, and the mixture was stirred at room temperature for 18 h. The mixture was added to 300 ml of water. The residue formed was filtered off with suction and washed with 50 ml of water. The crude product was dissolved in 50 ml of dichloromethane. The aqueous phase was separated off and the organic phase was dried over sodium sulfate. Removal of the solvent under reduced pressure gave 1.37 g (100% of theory) of the desired target compound.
Reaction SMILES: [CH3:1]CCCC.[H-].[Na+].[CH3:8][N:9]([CH3:37])[S:10]([N:13]1[CH:17]=[C:16]([CH:18]([OH:29])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[N:15]=[C:14]1[Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])(=[O:12])=[O:11].CI>C1COCC1>[CH3:8][N:9]([CH3:37])[S:10]([N:13]1[CH:17]=[C:16]([CH:18]([O:29][CH3:1])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[N:15]=[C:14]1[Si:30]([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:32])[CH3:31])(=[O:11])=[O:12]
Reactant: CCCCC
Reactant: CN(C)S(=O)(=O)n1cc(C(O)c2ccnc3ccccc23)nc1[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To pentane washed sodium hydride (0.048 g, 1.2 mmol) in 5 ml of THF at 0° C., 2-(tert-Butyldimethylsilyl)-4-(hydroxyquinolin-4-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (example 8, step A) (0.375 g, 0.811 mmol) was added slowly over a period of 5 minutes. After stirring at room temperature for 15 minutes, it was, again cooled to 0° C. and methyl iodide (0.1 ml, 1.62 mmol) was added neat. The reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure and partitioned between EtOAc (10 ml) and water (10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 0.32 g (83%) of the product as a syrup.
Reaction SMILES: O=[C:2]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:13]=2)[CH:8]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.[OH-].[Na+]>O1CCCC1>[CH2:18]([O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:5]1[S:43][C:2]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:3][N:4]=1)[CH:16]=[CH:15]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)NCC(=O)CCCCCC)ccc2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc2cc(-c3ncc(CCCCCC)s3)ccc2c1
Temperature: 0 °C
Yield: 52.7 %

Procedure:
Then, 0.40 g (0.88 mM) of 2-oxooctyl-(6-decyloxy-2-naphthoyl)amine, 0.38 g (0.94 mM) of Lawesson's reagent and 6 ml of tetrahydrofuran were placed in a 30 ml-round-bottomed flask, followed by heat-refluxing for 45 minutes under stirring. After the reaction, the reaction mixture was poured into a solution of 0.27 g of sodium hydroxide in 70 ml of ice water to precipitate a crystal. The crystal was recovered by filtration washed with water and dissolved in toluene, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/1) and recrystallized from a mixture solvent of acetonemethanol to obtain 0.21 g of 2-(6-decyloxy-2-naphthyl)-5-hexylthiazole (Yield: 52.7%). ##STR236##
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C@@H:5]([CH2:15][OH:16])[O:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:16][CH2:15][C@H:5]1[O:4][CH2:3][C@@H:2]([CH3:1])[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6]1)(=[O:27])=[O:26]
Reactant: C[C@@H]1CO[C@H](CO)CN1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](COS(C)(=O)=O)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 118.3 %

Procedure:
To a solution of [(2S,5R)-5-methyl-4-(phenylmethyl)-2-morpholinyl]methanol (5 g, 22.59 mmol) and triethylamine (9.45 mL, 67.8 mmol) in CH2Cl2 (50 mL) stirred under nitrogen at 0° C. was added a solution of methanesulfonyl chloride (4.37 mL, 56.5 mmol) in CH2Cl2 (15 mL) dropwise during 5 minutes. The reaction mixture was stirred at 25° C. for 2.5 hours. Then the reaction mixture was washed with saturated NaHCO3 aqueous solution (2×25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (8.0 g) as a yellow oil. LC-MS (ES) m/z=300 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:23][O:24][C:25]([C:27]1[CH:28]=[N:29][CH:30]=[C:31](Br)[CH:32]=1)=[O:26]>C(COC)OC.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>[CH3:23][O:24][C:25](=[O:26])[C:27]1[CH:32]=[C:31]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:30]=[N:29][CH:28]=1
Reactant: CC1(C)OB(c2cccc(Cl)c2)OC1(C)C
Reactant: COC(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1cncc(-c2cccc(Cl)c2)c1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
104 mg (0.09 mmol)Pd(PPh3)4, 1.5 g (6.29 mmol) of 3-chlorophenylboronic acid pinacol ester 2.86 ml (8.58 mmol) and 3M cesium carbonate solution were added under argon at room temperature to a solution of 1.24 g (5.72 mmol) methyl-5-bromo-pyridine-3-carboxylate in 45 ml dimethoxyethane and the mixture was heated to reflux for 30 min. The reaction mixture was cooled to room temperature and evaporated. The residue was taken up with ethyl acetate, washed with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 1.14 g (72%) of 5-(3-Chloro-phenyl)-nicotinic acid methyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][N:3]=1.ON1C2C=CC=CC=2N=N1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)Cc1ccnc(Cl)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccnc(Cl)c1)N1CCOCC1

Procedure:
A solution of (2-chloropyridin-4-yl)acetic acid (300 mg), 1-hydroxybenzotriazole (284 mg), triethylamine (0.487 mL), morpholine (0.183 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (469 mg) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 18 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (239 mg).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:19][CH3:20])[C:5](=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][CH3:17])[CH2:12][CH2:11]1)[CH3:3].CCN(C(C)C)C(C)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:19]([N:4]([CH2:2][CH3:3])[C:5](=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([N:16]([CH3:17])[S:38]([C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:37][CH:36]=2)(=[O:40])=[O:39])[CH2:14][CH2:15]1)[CH3:20]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](NC)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.8 g (2.6 mmol) trans-5-(4-Methylamino-cyclohexyl)-pentanoic acid diethylamide.hydrochloride in 20 ml CH2Cl2 was treated with 1.1 ml (6.3 mmol, 2.4 eq) Huenig's base, 706 mg (2.9 mmol, 1.1 eq) 4-(Trifluoromethyl)benzenesulfonyl chloride in 10 ml CH2Cl2 and 32 mg (0.26 mmol, 0.1 eq) DMAP. The solution was stirred at RT over night. Additonal 1.1 ml (6.3 mmol) Huenig's base, 706 mg (2.9 mmol) 4-(Trifluoromethyl)benzenesulfonyl chloride in 10 ml CH2Cl2 and 32 mg (0.26 mmol) DMAP were added and stirring was continued for 3 h. The mixture was partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The organic phase was washed with water, 1M KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with EtOAc/hexane 1:1 gave 1.06 g (84%) trans-5-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyl}-pentanoic acid diethylamide as colorless oil, MS: 477 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([Cl:19])=[C:11]2[Cl:20])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:23](=O)([O-])[O-:24].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CO.C(P(C(C)(C)C)C1C(OC)=CC=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[Cl:20][C:11]1[N:10]([C:4]2[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([O:24][CH3:23])[C:3]=2[O:21][CH3:22])[C:18]2[C:13]([C:12]=1[Cl:19])=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: COc1c(Br)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: COc1ccc(C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1nn(C)c(=O)c(-n2c(Cl)c(Cl)c3ccccc32)c1OC
Temperature: 110 °C
Yield: 66 %

Procedure:
6-bromo-4-(2,3-dichloroindol-1-yl)-5-methoxy-2-methyl-pyridazin-3-one (0.200 g, 0.496 mmol), Pd2Cl2(allyl)2 (2.7 mg, 0.00744 mmol), ditert-butyl-[6-methoxy-3-methyl-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (11.6 mg, 0.0248 mmol) and dicesium carbonate (0.243 g, 0.744 mmol) are suspended in toluene (3 mL) and methanol (60 μL). The resulting reaction mixture is heated under microwave irradiation to 110° C. for 20 min. The resulting reaction mixture is filtered, washing with EtOAc and concentrated under reduced pressure onto silica. Purification by flash chromatography (combiflash, 0 to 30% EtOAc/isohexane) afforded the desired product 4-(2,3-dichloroindol-1-yl)-5,6-dimethoxy-2-methyl-pyridazin-3-one (0.116 g, 0.3275 mmol, 66% yield) as a brown oil.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(P(C1C=CC=CC=1)C1C=CC=CC=1)CCP(C1C=CC=CC=1)C1C=CC=CC=1.CN([CH:43]=[O:44])C.[CH3:45][OH:46]>C(OCC)C.C(OCC)(=O)C.C(N(CC)CC)C>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([C:45]([O:44][CH3:43])=[O:46])=[N:7][CH:6]=1)(=[O:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: CO
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(C)=O)cn1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
1-(6-Bromopyridin-3-yl)ethanone (5.00 g), propane-1,3-diylbis(diphenyl phosphine) (1.546 g), DMF (55 mL), methanol (30 mL), and triethylamine (10.5 mL) were mixed, and the inside of the reaction vessel was degassed and replaced with argon. Palladium acetate (II) (842 mg) was added thereto, and then the inside of the reaction vessel was replaced with carbon monoxide and stirred at 70° C. for 2 days. After leaving to be cooled to room temperature, the reaction mixture was diluted with a mixed liquid of diethyl ether-ethyl acetate, and washed with water and saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 5-acetylpyridine-2-carboxylate (1.16 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.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>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COC(=O)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2ccc(O)cc2)n1
Temperature: 100 °C
Yield: 45.6 %

Procedure:
A mixture of methyl 6-bromo-2-pyridinecarboxylate (1.35 g, 6.22 mmol, 1 eq), (4-hydroxyphenyl)boronic acid (0.945 g, 6.85 mmol, 1.1 eq), Pd(PPh3)4 (0.718 g, 0.06 mmoles, 0.01 eq) and K2CO3 (1.7 g, 12.4 mmoles, 2 eq) in dioxane (15 mL) and water (8 mL) was heated at 100° C. for 2 h. Then AcOEt was added and the organic phase was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The crude compound was purified on flash chromatography on 50 g silica gel cartridge using a gradient of cyclohexane/ethyl acetate 10/0 to 7/3 as an eluent. Solvents were removed under reduced pressure to give the title compound as a yellow solid (650 mg, 46%). 1H-NMR (CDCl3, 400 MHz): δ 4.03 (3H, s), 5.28 (1H, s), 6.90-7.03 (2H, m), 7.80-7.98 (2H, m), 8.0-8.06 (3H, m). MS: (ES/+) m/z: 230 (M+H)+. C13H11NO3 requires 229.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1>[CH3:20][O:19][C:17](=[O:18])[NH:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COC(=O)Cl
Reactant: CCCOc1ccc2nc(N)sc2c1
Agent: Cl
Solvent: c1ccncc1
Product: CCCOc1ccc2nc(NC(=O)OC)sc2c1
Temperature: 25 °C

Procedure:
To a stirring solution of 24.45 g. of 2-amino-6-n-propyloxybenzothiazole-hydrochloride in 100 ml of pyridine maintained at 0° C. by an ice bath, is slowly added 9.45 g. of methyl chloroformate. After the addition is completed the mixture is allowed to warm up to room temperature. It is then poured on 300 g. of ice water. A solid is formed which is isolated by filtration and crystallized from ethanol yield 20 g m.p. 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[Cl:1][C:2]1[C:7]([N:8]([CH3:17])[C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: CN(C(=O)c1ccccc1)c1cccnc1Cl
Temperature: 25 °C
Yield: 84.7 %

Procedure:
4.6 g N-(2-chloro-pyridin-3-yl)-benzamide (20 mmol), 8.2 g potassium carbonate (K2CO3) (60 mmol), and 50 mL ethanol were added and stirred in a round-bottomed flask. 4.2 g methyl iodide (MeI) (30 mmol) was then added and reacted for 24 hr. After cooling to room temperature, the reaction was quenched by water. After extraction three times by ethyl acetate, removal of water by magnesium sulphate (MgSO4), concentration, and purification by column, 4.18 g white solid was obtained, with a yield of 85%.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3F)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Temperature: 90 °C

Procedure:
A mixture of (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (40 mg, 0.068 mmol), 2-fluorophenylboronic acid (18 mg, 0.128 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (3.9 mg, 0.005 mmol) and sodium carbonate (2M aqueous solution, 0.102 mL, 0.204 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 90° C. for 30 min. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness to afford crude (3-(3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone, which was used in step 5 without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])=[O:15])[C:8](=[O:11])[CH2:9]Br)(=[O:3])[CH3:2].[CH2:28]([N:30](CC)CC)[CH3:29].C(CN)O>C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:13]=2[C:14]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[O:15][CH2:29][CH2:28][N:30]2[CH2:9][C:8]1=[O:11])(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)OCCN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1F
Solvent: NCCO
Solvent: c1ccccc1
Product: CC(=O)OCCN1C(=O)CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc21
Reaction time: 65 h

Procedure:
A solution containing 1.5g (0.0033 M) of 2-[N-(2-acetoxyethyl)-N-(2-bromoacetyl)amino]-5-chloro-2'-fluorobenzophenone, 0.5 ml of triethylamine and 0.23g (0.0036 M) of ethanolamine in 15 ml of benzene was kept at room temperature for 65 hours and then was partitioned between 25 ml of ethyl acetate and 25 ml of water. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was partioned between 20 ml of ether and 20 ml of 1N hydrochloric acid. The acid layer was separated and extracted with 25 ml of ethyl acetate. The organic layer was then washed with 20 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was crystallized from ether and recrystallized from a mixture of methanol and water to give the above named product as white prisms, m.p. 120°-123°.
Reaction SMILES: Cl.CO.C=O.[C:6]([BH3-])#N.[Na+].[CH:10]1([NH:14][CH2:15][CH2:16][CH:17]([C:24]2[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12][CH2:11]1>CO>[CH:10]1([N:14]([CH3:6])[CH2:15][CH2:16][CH:17]([C:24]2[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:12][CH2:13]1
Reactant: Brc1ccc(OCc2ccccc2)c(C(CCNC2CCC2)c2ccccc2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(CCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 M HCl-methanol (0.46 mL, 2.32 mmol), formaldehyde (0.870 g, 28.97 mmol) and sodium cyanoborohydride (0.255 g, 4.056 mmol) were added to a solution of N-cyclobutyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (2.61 g, 5.79 mmol) in methanol (8 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was chromatographed on silica (hexane-triethylamine, 9:1). Yield 1.59 g (59%); 1H NMR (CDCl3) δ1.59 (m, 2H), 1.73 (m, 2H), 1.91 (m, 2H), 2.06 (s, 3H), 2.16 (m, 4H), 2.68 (m, 1H), 4.38 (t, 1H), 5.00 (s, 2H), 6.72 (d, IH), 7.12-7.58 (m, 12H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](I)=[C:7]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O-].[Na+].[CH3:21][O:22][CH:23]=[O:24]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:23]([O:22][CH2:21][CH3:18])=[O:24])=[C:7]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: COC=O
Reactant: CC(C)(C)c1ccc(I)c(OCC(F)(F)F)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(C(C)(C)C)cc1OCC(F)(F)F
Temperature: 60 °C
Yield: 52.4 %

Procedure:
To a degassed solution of 4-tert-butyl-1-iodo-2-(2,2,2-trifluoro-ethoxy)benzene (2.5 g, 6.9 mmol), sodium methoxide (0.57 g, 10.4 mmol) and dichlorobistriphenylphosphinepalladium (0.25 g, 0.3 mmol) in dioxane (6 mL) was added methylformate (0.86 mL, 14.0 mmol). The resulting mixture was heated in an oil bath (60° C.) for 18 h and then allowed to cool. The solution was diluted with dioxane and filtered through a plug of Celite and concentrated. Purification of the crude residue by flash chromatography over silica gel using 5-15% ethyl acetate in hexane gave ethyl 4-tert-butyl-2-(2,2,2-trifluoroethoxy)benzoate (1.1 g, 55%) as a clear oil.