Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[CH:12][C:13]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)=[N:14][CH:15]=1)=[O:9].Br[CH2:40][CH:41]1[CH2:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:36][C:33]([F:34])([F:35])[C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[CH:12][C:13]([C:16]2[CH2:17][CH2:18][N:19]([CH2:40][CH:41]3[CH2:43][CH2:42]3)[CH2:20][CH:21]=2)=[N:14][CH:15]=1)=[O:9]
Reactant: Cc1ccccc1-c1cc(C2=CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccccc1-c1cc(C2=CCN(CC3CC3)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.3 %

Procedure:
A mixture of 60 mg (0.11 mmol) 4-o-tolyl-1′,2′,3′, 6′-tetrahydro-[2,4′]bipyridinyl-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide (Example 42), 0.011 ml (0.11 mmol) (bromomethyl)cyclopropane and 19 mg (0.14 mmol) potassium carbonate in 1.5 ml acetonitrile was stirred at room temperature for 15 h. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with three portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. Column chromatography afforded 28 mg (42%) of the title compound as a light brown solid.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=3)[C@H:5]2[CH2:9][CH3:11])[CH2:2][CH2:3]1
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: COc1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(OC)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-ethylpyrrolidin-3-ol 0.5 oxalate (185 mg), 4-fluoro-2-methoxybenzonitrile (290 mg) and lithium carbonate (198 mg), the title compound was obtained as a pale-yellow solid (yield: 144 mg, yield: 55%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[CH2:36]=[O:37]>C1COCC1.O>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH2:15][CH2:36][OH:37])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)O)c(C)c1
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCOc1ccc(C(=O)O)c(CCO)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-butoxy-2-methylbenzoic acid (2.5 g) in THF (15 mL) was added dropwise to a solution of LDA (freshly prepared from diisopropylamine (4.86 g) and n-butyllithium (32 mL; 1.5 M in hexane)) in THF (50 mL) at −78° C. After 10 minutes, paraformaldehyde (1.44 g) was added, and the mixture was allowed slowly to warm to room temperature. After 4 hours, water (10 mL) was added, and the volatile organic constituents were removed in a rotary evaporator. The residue was partitioned between water and diethyl ether. The aqueous phase was mixed with dichloromethane and cautiously acidified with hydrochloric acid at 0° C. Concentration of the organic phase afforded the desired product with the molecular weight of 238.29 (C13H18O4); MS (ESI): 239 (M+H+).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]([CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH2:27])=[NH:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=1.Cl.[C:32](=[NH:37])(OCC)[CH3:33].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:32]([N:16]1[CH2:15][CH2:14][CH:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([N:5]([CH2:19]/[CH:20]=[CH:21]/[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH2:27])=[NH:26])[CH3:4])=[CH:7][CH:8]=2)[CH2:18][CH2:17]1)(=[NH:37])[CH3:33]
Reactant: CCOC(C)=N
Reactant: CN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CO
Product: CC(=N)N1CCC(Oc2ccc(N(C)C/C=C/c3cccc(C(=N)N)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 216.1 %

Procedure:
To a solution of 3-[3-[N-methyl-N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (368 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (290 mg) and triethylamine (0.65 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 10% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (288 mg, yield 72%) as a pale brown amorphous solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:17][C@@H:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[NH:24]C(=O)OC(C)(C)C)=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C@@H:19]1[C@H:18]([NH:17][C:6]2[N:7]=[C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:3]([C:1]#[N:2])=[N:4][CH:5]=2)[CH2:23][CH2:22][O:21][CH2:20]1
Reactant: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3N)cnc2C#N)cc1

Procedure:
To a suspension of tert-butyl (3R,4R)-4-(5-cyano-6-(p-tolylamino)pyrazin-2-ylamino)tetrahydro-2H-pyran-3-ylcarbamate in DCM (1 mL) was added TFA (1 ml), after completion, the solution was concentrated to give 5-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-3-(p-tolylamino)pyrazine-2-carbonitrile as crude residue.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>N1C=CC=CC=1>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCCCCCCCCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCl)cc1

Procedure:
20.5 Grams of p-toluenesulphonyl chloride were added to a mixture of 17.7 g 8-chloro-1-octanol and 50 ml of pyridine at 0°. After an hour the solution was added to ice and the mixture was extracted with ether. The ethereal solution was washed with dilute hydrochloric acid, dried with magnesium sulfate, and evaporated to yield the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([SH:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:24][CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[C:29]=1[CH2:38][CH2:39][CH3:40].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([S:22][CH2:24][CH2:25][CH2:26][S:27][C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[C:29]=2[CH2:38][CH2:39][CH3:40])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(S)ccc(C(C)=O)c1OCCCC(=O)OCC
Reactant: CCCc1c(SCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SCCCSc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 9 h
Yield: 51.9 %

Procedure:
A mixture of ethyl 4-(6-acetyl-3-mercapto-2-propylphenoxy)butyrate (2.0 g), (4-(3-bromopropylthio)-2-hydroxy-3-propylphenyl)ethanone (2.0 g), potassium iodide (0.5 g) and potassium carbonate (1.7 g) in acetone (40 ml) was heated with refluxing and stirring for 9 hours. After cooled, inorganic materials were separated by filtration and the filtrate was concentrated. The resultant residue was separated, and was purified through silicagel column chromatography (eluting with benzene:ethyl acetate=9:1) to give the title compound (1.8 g, 50.8%) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[NH2:63][C@@H:64]([CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:65]([C@@:67]1([CH3:70])[CH2:69][O:68]1)=[O:66].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:63][C@@H:64]([CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:65]([C@@:67]2([CH3:70])[CH2:69][O:68]2)=[O:66])=[O:12])=[CH:15][CH:16]=1
Reactant: C[C@]1(C(=O)[C@@H](N)Cc2ccccc2)CO1
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (10.0 g, 33.9 mmol) in DMF (10 mL) at 0° C. was added HOBt (4.81 g, 37.3 mmol) and HBTU ((14.1 g, 37.3 mmol). The mixture was stirred for 5 min to the dissolve solids at which time (S)-2-amino-1-((R)-2-methyloxiran-2-yl)-3-phenylpropan-1-one TFA salt (10.2 g, 33.9 mmol) and DIEA (17.4 mL, 0.101 mol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-60% ethyl acetate/heptane) provided tert-butyl ((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (13.4 g, 82%) as an colorless amorphous solid. MS (EI) for C27H34N2O6, found 483.3 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4](O)CCC.C(O)(=O)C.O.BrC[C:16]1[CH:24]=[CH:23][C:19]([CH2:20][C:21]#[N:22])=[CH:18][CH:17]=1>CO>[CH3:1][N:2]([CH2:4][CH:20]([C:21]#[N:22])[C:19]1[CH:18]=[CH:17][CH:16]=[CH:24][CH:23]=1)[CH3:3]
Reactant: N#CCc1ccc(CBr)cc1
Reactant: CNC
Reactant: CCCCO
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CN(C)CC(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 1 liter round bottomed flask with condenser and thermometer 8.2 g of 4-bromomethylbenzylcyanide are dissolved in 453 ml methanol and cooled to +3° C. At this temperature 12.7 ml of 40% dimethylamine solution are added drop-by-drop. The solution is subsequently stirred for 1/4 hour at +5° C. and 2 hours at room temperature. The reaction sequence is controlled by means of thin-layer chromatography (0.57 ml of specimen+0.43 ml methanol: eluent n-butanol: acetic acid: water=4:1:1; v/v; 10 μl coating; HPTLC finished plated diatomaceous earth 60 F 254). Following removal of the volatile components is a rotary evaporator (20 torr, 40° C. bath temperature) the residue is absorbed in 20 ml 1N hydrochloric acid and extracted with a total of 150 ml of diethyl ether. The clear, aqueous phase is treated with 30 ml of 1N sodium hydroxide solution (ice cold) and extracted subsequently with 250 ml of diethyl ether. The organic phase is washed to neutrality with a saturated solution of common salt, dried with sodium sulfate and evaporated to dryness in a rotary evaporator (30° C. bath temperature, 20 torr).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][C:16]2[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2Cl)=[N:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:29]=1Cl.Br[CH2:40]C1C=CC(C(N)=O)=CC=1Cl.BrCC1C=CC(S(N)(=O)=O)=CC=1Cl>>[Br:1][C:2]1[C:3]([O:15][C:16]2[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[CH3:40])=[N:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Cc1cc(C#N)cc(Cl)c1Oc1nc(NC2CCNCC2)ncc1Br
Reactant: NC(=O)c1ccc(CBr)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: NS(=O)(=O)c1ccc(CBr)c(Cl)c1
Product: Cc1cc(C#N)cc(C)c1Oc1nc(NC2CCN(Cc3ccc(S(C)(=O)=O)cc3)CC2)ncc1Br

Procedure:
I-51, I-59 and I-60 were prepared analogously except 56 was replaced with 4-[5-bromo-2-(piperidin-4-ylamino)-pyrimidin-4-yloxy]-3-chloro-5-methyl-benzonitrile and 59 was replaced with 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene, 4-bromomethyl-3-chloro-benzamide and 4-bromomethyl-3-chloro-benzenesulfonamide respectively.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:15]2[O:22][CH:21]=[C:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1.[F:29][C:30]([F:46])([F:45])[C:31]1[CH:32]=[C:33]([S:41](Cl)(=[O:43])=[O:42])[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1.O>N1C=CC=CC=1.C(Cl)Cl>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:33]([S:41]([N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[C:16]4[N:17]=[CH:18][N:19]=[C:14]([NH:13][C:4]5[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:8][C:3]=5[F:2])[C:15]=4[O:22][CH:21]=3)[CH2:24][CH2:25]2)(=[O:42])=[O:43])[CH:32]=[C:31]([C:30]([F:46])([F:45])[F:29])[CH:36]=1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCNCC4)coc23)c(F)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCN(S(=O)(=O)c5cc(C(F)(F)F)cc(C(F)(F)F)c5)CC4)coc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 41.1 %

Procedure:
N-[2-Fluoro-4-(methylsulfonyl)phenyl]-7-(piperidin-4-yl)furo[3,2-d]pyrimidine-4-amine hydrochloride (10 mg, 0.023 mmol) was dissolved in pyridine (0.1 mL), a solution of 3,5-bis(trifluoromethyl)benzene-1-sulfonyl chloride (14 mg, 0.046 mmol) in anhydrous methylene chloride (0.4 mL) was added under ice-cooling, followed by stirring at room temperature for 1 hour and 45 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel preparative thin layer chromatography (chloroform:methanol=50:1) to give the titled compound (6.3 mg, 41%) as a white solid.
Reaction SMILES: NC1C=CC=CC=1.CC/C=C\C/C=C\C/C=C\CCCCCCCC(O)=[O:26].ClC(Cl)=C(Cl)Cl.[C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:36])[CH3:35]>C(O)CCC>[C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:36])[CH2:35][OH:26]
Reactant: CCCCOC(C)=O
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Solvent: CCCCO
Solvent: Nc1ccccc1
Solvent: ClC(Cl)=C(Cl)Cl
Product: CCCCOC(=O)CO
Temperature: 100 °C
Reaction time: 3 h

Procedure:
87.7 parts of an epoxide obtained from 2,2-bis-(4'-hydroxyphenyl)-propane and epichlorohydrin (0.05 epoxy group equivalent, the epoxide containing 0.57 epoxy group equivalent/kg) are dissolved in 27.5 parts of butyl acetate and 5 parts of n-butanol. 2.3 parts of aniline (0.025 mol) and 7.25 parts of a technical mixture of about 75% of C36 dimerised acid and about 25% of C54 trimerised acid, based on linoleic acid and linolenic acid (0.025 acid equivalent, the mixture containing 3.45 acid equivalents/kg) are added to this solution. The reaction mixture is heated to 100° C. and kept at this temperature for 3 hours. Dilution with 65.5 parts of perchloroethylene and 47.8 parts of butyl glycolate gives a clear, viscous solution of the reaction product, the solution having a solids content of 40% and an acid number of 17.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:9])[CH3:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>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.O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[CH3:8])=[CH:14][CH:13]=1
Reactant: CC(=O)c1sccc1Br
Reactant: COc1ccc(B(O)O)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccsc2C(C)=O)cc1
Temperature: 80 °C
Yield: 45.1 %

Procedure:
A flask was charged with 1-(3-bromothiophen-2-yl)ethanone (1.00 g, 4.88 mmol), 4-methoxyphenylboronic acid (0.740 g, 4.88 mmol), tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol), dimethoxyethane (50 mL), and 2 N aqueous Na2CO3 (7.3 mL) and then warmed to 80° C. for 7 h. At that time the reaction mixture was poured into H2O and extracted with EtOAc. The organic phase was separated and washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified via flash chromatography, eluting with 5-15% EtOAc/hexanes to afford the product (0.50 g, 2.2 mmol). MS (M+H)+ 233.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:15][CH3:16])[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[CH3:34])[N:30]([CH2:35][C:36]([OH:38])=O)[C:29](=[O:39])[CH:28]=[CH:27]2.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][C:4]([CH:7]([N:15]([CH3:16])[C:36](=[O:38])[CH2:35][N:30]2[C:31]3[C:26](=[CH:25][C:24]([CH3:23])=[C:33]([CH3:34])[CH:32]=3)[CH:27]=[CH:28][C:29]2=[O:39])[CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:5][CH:6]=1
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: Cc1cc2ccc(=O)n(CC(=O)O)c2cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2ccc(=O)n(CC(=O)N(C)C(CN3CCOCC3)c3ccc(-c4ccccc4)cc3)c2cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
[1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine (150 mg, 0.52 mmol) was added to a solution of (6,7-dimethyl-2-oxo-1(2H)-quinolinyl)acetic acid (100 mg, 0.43 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexafluorophosphate (BOP) (230 mg, 0.52 mmol) and diisopropylethylamine (280 mg, 2.15 mmol) in dimethylformamide (DMF) (5 mL). The reaction mixture was stirred at room temperature for 3 h, filtered and washed with DMF. The crude was purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% over 10 min, UV detection at 214 nm) to give the title compound (43 mg, 16%), MS (ES) m/e 510 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.Cl[S:25]([N:28]=C=O)(=[O:27])=[O:26]>O>[S:25](=[O:27])(=[O:26])([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[NH2:28]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Yield: 54.4 %

Procedure:
A mixture composed of 215 mg of 2′-nitrobiphenyl-4-ol and 1 ml of toluene was cooled with ice, and 148 mg of chlorosulfonyl isocyanate was added dropwise thereto, followed by refluxing for 17 hours. After water was added to the reaction mixture under cooling with ice, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 10:1 mixture of chloroform and methanol as the developing solvent) to obtain 160 mg of 2′-nitrobiphenyl-4-yl sulfamate.
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[S-:10][C:11]#[N:12].[NH4+]>C1C=CC=CC=1>[CH2:1]([O:3][P:4]([N:12]=[C:11]=[S:10])([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: N#C[S-]
Reactant: CCOP(=O)(Cl)OCC
Agent: [NH4+]
Solvent: c1ccccc1
Product: CCOP(=O)(N=C=S)OCC

Procedure:
The title compound is prepared by the method of M. Kulka [Canadian Journal of Chemistry, 37, 525(1959)]by allowing diethylphosphorchloridate and ammonium thiocyanate to react in benzene; b.p. 76° C. to 83° C./0.5 Torr; nD25 1.4758.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:13][C:12]=12.N1CC(C2C=CC(C(NCC3C=CN4C=CN=C4C=3)=O)=CC=2)C1>>[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]3[CH:21]=[CH:22][C:23]([CH:26]4[CH2:30][CH2:29][N:28]([S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH2:27]4)=[CH:24][CH:25]=3)=[CH:13][C:12]=12
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNC2)cc1
Agent: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CNC2)cc1
Product: CC(C)S(=O)(=O)N1CCC(c2ccc(C(=O)NCc3ccn4ccnc4c3)cc2)C1

Procedure:
The title compound was prepared as described in Example 557C, substituting propane-2-sulfonyl chloride for propane-2-sulfonyl chloride and N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(pyrrolidin-3-yl)benzamide for 4-(azetidin-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide. 1H NMR (501 MHz, DMSO-d6) δ ppm 9.04 (t, J=6.0 Hz, 1H), 8.47 (d, J=6.9 Hz, 1H), 7.87 (m, 3H), 7.50 (d, J=1.2 Hz, 1H), 7.43 (m, 2H), 7.37 (s, 1H), 6.84 (dd, J=7.0, 1.6 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H), 3.77 (m, 1H), 3.52 (m, 2H), 3.42 (m, 2H), 3.25 (m, 1H), 2.30 (m, 1H), 2.04 (m, 1H), 1.25 (dd, J=6.8, 1.4 Hz, 6H); MS (ESI(+)) m/e 427 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].C(OCC)(=O)C.Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C=C(C)C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C=C(C)C)ccc1C(=O)O
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
To a solution of methyl 2-methoxy-4-(2-methyl-1propenyl)benzoate (178 mg) in methanol (3 ml) and 1,4-dioxane (3 ml) was added 1N aqueous solution of sodium hydroxide (2 ml). The mixture was stirred at 50° C. for 3 hours, and then poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate. Evaporation of the solvent gave 2-methoxy-4-(2-methyl-1propenyl)benzoic acid (142 mg) as solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1ccc(F)cc1C(=O)c1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 108 mg of (2-Amino-5-fluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.25 (s, 9H), 6.98 (dd, 1H, J=8.8 Hz, 3.2 Hz), 7.30-7.38 (m, 3H), 7.43 (m, 2H), 7.62 (m, 2H), 7.80 (dd, 1H, 9.2 Hz, 4.8 Hz), 8.82 (d, 2H, 4.8 Hz), 9.82 (s, 1H). MS: m/z413.5 (M++1).