Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[N:27]([CH3:29])[CH3:28]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:24]=[CH:25][C:26]=1[N:27]([CH3:29])[CH3:28]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: CN(C)c1ccc(B(O)O)cc1Cl
Product: CN(C)c1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 96.9 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.25 g (6.48 mmol) of 1-bromo-4,5-difluoro-2-[4(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.68 g (8.42 mmol) of 3-chloro-4-(N,N-dimethylamino)phenylboronic acid (Step 2). Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (3:7) gave 2.65 g (97%) of 2-chloro-4-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-N,N-dimethylbenzenamine as a colorless solid: mp 129.0-130.0° C.; NMR (CDCl3) δ 2.81 (s, 6H), 3.05 (s, 3H), 6.76-6.91 (m, 2H), 7.08 (d, J=2 Hz, 1H), 7.17-7.26 (m, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H). MS (FAB): m/e 428 (M+Li). Anal. Calc'd for C21H18ClF2NO2S: C, 59.79; H, 4.30;N, 3.32. Found: C, 59.40; H, 4.29; N, 3.24.
Reaction SMILES: [CH3:1][NH2:2].Cl.[CH3:4][N:5]([CH3:21])[C:6]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.[C-:22]#[N:23].[K+]>CO.O>[CH3:4][N:5]([CH3:21])[C:6]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:11][CH2:10][C:9]([NH:23][CH3:22])([C:1]#[N:2])[CH2:8][CH2:7]1
Reactant: [C-]#N
Reactant: COc1ccc(C2(N(C)C)CCC(=O)CC2)cc1
Reactant: CN
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNC1(C#N)CCC(c2ccc(OC)cc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
40% aqueous methylamine solution (3.50 mL, 40.1 mmol) was added in drops to a mixture of 4N hydrochloric acid (1.98 mL) and methanol (2.3 mL) with ice cooling. A solution of the title compound from step 2 (2.00 mg, 8.09 mmol) in methanol (30 mL) and potassium cyanide (1.32 g, 20.3 mmol) were then added. The mixture was stirred for 3 d at RT and then after adding water (10 mL) was extracted 4× with ether. The combined organic phases were dried over Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][C@@H:17]([CH3:19])[C@H:16]([CH3:20])[C@@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1.CCCCCC.C(OCC)(=O)C>CCCCCC.C(O)C>[CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][CH:17]([CH3:19])[CH:16]([CH3:20])[CH:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@H]3O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)OC(C)C(C)C3O

Procedure:
The synthetic (±)-1 was resolved into enantiomers, (±)-calanolide A and (-) calanolide A, by preparative HPLC. Thus, using a normal phase silica gel HPLC column (250 mm×4.6 mm I.D. Zorbasil, 5 μm particle size, MAC-MOD Analytical, Inc., PA, USA), the synthetic (±)-1 appeared as one peak with a retention time of 10.15 minutes when hexane/ethyl acetate (70:30) was used as the mobile phase at a flow rate of 1.5 mL/min and a wavelength of 290 nm was used as the uv detector setting. However, on a chiral HPLC column packed with amylose carbamate (250 mm×4.6 mm I.D. Chiralpak AD, 10 μm particle size, Chiral Technologies, Inc., PA, USA), two peaks with retention times of 6.39 and 7.15 minutes in a ratio of 1:1 were observed at a flow rate of 1.5 mL/min. The mobile phase was hexane/ethanol (95:5) and the uv detector was set at a wavelength of 254 nm. These two components were separated using a semi-preparative chiral HPLC column, providing the pure enantiomers of calanolide A. The chemical structures of the separated enantiomers, which were assigned based on their optical rotations and compared with the reported natural product, were characterized by spectroscopic data. HPLC chromatograms (±)-calanolide A and its optical forms are shown in FIG. 6.
Reaction SMILES: [C:1]12([NH2:11])CC3CC(CC(C3)C1)C2.[Br:12][C:13]1[C:14]([CH3:22])=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[C:23]12(C(Cl)=O)[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2>>[Br:12][C:13]1[C:14]([CH3:22])=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([N:11]([CH3:1])[CH:24]1[CH:25]2[CH2:31][CH:29]3[CH2:28][CH:27]([CH2:32][CH:23]1[CH2:30]3)[CH2:26]2)=[O:17]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1c(Br)cccc1C(=O)Cl
Product: Cc1c(Br)cccc1C(=O)N(C)C1C2CC3CC(C2)CC1C3

Procedure:
The title compound was prepared by substituting N-adamantan-2-yl-N-methyl-amine for 1-adamantanamine and 3-bromo-2-methylbenzoyl chloride for 1-adamantanecarbonyl chloride in EXAMPLE 50A.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:13]=[CH:12][C:11]=2[O:24]C)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(Cl)Cl.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:13]=[CH:12][C:11]=2[OH:24])=[CH:27][CH:28]=1
Reactant: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(O)c(C(=O)NCc3ccc(C(F)(F)F)cc3)c2)S1
Reaction time: 72 h
Yield: 79.8 %

Procedure:
To a suspension of N-(4-trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide (800 mg) in anhydrous methylene chloride (30 ml), a 1.0N boron tribromide-methylene chloride solution (2.20 ml) was slowly added dropwise in an argon atmosphere under cooling with dry ice-acetone and stirring. After stirred for 6 hours at room temperature, the reaction liquor was allowed to stand for 3 days. After water was added and the mixture was stirred for 30 minutes, this was concentrated under reduced pressure. Ethyl acetate was added to the residue, which was washed with water and then dried over anhydrous sodium sulfate. This was concentrated under reduced pressure and the residue was purified by means of silica gel column chromatography (developing solvent; methylene chloride:methanol=40:1) to obtain 618 mg (80%) of aimed compound as crystals. These were recrystallized from ethanol-water to obtain purified aimed compound as a light brown powdery crystals. Melting point 146.0~148.0° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH2:16])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:6]=1.[CH3:17][O:18][CH:19]([O:30][CH3:31])[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22](F)[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C.O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([NH:1][C:22]2[CH:21]=[C:20]([CH:19]([O:30][CH3:31])[O:18][CH3:17])[CH:25]=[CH:24][C:23]=2[N+:26]([O-:28])=[O:27])[S:3][C:4]=1[C:14]([NH2:16])=[O:15]
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NC(=O)c1sc(N)nc1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3ccccc3Cl)c(C(N)=O)s2)c1
Yield: 89.1 %

Procedure:
A mixture of 0.15 g (0.60 mmole) of 2-amino-4-(2-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.20), 0.15 g (0.72 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitrobenzene, 0.99 g (3.0 mmole) of cesium carbonate and 10 mL of dimethylformamide was heated at 70 degrees for one day. The reaction mixture was diluted with ethyl acetate and water. The precipitate was collected by filtration, washed with water and dried under vacuum to give 0.24 g of 4-(2-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.20a).
Reaction SMILES: [OH:1][CH:2]([CH2:5][OH:6])[CH2:3][NH2:4].[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([NH:4][CH2:3][CH:2]([OH:1])[CH2:5][OH:6])[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: NCC(O)CO
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCC(O)CO)n4)cc3)cc12

Procedure:
Using 2,3-dihydroxy-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 457 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH:14]=[CH:13][N:12]=1)[CH3:9].[CH3:26][S:27](Cl)(=[O:29])=[O:28].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:4][CH:3]1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH:14]=[CH:13][N:12]=1)[CH3:9]
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CNCCN1C
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CN(S(C)(=O)=O)CCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a 0° C. solution of 2-[1-(1-methylpiperazine-2-yl)-ethylamino]-4[-benzimidazol-1-yl]-pyrimidine (EXAMPLE 20; 6 mg) in 1 mL of CH2Cl2 and 0.5 mL of pyridine was added methanesulfonyl chloride (2.5 mg). The mixture was allowed to warm to room temperature and stirred overnight, then poured into 10 mL of 1M NaHSO4, extracted with 2×5 mL of CH2Cl2, basified (pH>10) with 5N NaOH, and extracted with 5×5 mL of EtOAc. The combined EtOAc extracts were washed with 5 mL of brine, dried over Na2SO4 and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 9:1 CH2Cl2—2M NH3 in MeOH to provide 1.0 mg of the title compound. Mass spectrum (ESI) 416.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH2:22])=[N:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])=[N:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16])[CH3:13]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Product: CCOC(=O)c1sc(NC(=O)c2cc(Cl)ccc2O)nc1-c1ccccc1
Yield: 69.4 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195(3) gave the title compound.
Reaction SMILES: C1N=CN([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])C=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1.NCC1[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:6](=[O:7])[NH:8][CH2:9][C:10]2[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=2)[CH:14]=1
Reactant: NCc1ccc(CO)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc(CO)cc1)OCc1cccnc1
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
To a solution of N,N-carbonyldiimidazole (2.1 g, 12.8 mmol) in THF (15 mL) was added a solution of 3-pyridylcarbinol (1.3 g, 11.6 mmol) in THF (15 mL). After stirring for 30 minutes, a solution of (4-aminomethylphenyl)methanol (1.4 g, 10.4 mmol) in THF (15 mL) and triethylamine (3.2 mL, 23.2 mmol) were added, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL) and extracted with 10% MeOH in CHCl3 (30 mL×2). The organic layer was dried (Na2SO4), evaporated under reduced pressure, and the residue was purified by MPLC on silica gel (5% MeOH in CHCl3) to afford the titled compound (1.31 g, 46%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.ClCC(CCl)=O.[C:22]1([CH3:28])[CH:27]=CC=CC=1.O.O.O.[C:32]([O-:35])(=[O:34])[CH3:33].[Na+]>CO.CS(C)=O>[C:32]([O:35][CH2:28][C:22]1[N:13]=[C:11](/[CH:10]=[CH:9]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)[O:12][CH:27]=1)(=[O:34])[CH3:33]
Reactant: NC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)[O-]
Reactant: Cc1ccccc1
Agent: O=C(CCl)CCl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)OCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Temperature: 72.5 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (10.0 g,46.5 mmol) and 1,3-dichloroacetone (11.0 g, 86.6 mmol) were added to toluene (50 ml), and the mixture was subjected to refluxing azeotropic dehydration using a Dean-Stark tube for 8.5 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added dimethyl sulfoxide (50 ml) and sodium acetate trihydrate (15.8 g, 116.1 mmol). The mixture was stirred at 70-75° C. for 4 hours. Methanol (50 ml) was added. After allowing-to cool to room temperature and stirring; the mixture was stirred under ice-cooling for 1 hour. The precipitated crystals were collected by filtration, washed with cold-methanol (30 ml) and dried under reduced pressure to give 4-(acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (13.1 g, yield 65%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>CC#N.CCOC(C)=O>[F:13][C:14]1[CH:21]=[C:20]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(N2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Piperazine (20.0 g, 232.3 mmol) and K2CO3 (16.0 g, 118.5 mmol) are dissolved in CH3CN (85 ml). 2,4-Difluoro-benzonitrile (8.5 g, 61.1 mmol) is added and the mixture is stirred for 2 h at rt, then diluted with AcOEt and washed with water. The organic layer is separated, dried over Na2SO4 and evaporated. Excess piperazine is removed by MPLC (100 g silica gel, eluent CH2Cl2:MeOH 85:15). A second chromatographic purification (300 g silica gel, eluent toluene:EtOH:AcOH 4:4:1) yields the acetate salt of 2-fluoro-4-(piperazin-1-yl)-benzonitrile that is crystallized from AcOEt, filtered off and washed with ether. The free base is isolated by extraction with sat. aq. Na2CO3 solution/AcOEt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14](B(O)O)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH:25][CH2:26][C:27](=O)[CH2:28][OH:29].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.CO>[CH2:31]([NH:38][C:27]([C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:15]=1)([CH2:28][OH:29])[CH2:26][OH:25])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(CO)CO
Reactant: NCc1ccccc1
Reactant: OB(O)C1=Cc2ccc(OCc3ccccc3)cc2CC1
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: OCC(CO)(NCc1ccccc1)C1=Cc2ccc(OCc3ccccc3)cc2CC1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 15 %

Procedure:
The intermediate, 6-(benzyloxy)-3,4-dihydronaphthalen-2-ylboronic acid, from previous step was dissolved in ethanol (400 mL, 7 mol). 1,3-Dihydroxy-2-propanone (6.22 g, 0.0690 mol) was added followed by benzylamine (7.54 mL, 0.0690 mol). The solution turned into a yellow suspension in 1 min. The mixture was stirred at r.t. for 2 hours under an atmosphere of nitrogen. The mixture was filtered. The filtrate was concentrated and the residue was dissolved in EtOAc/MeOH (300 mL/30 mL), washed with saturated NaHCO3/water (50 mL/50 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL), brine, dried with Na2SO4, filtered, concentrated and dried in high vacuum to give a red-brown solid product as the first crop. The collected solid was dissolved in DCM-MeOH (50 ml/50 mL) and stirred at r.t. overnight under an atmosphere of nitrogen. The solution was concentrated. The residue was treated as the first crop with EtOAc-MeOH-aqueous NaHCO3 to afford the second crop of product (4.40 g, 15%). 1H NMR (CHLOROFORM-d) δ: 6.98-7.66 (m, 13H), 6.77 (br. s., 1H), 5.05 (br. s., 2H), 3.75-4.21 (m, 6H), 2.78 (m, 2H), 1.88-2.54 (m, 2H). MS (M+1): 416.0.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].N1(C2C=CC(C#N)=CC=2)CCNCC1.ClCC(Cl)=O.[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C@H:48]2[CH2:53][CH2:52][C@H:51]([OH:54])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[C:55]([F:58])([F:57])[F:56])([O-:40])=[O:39]>>[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C@H:48]2[CH2:53][CH2:52][C@H:51]([O:54][CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[C:55]([F:56])([F:57])[F:58])([O-:40])=[O:39]
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Reactant: N#Cc1ccc(N2CCN(C(=O)CCl)CC2)cc1
Agent: N#Cc1ccc(N2CCNCC2)cc1
Agent: O=C(Cl)CCl
Product: N#Cc1ccc(N2CCN(C(=O)CO[C@H]3CC[C@H](Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1

Procedure:
4-(4-{2-[Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetyl}-piperazin-1-yl)-benzonitrile was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-benzonitrile)-piperazine (also known as 4-[4-(2-chloroacetyl)-piperazin-1-yl]-benzonitrile) was prepared from 4-(piperazin-1-yl)-benzonitrile and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 4-(4-{2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetyl]-piperazin-1-yl)-benzonitrile was prepared from the 1-chloracetyl-4-(4-benzonitrile)-piperazine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (39% yield). The structure was confirmed using Protocol II-A. Calculated mass=532; observed mass=532; HPLC retention time=4.14 min.
Reaction SMILES: [C:1]1([NH:7][C:8](N(CC)CC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(O)C>CC1C=CC=CC=1C>[C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)C(=O)Nc1ccccc1
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Solvent: CCO
Product: O=C=Nc1ccccc1
Temperature: 114 °C

Procedure:
A mixture of 1.95 g (10.1 mmoles) of 1-phenyl-3, 3-diethylurea and 3.24 g, (43.2 mmoles) of pyridine in 100 g of o-xylene was added to a 250 ml round bottom flask fitted with a magnetic stirrer, condenser, and a thermocouple for measuring reaction temperature. A nitrogen atmosphere was maintained over the reaction mixture. The mixture was heated to 114° C. for 60 minutes. A sample was taken from the flask and analyzed by infrared spectroscopy. There was no peak for the NCO band in the spectrum. Another sample was taken and reacted with ethanol. Any phenyl isocyanate that would have been formed would be converted to the carbamate derivative. This sample was then analyzed by high pressure liquid chromatography (HPCL). Only unreacted starting material was observed confirming that no thermal decomposition of the urea to isocyanate occurred.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:24]1([C:27]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[O:28])[CH2:26][CH2:25]1
Reactant: O=C(O)C1CC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NC(=O)C1CC1)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (80 mg, 0.26 mmol, 1.0 eq.), cyclopropanecarboxylic acid (33 mg, 0.34 mmol, 1.5 eq.), N,N-diisopropylethylamine (63 mg, 0.51 mmol, 2.0 eq.) in dichloromethane (4 mL) was added a solution of phosphorus oxychloride (45 mg, 0.31 mmol, 1.2 eq.). Then the reaction mixture was stirred at room temperature for 30 min. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water and extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=2:1) to afford 57 mg of methyl 2-(2-(cyclopropanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 58%. MS (ESI+APCI) M+1=379.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:18][C:19]([NH2:21])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:18][C:19]#[N:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#CCCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.44 g of 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanamide (example 24) and 0.52 ml pyridine in 5.8 ml dioxane is cooled to 0° and 0.51 ml trifluoroacetic anhydride is added over a period of 1 h. The mixture is then stirred at room temperature for 3 h. The reaction is quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted with methylene chloride (2×20 ml). The combined organic extracts are dried, filtered and evaporated to give 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanenitrile.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[ClH:1].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)CC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CC(C)CC1(CCCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2ccccc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 3-(4-chlorobutyl)-3-isobutyl-1,3-dihydro-2H-indol-2-one and 1-(3-chlorophenyl)-piperazine.