Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1COCC1.O>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1[C:4]1[CH:3]=[CH:2][N:7]=[N:6][C:5]=1[N:8]([CH3:19])[CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1
Reactant: COc1cccc(F)c1B(O)O
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(F)c1-c1ccnnc1N(C)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Intermediate 1-1 (2.83 g, 10.0 mmol), (2-fluoro-6-methoxyphenyl)boronic acid, and K3PO4 (5.52 g, 26.0 mmol) were added to a microwave vial. 2nd Generation XPhos Precatalyst (0.32 g, 0.40 mmol) was then added to the mixture followed by addition of 1:1 THF/water (50 mL). The reaction mixture was sealed and stirred at RT for 4 h then extracted with CH2Cl2 (2×). The crude material was purified by catch and release using SiliaBond Propylsulfonic Acid® (3 eq, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo to afford the title compound as a brown gel (2.87 g, 77%). [M+H]: 373.4; 1H NMR (400 MHz, DMSO) δ 7.43 (td, J=8.5, 7.0 Hz, 1H), 7.36 (d, J=9.5 Hz, 1H), 7.08 (d, J=9.5 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.92 (td, J=8.5, 1.0 Hz, 1H), 5.07 (bs, 1H), 3.74 (s, 3H), 3.31 (s, 3H), 1.47-1.55 (m, 2H), 1.33-1.48 (m, 2H), 1.24 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([C:15]#[N:16])[C:13]#[N:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:18][NH2:19]>C(O)C>[C:1]1([CH2:11][C:12]2[C:13]([NH2:14])=[N:18][NH:19][C:15]=2[NH2:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(C#N)Cc1cccc2ccccc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c(N)c1Cc1cccc2ccccc12
Yield: 57.2 %

Procedure:
To a mixture of malononitrile (1.32 g, 20 mmol) in Ethanol (50 mL) and Water (2.50 mL) was added 1-naphthalenecarbaldehyde (3.12 g, 20 mmol). The reaction was stirred at rt for 7 days. The mixture was cooled to 0° C. in an ice bath. Sodium borohydride (0.204 g, 5.40 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (20 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave (1-naphthalenylmethyl)propanedinitrile (3.3 g, 80%). To a solution of (1-naphthalenylmethyl)propanedinitrile (3.3 g, 16 mmol) in Ethanol (80 mL) was added hydrazine hydrate (0.785 mL, 16.00 mmol). The mixture was heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (MeOH/DCM: 0˜10%) to give the product (2.18 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s, 2H) 7.26 (d, J=7.07 Hz, 1H) 7.31-7.44 (m, 1H) 7.45-7.58 (m, 2H) 7.74 (d, J=8.08 Hz, 1H) 7.85-7.97 (m, 1H) 8.12-8.26 (m, 1H) 10.05 (bs, 1H). LC/MS: MS (ES+) m/e 239.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[C:16]1[N:17]([CH3:22])[N:18]=[CH:19][C:20]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)=[O:32])=[CH:11][C:10]=1[C:16]1[N:17]([CH3:22])[N:18]=[CH:19][C:20]=1[Br:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCc1ccccc1
Yield: 44.4 %

Procedure:
4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.023 g, 0.09 mmol) was treated with 4-chlorophenyl isocyanate (0.016 g, 0.10 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 61 (0.019 g, 0.04 mmol, 42%) as a white solid. LCMS m/z (%)=511 (M+H79Br35Cl, 82), 513 (M+H81Br35Cl, 100), 515 (M+H81Br37Cl, 33). 1H NMR (400 MHz, acetone-d6) δ: 8.22 (s, 1H), 8.16 (s, 1H), 7.66 (dd, J=2.4, 8.9 Hz, 1H), 7.55 (d, J=8.7 Hz, 2H), 7.50 (s, 1H), 7.46 (d, J=2.5 Hz, 1H), 7.28-7.35 (m, 5H), 7.28 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.9 Hz, 1H), 5.13 (AB quartet, J=12.0, 24.3 Hz, 2H), 3.69 (s, 3H).
Reaction SMILES: O1C2CCCCC=2C=C1C1C=CC(OCC2OC2)=CC=1.Cl.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH:23]1[NH:32]CC(O)COC1C=CC(C2OC3CCCCC=3C=2)=CC=1>C(O)C>[NH2:32][CH:23]1[CH2:24][CH2:25][C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22]1
Reactant: OC(CNC1CCc2ccccc2C1)COc1ccc(-c2cc3c(o2)CCCC3)cc1
Agent: Cl
Agent: c1cc(-c2cc3c(o2)CCCC3)ccc1OCC1CO1
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 4-(4,5,6,7-tetrahydrobenzofuran-2-yl)-1-(2,3-epoxypropoxy)benzene (27 g), obtained according to the teaching of U.S. Pat. No. 3,894,058, and 2-aminotetralin (14.85 g) in ethanol (150 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-[[4-(4,5,6,7-tetrahydrobenzofuran-2-yl)]phenoxy]propanamine hydrochloride is obtained ((i): R=H, Ar=radical 31 wherein Z is H, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([CH3:16])([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])[CH:3]=1.[N-:17]=[N+]=[N-].[Na+].CN(C)CCN>CS(C)=O.C(OCC)(=O)C.[Cl-].[NH4+].[Cu]I>[CH3:10][C:9]([NH:8][C:4]1[CH:3]=[C:2]([NH2:17])[CH:7]=[CH:6][N:5]=1)([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:16]
Reactant: CC(C)(C)CC(C)(C)Nc1cc(Br)ccn1
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: CN(C)CCN
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(C)(C)Nc1cc(N)ccn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 3.5 %

Procedure:
A mixture of 4-bromo-N-(2,4,4-trimethylpentan-2-yl)pyridin-2-amine (7.5 g, 260 mmol), sodium azide (5.07 g, 780 mmol), CuI (1.4 g, 7.8 mmol), N,N-dimethylethane-1,2-diamine (1.3 g, 15 mmol) in dimethylsulfoxide (150 mL) was heated in a sealed reaction vessel at 90° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (500 mL), saturated ammonium chloride (1000 mL) and stirred for 1 hour. The organic layer was separated and the aqueous layer was again extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated to give brown sticky mass which was purified by silica gel column chromatography using methanol and dichloromethane as eluent to yield 2 g (34%) of N2-(2,4,4-trimethylpentan-2-yl)pyridine-2,4-diamine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]CC)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1.O[Li].O>C1COCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1
Reactant: CCOC(=O)c1ccc2c(c1)c(-c1ccccc1)nn2C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2)c2cc(C(=O)O)ccc21
Yield: 140.8 %

Procedure:
A solution compound 54b (230 mg, 0.58 mmol), and LiOH.H2O (98 mg, 2.33 mmol) in THF/H2O (10/10 mL) was stirred at 45° C. for 8 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 54c (206 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 253.1.
Reaction SMILES: CC(C)([O-])C.[Na+].CN(C)C=O.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@:25]1([CH2:32]I)[O:29][CH2:28][C@@H:27]([CH2:30][OH:31])[CH2:26]1>CN(C)C1C=CN=CC=1.ClCCl.O>[N:12]1([CH2:32][C@@:25]2([C:19]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=3[F:17])[O:29][CH2:28][C@@H:27]([CH2:30][OH:31])[CH2:26]2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: OC[C@@H]1CO[C@@](CI)(c2ccc(F)cc2F)C1
Reactant: c1nc[nH]n1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OC[C@@H]1CO[C@@](Cn2cncn2)(c2ccc(F)cc2F)C1
Temperature: 105 °C
Reaction time: 18 h

Procedure:
Added 4-dimethylaminopyridine (8.61 g) and sodium tertiary butoxide (339 g) to a mixture of dimethylformamide (2500 ml) and 1,2,4-triazole (243.6 g) and stirred the reaction mixture for 30-45 minutes at 25-35° C. ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl)methanol compound of formula-8 (250 g) was added to the reaction mixture. The reaction mixture was heated to 100-110° C. and stirred for 18 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-35° C. and then poured into water. Added dichloromethane to the reaction mixture. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloro methane. The combined dichloromethane layers were extracted with 50% aqueous HCl and separating both the aqueous and organic layers then pH of the aq. layer was adjusted to 8-9 with 50% aqueous sodium hydroxide. Both organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was washed with water followed by sodium chloride solution and then distilled to get title compound as a residue. The obtained residue containing the title compound of formula-9 was taken to next step without isolation.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].O1CCCCC1OCCCI.CI.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(CCCC=O)s1
Agent: CC(C)[N-]C(C)C
Agent: ICCCOC1CCCCO1
Agent: O=C([O-])[O-]
Solvent: CI
Product: COC(=O)c1ccc(CCCCO)s1

Procedure:
A synthetic scheme that is particularly useful for preparation of aldehydes of formula III where n is 3 or 4 and A is 2,5-thienylene or 2,5-furylene is illustrated by the method of synthesis of methyl 5-(4-oxobutyl)thiophene-2-carboxylate (XXII): ##STR36## an aldehyde of formula II where A is 2,5-thienylene, n is 3, and R8 is methyl. Here, the dianion prepared by the action of lithium diisopropylamide on 5-methylthiophene-2-carboxylic acid is alkylated with 3-(tetrahydro-2H-pyran-2-yloxy)propyl iodide. The product of alkylation is esterified with methyl iodide and potassium carbonate and the THP protecting group removed by acid-catalyzed hydrolysis to give methyl 5-(4-hydroxybutyl)thiophene-2-carboxylate. Oxidation of the primary alcohol functional group with chromium trioxide affords the aldehyde intermediate XXII.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29]>C(O)(C)C>[OH:32][C:27]1([C:28]([F:31])([F:30])[F:29])[CH2:26][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:13]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccccn2)cc1
Yield: 17.8 %

Procedure:
To a mixture of the amidine of step 1 (4.4 g, 16 mmol) and sodium bicarbonate (2.7 g, 32 mmol) in isopropanol (400 ml), 3-bromo-1,1,1-trifluoroacetone (2.5 ml, 24 mmol) was added. After heating at 75°-80° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude product (16.2 g) was chromatographed (silica gel, ethyl acetate/toluene 1/1) to give 2-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (1.1 g, 18%) as a white solid: mp 195°-198° C. Anal. Calc'd. for C16H14N3SO3F3 : C, 49.87, H, 3.66, N, 10.90. Found: C, 50.13 , H, 3.66, N, 10.30.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][CH:42]2[CH2:46][CH2:45][CH2:44][O:43]2)=[CH:38][C:37]=1[CH3:50]>>[CH3:50][C:37]1[CH:38]=[C:39]([O:40][CH2:41][CH:42]2[CH2:46][CH2:45][CH2:44][O:43]2)[CH:47]=[C:48]([CH3:49])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCC2CCCO2)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6CCCO6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-((4-bromo-3,5-dimethylphenoxy)methyl)-tetrahydrofuran following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 1): tR=1.48 min; Mass spectrum (ESI+): m/z=569 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][S:15][C:11]=3[CH:10]=2)=[O:7])=[C:4]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:3]=1.[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=S)[CH:30]=1>C(Cl)CCl>[CH3:26][O:27][C:28](=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]2[NH:1][C:2]3[CH:3]=[C:4]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:17]=[CH:16][C:12]5[N:13]=[CH:14][S:15][C:11]=5[CH:10]=4)=[CH:18][C:19]=3[N:20]=2)[CH:30]=1
Reactant: CCN(CC)c1cc(N)c(N)cc1C(=O)Nc1ccc2ncsc2c1
Reactant: COC(=O)c1cccc(N=C=S)c1
Solvent: ClCCCl
Product: CCN(CC)c1cc2[nH]c(Nc3cccc(C(=O)OC)c3)nc2cc1C(=O)Nc1ccc2ncsc2c1

Procedure:
4,5-Diamino-N-benzothiazol-6-yl-2-diethylaminobenzamide (0.3 mmol; see Example 133) from above was reacted with 3-isothiocyanatobenzoic acid methyl ester (0.3 mmol) followed by cyclization in situ using EDC as described in general procedure B to obtain 3-[5-(benzothiazol-6-ylcarbamoyl)-6-diethylamino-1H-benzoimidazol-2-ylamino]-benzoic acid methyl ester. MS: m/z 515 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:27]#N)[CH2:14][CH2:13][N:12]([CH:15]3[C:25]4=[C:26]5[C:21](=[CH:22][CH:23]=[CH:24]4)[CH:20]=[CH:19][CH:18]=[C:17]5[CH2:16]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(OCC)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH:15]1([N:12]2[CH2:11][CH2:10][C:9]3([N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:32](=[O:33])[CH2:27]3)[CH2:14][CH2:13]2)[C:25]2=[C:26]3[C:21](=[CH:22][CH:23]=[CH:24]2)[CH:20]=[CH:19][CH:18]=[C:17]3[CH2:16]1
Reactant: N#CC1(Nc2ccc(F)cc2)CCN(C2Cc3cccc4cccc2c34)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CC2(CCN(C3Cc4cccc5cccc3c45)CC2)N1c1ccc(F)cc1

Procedure:
Reaction of (RS)-4-(4-fluoro-phenylamino)-1-(acenaphthen-1-yl)-piperidine-4-carbonitrile in accordance with the general method of example 1 and treatment of the base with fumaric acid in diethyl ether yielded the title compound, white solid, m.p. 210° C. and MS: m/e=387.2 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1.[C:21](=[O:23])=[O:22].[OH-].[Na+]>O1CCCC1.CCCCCC.O>[Br:13][C:14]1[CH:19]=[C:18]([C:17]([Cl:20])=[CH:16][N:15]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: Clc1ccc(Br)nc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ncc1Cl
Temperature: -70 °C

Procedure:
To a stirred solution of di-isopropylamine (16 ml) in anhydrous tetrahydrofuran (300 ml) at −5° C. was added, dropwise a solution of n-butyl lithium in hexane (2.5 molar, 44 ml) and the resulting solution was stirred for 30 minutes and was then cooled to −70° C. To the cooled solution was added a solution of 2-bromo-5-chloropyridine (19.2 g) in anhydrous tetrahydrofaran (50 ml) maintaining the internal temperature of the reaction below −65° C. The reaction was maintained at −70° C. for 15 minutes and then a steady stream of dried carbon dioxide was passed through the reaction mixture for 30 minutes. The reaction was allowed to warm to room temperature and was poured into a mixture of water (300 ml) and aqueous sodium hydroxide solution (2M, 30 ml). The mixture was extracted with ether and (2×100 ml) and the combined ethereal extracts were back extracted with aqueous sodium hydroxide solution (1M, 2×100 ml). The combined aqueous extracts were acidified to pH 1 with concentrated hydrochloric acid and the resulting solid filtered and dried under vacuum at 50° C. to afford the sub-titled compound as a white solid (14.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(C)=O>CN(C=O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
2-Bromo-5-hydroxypyridine (347 mg, 2 mmol) in DMF (3 mL) was added dropwise over a period of 10 min to a suspension of NaH (88 mg, 2.3 mmol) in DMF (2 mL) at 0° C. under Ar(g). The reaction mixture was then stirred at rt for 10 min, after which it was again cooled down at 0° C., and benzyl bromide (0.25 mL, 2.1 mmol) was added. The reaction mixture was stirred at rt for 2.5 h, after which it was poured onto brine (20 mL) and EtOAc (20 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (20 mL). The organic phases were combined, dried over MgSO4, filtered and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (95:5 to 90:10) to furnish I as a colourless oil (380 mg, 72%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14]([C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[S:29](Cl)(=[O:31])=[O:30])([CH3:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH:14]([C:17]1[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[S:29]([C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:31])=[O:30])([CH3:15])[CH3:16]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2cccc3c2Cc2ccccc2-3)c(C(C)C)c1

Procedure:
For example, fluorene can be reacted with 2,4,6-triisopropylbenzenesulfonyl chloride in the presence of aluminum chloride to yield 2 (2,4,6-tri-isopropylphenylsulfonyl)fluorene, which can be refluxed with sodium dichromate dihydrate in glacial acetic acid to yield 2 (2,4,6-triisopropylphenyl sulfonyl)fluorenone, which in turn can be refluxed with malononitrile in methanol in the presence of piperidine to yield 2 (2,4,6-triisopropylphenylsulfonyl)-9-(dicyanomethylene)fluorene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:26])[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:12]([O:16][C:17](=[O:26])[NH:18][CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:24][CH2:25]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 110 °C
Yield: 61.8 %

Procedure:
A solution of 1-bromo-4-trifluoromethyl-benzene (50.0 g; 220 mmol) and piperidin-4-ylmethyl-carbamic acid tert-butyl ester (48.1 g; 220 mmol) in dioxane (1 L) was added to a suspension of palladium (II) acetate (7.41 g; 33 mmol), cesium carbonate (144.8 g; 440 mmol), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (31.8 g; 45 mmol) in dioxane (1 L). The resulting mixture was heated to 110° C., and then maintained at that temperature for 28 hr with stirring. The mixture was then allowed to cool to room temperature. Afterward, the reaction mixture was treated with water (2 L) and extracted with dichloromethane (2×1 L). The combined organic phases were dried over sodium sulfate and filtered, and then the solvents were removed under reduced pressure. The resulting residue was dissolved in acetonitrile (1.5 L). Water (1.5 L) was then added with stirring. This resulting in a precipitate, which was filtered and then dried overnight at 40° C. at a pressure of 3 mbar to afford the desired product (48.9 g; 136 mmol).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](O)(=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)O.S(=O)(=O)(O)O>C(O)(=O)C>[OH:2][C:1]1[CH:8]=[CH:7][C:5]2[O:6][C:9](=[O:18])[CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=C(O)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1Oc2ccc(O)cc2C1c1ccccc1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
A mixture of hydroquinone (15 g), mandelic acid (15 g), acetic acid (95 cm3) and sulphuric acid (5 cm3) was stirred at ambient temperature before filtering off solid material. The solid was washed with water and dried to give 5-hydroxy-2-oxo-3-phenyl-2,3-dihydrobenzofuran (14 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:11].C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>C(Cl)Cl>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([NH:11][CH:6]1[C:7]2[C:3](=[C:2]([F:1])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)=[O:24]
Reactant: O=C=NCCCl
Reactant: NC1CCc2c(F)cccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCl)NC1CCc2c(F)cccc21
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a stirred, cold (0° C.) solution of 7.0 grams (0.046 mole) of 4-fluoroindanylamine (known compound) and 5.7 grams (0.056 mole) of triethylamine in 100 mL of methylene chloride was added 5.4 grams (0.051 mole) of 2-chloroethyl isocyanate. The cold reaction mixture was stirred for three hours at which time it was filtered. The filter cake was rinsed with methylene chloride. The filtrates were combined and concentrated under reduced pressure to a residue. The residue was triturated with hexanes and the mixture filtered. The filter cake was dried under reduced pressure to yield 4.0 grams of [(2-chloroethyl)amino]-N-(4-fluoroindanyl)carboxamide. The NMR spectrum was consistent with the proposed structure.