Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[OH:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:2]([O:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:17]=1[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCBr
Reactant: Cc1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1cccc(C)c1C
Yield: 77.7 %

Procedure:
The product was generated via general protocol A using 1-bromotetradecane (45.0 mL, 147.9 mmol), 2,3-dimethylphenol (20.15 g, 163.3 mmol), K2CO3 (81.76 g, 591.6 mmol) and CH3CN (200 mL). Yielded 36.6 g (77.7%) of a brown liquid. 1H NMR (CDCl3, 400 MHz) δ: 7.03 (t, 3J=7.8 Hz, 1H, Ar—H), 6.76 (d, 3J=7.4 Hz, 1H, Ar—H), 6.70 (d, 3J=8.1 Hz, 1H, Ar—H), 3.93 (t, 3J=6.5, 2H, O—CH2), 2.27 (s, 3H, Ar—CH3), 2.16 (s, 3H, Ar—CH3), 1.79 (p, 3J=6.9, 2H, O—CH2—CH2), 1.48 (p, 3J=7.1, 2H, O—CH2—CH2—CH2), 1.27 (m, 22H), 0.88 (t, 3J=6.3, 3H, CH2—CH3). 13C NMR (CDCl3, 100 MHz) δ: 157.20, 137.86, 125.84, 125.33, 122.08, 108.98, 68.23, 32.07, 29.86, 29.83, 29.78, 29.61, 29.58, 29.54, 26.33, 22.88, 20.17, 14.24, 11.70.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1.O>O1CCOCC1>[Cl:8][C:5]1[N:4]=[N:3][C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(Cl)nn2)cc1

Procedure:
Under an argon atmosphere a solution of 1.08 g (7.05 mmol) 3,6-dichloro-pyridazin, 10 mL 2 M Na2CO3 solution and 80 mg (0.14 mmol) chlorine(di-2-norbornylphosphino)(2′-dimethylamino-1-1′-biphenyl-2-yl)palladium(II) in 150 mL 1,4-dioxane is heated to 110° C. At this temperature a solution of 1.13 g (7.05 mmol) 4-chlorophenyl-boric acid in 50 mL 1,4-dioxane is added dropwise within 2 h and the reaction mixture is heated for another hour. After cooling it is combined with 100 mL water, extracted with 100 mL EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 8:2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[CH3:17][C:18]([CH3:31])([CH3:30])[C:19]([O:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20]>>[CH3:17][C:18]([CH3:31])([CH3:30])[C:19]([O:21][N:22]([S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
tert-Butyl [(2,2-dimethylpropanoyl)oxy]{[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (46) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. (1.5 g, 78%), 1H NMR (250 MHz, DMSO-d6) δ ppm 8.18-8.37 (2H, m), 7.94-8.15 (2H, m), 3.46 (3H, s), 1.30 (9H, s), 1.29 (9H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)(OC(C)(C)C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[N:1]1([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C1CCN(N2CCNCC2)CC1
Reaction time: 8 h
Yield: 225.5 %

Procedure:
The product of step 4 (1.9 g, 5.79 mmol), N-BOC-4-piperidone (5.73 g, 28.8 mmol), NaBH(OAc)3 (6.1 g, 28.8 mmol) and 2M AcOH (5.76 ml, 11.52 mmol) were combined in CH2Cl2 (150 ml) and the mixture was stirred overnight. After the solvent was removed, NaOH (3N) was added and extractive work up with EtOAc followed by silica gel chromatography afforded pure piperazino-piperidine (2.21 g, 75% yield, Rf=0.18, hexanes/EtOAc, 1:1) as a syrup.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[S:5](Cl)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6]>N1C=CC=CC=1>[CH3:12][C:11]1[CH:13]=[CH:14][C:8]([S:5]([O:4][CH2:3][CH2:2][F:1])(=[O:7])=[O:6])=[CH:9][CH:10]=1
Reactant: OCCF
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCF)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a 0° C. solution of 2-fluoroethanol (1.0 g, 15.6 mmol) in pyridine (15 mL) was added tosyl chloride (6.5 g, 34.1 mmol) over 30 min. The reaction mixture was stirred at 0° C. for 4 h and quenched by adding ice-cold water and EtOAc. The layers separated and the organic layer was washed successively with water, 1M HCl (5×), saturated Na2CO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (12 g) using 5% to 40% EtOAc in hexane as the eluant to obtain fluorotosylate 20 (3.2 g, 95%) as a slightly yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=10.0 Hz, 1H), 7.38 (d, J=10.0 Hz, 2H), 4.59 (dt, J=50.0 & 5.0 Hz, 2H), 4.28 (dt, J=30.0 & 5.0 Hz, 2H), 2.47 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@@H:10]([OH:15])[C@@H:9]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[C:8]=2[CH:27]=1)(=[O:3])[CH3:2].O.FC(F)(F)C(O)=[O:32].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>C(#N)C>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[C:17]([NH:16][C@H:9]1[C:8]2[CH:27]=[C:4]([C:1](=[O:3])[CH2:2][OH:32])[CH:5]=[CH:6][C:7]=2[O:12][C:11]([CH3:14])([CH3:13])[C@H:10]1[OH:15])=[O:26]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccc(F)c(Cl)c1)[C@H](O)C(C)(C)O2
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC1(C)Oc2ccc(C(=O)CO)cc2[C@H](NC(=O)c2ccc(F)c(Cl)c2)[C@@H]1O
Yield: 23.5 %

Procedure:
(3S,4S)-6-Acetyl-4-(3-chloro-4-fluorobenzamido)-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran D4 (1.97 g, 5.0 mmol) (Example 17 of WO95/34545) was dissolved in acetonitrile (25 ml), water (5 ml) and trifluoroacetic acid (0.77 ml, 10.0 mmol). [Bis(trifluoroacetoxy)iodo]benzene (4.30 g, 10.0 mmol) was added and the reaction stirred under reflux for three hours. The reaction mixture was allowed to cool and the acetonitrile was removed in vacuo giving a yellow solid which was isolated by filtration and recrystallised from ethyl acetate/hexane to give the title compound as a white solid (0.48 g, 24%), m.p. 200° C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[Cl:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:5][C:6]1[C:11]([N:12]=[C:1]=[S:2])=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc(N)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(N=C=S)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A solution of thiophosgene (3.871 g, 33.66 mmol) in dichloromethane (10 mL) was added to a mixture of 2-chloro-6-methylpyridin-3-amine (4.00 g, 28.05 mmol) and sodium carbonate (5.947 g, 56.11 mmol) in dichloromethane (200 mL). The reaction was stirred overnight at ambient temperature, then washed with water, brine, dried, and concentrated to afford the desired product (5.2 g, 100.4% yield) as a tan powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:19]([O-])=O)[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>N1C=CC=CC=1.O>[NH2:19][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 3,5-dinitro-4-phenylbenzoic acid (135 g) in a mixture of pyridine (625 ml) and water (625 ml), sodium dithionite (235 g) is added in portions during about 30 minutes, keeping the temperature at 12°-15° C by external cooling. After additional stirring at this temperature for about 15 minutes, the resulting solution is acidified by the addition of conc. hydrochloric acid (750 ml), keeping the temperature below 25° C by the addition of ice to the reaction mixture. The mixture is left for about 20 hours, and the resulting precipitate is then collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, 3-amino-5-nitro-4-phenylbenzoic acid is obtained with a melting point of 247°-249° C (dec.).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br:16][C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH:2]([CH3:4])[CH3:3])=[CH:21][N:22]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Br)nc1
Reaction time: 2 h

Procedure:
2-Bromopropane (1.13 mL, 12 mmol) and potassium carbonate (1.43 g, 10.4 mmol) were successively added to a DMF (10 mL) solution of 6-bromopyridin-3-ol (1 g, 5.75 mmol), and the mixture was stirred at 80 degrees for 2 hours. The solution was brought back to room temperature, diluted with ethyl acetate, and washed twice with distilled water, and once with saturated brine. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain the target (1.28 g, 100%).
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([N:7]1[CH2:20][CH2:19][CH2:18][C@H:8]1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])=[O:6])[CH3:4].[OH-].[Na+].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([NH:2][C@H:3]([C:5]([N:7]2[CH2:20][CH2:19][CH2:18][C@H:8]2[C:9]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[O:6])[CH3:4])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)N2CCC[C@H]2C(=O)Nc2ccccc2)cc1
Reaction time: 1.5 h
Yield: 93.4 %

Procedure:
1.71 g (0.005 mol) of L-alanyl-L-proline anilide hydrobromide were suspended in 20 ml of dichloromethane. To the suspension were added 22 ml of 0.5-N sodium hydroxide solution followed by 1.05 g (1.1 equivalents) of p-toluenesulphonyl chloride. The mixture was stirred vigorously for 90 minutes. 50 ml of dichloromethane were added, the organic layer was separated, washed with 50 ml of brine, dried over magnesium sulphate and evaporated to an oil which crystallised upon the addition of petroleum ether. The solid was filtered off, washed with petroleum ether and dried to yield 1.94 g (93%) of N-(p-toluenesulphonyl)-L-alanyl-L-proline anilide of melting point 145°-147° C.; [α]D20 =-126.2° (c=1.00% in glacial acetic acid).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[NH:28][C:29]4[CH:39]=[CH:38][C:37]5[C:32](=[C:33]([OH:44])[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=5)[C:30]=4[N:31]=3)[CH:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20].C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[S:40]([C:35]1[CH:36]=[C:37]2[C:32](=[C:33]([OH:44])[CH:34]=1)[C:30]1[N:31]=[C:27]([C:23]3[CH:22]=[C:21]([C:16]4[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([CH3:13])[CH:15]=4)[CH:26]=[CH:25][CH:24]=3)[NH:28][C:29]=1[CH:39]=[CH:38]2)(=[O:42])=[O:41])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)Cl)cc(O)c54)[nH]3)c2)cc1C
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)N6CCC[C@H]6C(=O)OC(C)(C)C)cc(O)c54)[nH]3)c2)cc1C
Reaction time: 15 h

Procedure:
To an agitated suspension of (S)-pyrrolidine-2-carboxylic acid tert-butyl ester (0.036 g, 0.21 mmol) in DMF (1 mL) was added 2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxyl-3H-naphtho[1,2-d]imidazole-7-sulfonyl chloride (0.064 g, 0.14 mmol) and triethyl amine (0.022 g, 0.21 mmol). After agitated for 15 hrs, the reaction mixture was concentrated under reduced pressure to give (S)-1-[2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazole-7-sulfonyl]-pyrrolidine-2-carboxylic acid tert-butyl ester. The crude product was treated with 90% trifluoroacetate acid (2 ml). After agitated for 1 hour, the mixture was concentrated under reduced pressure, then subjected to to HPLC (ODS-A, gradient 10-90% CH3CN/water 0.1% TFA) to provide the title compound (0.006 g, 8%) MS(ES) m/z 542 [M+H].
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Agent: [Na+]
Product: Cc1ccc(-c2cccc3c2OC(CN=[N+]=[N-])C3)cc1

Procedure:
Treatment of (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.01 g, 2.56 mmol) with sodium azide (0.664 g, 10.24 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.03 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.528 g (75%) of (±)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 231-232° C.; Anal. calcd. for C16H17NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 66.26; H, 7.0; N, 4.73.
Reaction SMILES: Cl.[C:2]([Cl:10])(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[C@@H:32]3[C@@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:25]([CH:34]3[CH2:39][CH2:38][N:37](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:36][CH2:35]3)[N:24]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12]>>[ClH:10].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:23]2[C@@H:32]3[C@@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:25]([CH:34]3[CH2:35][CH2:36][N:37]([C:2]([C:3]4[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=4)=[O:9])[CH2:38][CH2:39]3)[N:24]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:12]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Agent: Cl
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)c4ccncc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from isonicotinoyl chloride hydrochloride and starting compound A2 as described for compound 1. After evaporating the dichloromethane solution, the residue is dissolved in diethyl ether. After addition of a saturated solution of hydrochloric acid in ether, the titel compound precipitates. M.p. 66-68° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:11]=1)[C:8](=[O:25])[NH:7][CH:6]=[CH:5]2.[CH3:26][O:27][C:28]1[CH:33]=[N:32][CH:31]=[C:30]([Sn](CCCC)(CCCC)CCCC)[N:29]=1>CN(C=O)C>[CH3:26][O:27][C:28]1[N:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[CH:15][CH:14]=4)[N:11]=2)[C:8](=[O:25])[NH:7][CH:6]=[CH:5]3)[CH:31]=[N:32][CH:33]=1
Reactant: O=c1[nH]ccc2cc(Cl)nc(Nc3ccc(N4CCOCC4)cc3)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(OC)n1
Solvent: CN(C)C=O
Product: COc1cncc(-c2cc3cc[nH]c(=O)c3c(Nc3ccc(N4CCOCC4)cc3)n2)n1

Procedure:
6-chloro-8-(4-morpholinophenylamino)-2,7-naphthyridin-1(2H)-one (30 mg, 0.084 mmol) was dissolved in DMF (1 mL) in a microwave vial and 2-methoxy-6-(tributylstannyl)pyrazine (40 mg, 0.1 mmol) was added followed by PdCl2dppf (6.1 mg, 0.0084 mmol) at room temperature. The vial was flushed with nitrogen and closed the cap and subjected to microwave irradiation at 135 C for 60 minutes. The reaction mixture was diluted with DMSO and purified by prep HPLC. The compound was isolated as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.96 (s, 1H), 8.33 (s, 1H), 7.68 (s, 1H), 7.67 (d, 2H, J=8.8 Hz), 7.38 (m, 1H), 6.95 (d, 2H, J=8.8 Hz), 6.57 (d, 1H, J=7.2 Hz), 4.0 (s, 3H), 3.69 (t, 4H, J=4.8 Hz), 3.04 (t, 4H, J=4.8 Hz); MS m/z 431.2 (M+1).
Reaction SMILES: BrC[C:3]1[C:11]([F:12])=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]=1[F:13].C([O-])(=O)C.[K+].O.[C:20]([O:23][CH2:24]C)(=[O:22])[CH3:21]>CN(C)C=O>[C:20]([O:23][CH2:24][C:8]1[S:7][C:6]2[CH:10]=[C:11]([F:12])[CH:3]=[C:4]([F:13])[C:5]=2[CH:9]=1)(=[O:22])[CH3:21]
Reactant: CCOC(C)=O
Reactant: Fc1cc2sccc2c(F)c1CBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1cc2c(F)cc(F)cc2s1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 0.18 g of 5-bromomethyl-4,6-difluorobenzo[b]thiophene in 5 ml of N,N-dimethyl-formamide is added 0.23 g of potassium acetate, and the resulting mixture is stirred at 60° C. for one hour. The temperature of the thus stirred mixture is lowered to room temperature, and 10 ml of water and 10 ml of ethyl acetate are added thereto. Thereafter, the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under educed pressure, to obtain 0.14 g of colorless, oily acetoxymethyl-4,6-difluorobenzo[b]thiophene.
Reaction SMILES: [CH3:1][P:2]1(=[O:21])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].FC1[CH:37]=[CH:38][C:39]([N+:44]([O-:46])=[O:45])=[C:40]([O:42][CH3:43])[CH:41]=1>C(Cl)Cl>[CH3:43][O:42][C:40]1[CH:41]=[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([N:5]3[CH2:4][CH2:3][P:2](=[O:21])([CH3:1])[CH2:7][CH2:6]3)[CH2:13][CH2:12]2)[CH:37]=[CH:38][C:39]=1[N+:44]([O-:46])=[O:45]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCP(C)(=O)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
To a stirring solution of tert-butyl 4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate (178 mg, 0.563 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (0.5 mL). After 20 min, the solution was concentrated and the resulting residue was redissolved in DMF (2 mL). Potassium carbonate (160 mg, 1.16 mmol) was added portionwise to the stirring solution followed by 5-fluoro-2-nitroanisole (158 mg, 0.930 mmol). The reaction mixture was heated to 50° C. After 2 h, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the compound as a bright yellow solid (176 mg, 86% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[C:8]#[N:9].[OH-:18].[K+].Cl>CCO>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[C:8]([NH2:9])=[O:18]
Reactant: COc1cc(-c2ccccc2)cc(N)c1C#N
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1cc(-c2ccccc2)cc(N)c1C(N)=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
A mixture of 3-amino-5-methoxy-[1,1′-biphenyl]-4-carbonitrile (4, 0.64 g, 2.86 mmol) and KOH (1.12 g, 20 mmol) in EtOH (24 mL) in a sealed tube was heated at 100° C. for 18 h. Additional KOH (0.56 g, 10 mmol) was added and heating was continued for another 18 h. After this time, the mixture was cooled to room temperature, and the pH was adjusted to ˜2 by addition of concentrated HCl. After concentration, the residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The extracts were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with methanol in dichloromethane (0-20%) to afford the title compound (0.28 g, 40%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 7.62-7.60 (m, 2H), 7.58 (s, 1H), 7.47-7.44 (m, 2H), 7.39-7.36 (m, 1H), 7.28 (s, 1H), 6.61 (d, J=1.5 Hz, 1H), 6.56 (s, 2H), 6.43 (d, J=1.5 Hz, 1H), 3.87 (s, 3H); ESI MS m/z 243 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:19])=O>CN(C=O)C>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([Cl:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C(CC1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the title B compound, 3-cyclopentyl-2-phenylpropionic acid (3.1 g, 14.2 mmol) is added 10 mL of thionyl chloride and one drop of DMF. The reaction mixture is stirred at ambient temperature for 2 h. The excess thionyl chloride is evaporated and the residue is twice treated with toluene and evaporated to yield 3-cyclopentyl-2-phenylpropionyl chloride as an orange-yellow oil which is selected as such without further purification.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10](=[O:12])[CH3:11].C(O)(=O)C>CCOCC>[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:3])=[O:20])[C:10](=[O:12])[CH3:11]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCC(O)CCCN(CCCCCCC(=O)OC)C(C)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 7-[N-(4-hydroxynonyl)acetamido]heptanoic acid (9.8 g., 0.03 mole) (Example 1, Step C) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-[N-(4-hydroxynonyl)acetamido]-heptanoate as a viscous oil.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13]([CH2:14]Cl)=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].[NH2:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13]([CH2:14][C:19]3([NH2:18])[N:23]=[C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]4=[N:20]3)=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2CC2(N)N=c3ccccc3=N2)cc1
Temperature: 80 °C

Procedure:
The compound described in Example 26, Step 1 [1-(4-cyanobenzyl)-5-(chloromethyl)imidazole hydrochloride] (0.75 mmol, 0.20 g), 2-aminobenzimidazole (0.90 mmol, 0. 12 g) and diisopropylethylamine (2.25 mmol, 0.29 g) were dissolved in acetonitrile and placed in a nitrogen purged sealed tube and warmed at 80° C. for 18 hr. The precipitate was filtered off to yield 1-(4-cyanobenzyl)-5-(2-amino-1-benzimidazolylmethyl)imidazole.