Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17](C(OC)=O)([F:19])[F:18]>CN(C=O)C.O>[F:18][CH:17]([F:19])[O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: COC(=O)C(F)(F)Cl
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a solution of 4-hydroxybenzonitrile (4.76 g, 40 mmol) in 150 mL of DMF was added 5.52 g (40 mmol) of K2CO3. The mixture was heated at 95° C. and 5.27 mL (50 mmol) of CICF2CO2Me was added slowly over 10 minutes. The reaction was stirred at 95 ° C. for 15 minutes and a 1.5 mL portions of ClCF2CO2Me were added until no changes were observed by TLC. The reaction was stirred overnight at room temperature diluted with water (300 mL) and extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford the corresponding nitrile as a white solid (3.0 g, 44%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.F[S:9]([C:12]1[N:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10]>CN(C=O)C>[CH3:19][O:18][C:15]1[N:14]=[N:13][C:12]([S:9]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)F)nn1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2cccc2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To an ice-cold suspension of sodium hydride (1.86 mmol, 74 mg) in DMF (1 mL) was added a solution of pyrrole (1.86 mmol, 125 mg) in DMF (2 mL). To this was added 3-fluorosulfonyl-6-methoxypyridazine (1.55 mmol, 298 mg) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with H2O (20 mL) and EtOAc (20 mL) and the EtOAc layer was collected, dried, filtered and evaporated to a residue. The residue was purified by silica gel chromatography (eluent: hexanes:EtOAc::9:1) to obtain 3-methoxy-6-(pyrrole-1-sulfonyl)-pyridazine (30%, 112 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].[CH:15]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O1CCCC1.Cl>O1CCCC1>[CH:15]1([CH:7]([C:6]2[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:3][C:2]=2[CH3:1])[OH:8])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1sc(-c2ccccc2)cc1C=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)cc1C(O)C1CCCCC1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 2-methyl-5-phenylthiophene-3-carbaldehyde (1.72 g) synthesized above in tetrahydrofuran (40 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (12.8 mL) at 0° C., and the mixture was stirred for 2 hr. 1.0M Cyclohexylmagnesium bromide-tetrahydrofuran solution (5 mL) was added dropwise again, and the mixture was further stirred at 0° C. for 1 hr. 1N Hydrochloric acid was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (2.33 g, 96%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH2:39][C@@H:40]([NH2:44])[C:41]([OH:43])=[O:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34]([NH:44][C@H:40]([CH2:39][CH3:38])[C:41]([OH:43])=[O:42])=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H](N)C(=O)O
Reactant: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(I)cc3)cc2)cc1
Product: CC[C@@H](Nc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
2-(4′-tert-Butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(4-iodo-phenyl)-1H-imidazole (191 mg, 0.3 mmol) was treated as described in general procedure R using D-2-aminobutyric acid (310 mg, 3 mmol) to give (R)-2-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-butyric acid, which was then treated as described in general procedure F to give (4R)-5-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-ethyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH2:13][N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(O)C=CC=CC=1.Br.CC(O)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCOC(c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: O=[N+]([O-])c1ccc(C2CNCCO2)cc1
Temperature: 75 °C

Procedure:
A mixture of 2-(4-Nitrophenyl)-4-tosylmorpholine (185) (430 mg, 1.19 mmol), phenol (670 mg, 7.12 mmol) and 33% HBr/AcOH (2.2 mL) was heated in a sealed tube (microwave tube, conventional heating) at 75° C. for twenty hours. The cooled mixture was concentrated and the residue loaded onto a 10 g SCX cartridge in methanol. The cartridge was washed with methanol (200 mL), then eluted with 1% methanolic methylamine (100 mL). The methylamine eluent was evaporated to give the title compound (I86) (204 mg, 83%) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.27-8.18 (m, 2H), 7.57-7.51 (m, 2H), 4.63 (dd, J=10.3, 2.5 Hz, 1H), 4.13-4.04 (m, 1H), 3.82 (td, J=11.3, 3.1 Hz, 1H), 3.13 (dd, J=12.3, 2.5 Hz, 1H), 3.06-2.92 (m, 2H), 2.74 (dd, J=12.3, 10.3 Hz, 1H). LCMS Method C: rt 1.49, 1.58 min; m/z 209.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Nc2cc(Br)cn(C)c2=O)nn1
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C)nn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Yield: 37.3 %

Procedure:
Following the procedure in Example 283b, and starting with 293c (150 mg, 0.53 mmol, 1.0 eq.) and {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (629 mg, 1.59 mmol, 3.0 eq.) afforded 293d as a yellow solid (110 mg, 37%). MS-ESI: [M+H]+ 557.4.
Reaction SMILES: I[CH:2]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=2)[C:9]2[C:4](=[CH:5][C:6]([O:31][CH3:32])=[CH:7][CH:8]=2)[CH2:3]1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:32][O:31][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:22][CH:23]=3)[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:2]=[CH:3]2)=[CH:8][CH:7]=1
Reactant: COc1ccc2c(c1)CC(I)C(c1ccccc1)C2c1ccc(OC(=O)C(C)(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C=CC(c1ccccc1)C2c1ccc(OC(=O)C(C)(C)C)cc1
Reaction time: 0.25 h
Yield: 75 %

Procedure:
2-iodo-7-methoxy-3-phenyl-4-(4-pivaloyloxyphenyl)-1,2,3,4-tetrahydronaphthalene (5, 39.4 mg, 0.0729 mmol) was dissolved in toluene (1.5 mL), and 1,8-diaza-bicyclo[5.4.0]undecene-7 (DBU, 0.035 mL, 0.234 mmol) was added, with heating and stirring at 80° c. for 15 min. After standing to cool, a saturated ammonium chloride aqueous solution (10 mL) was added under ice cooling, vigorously stirred, and next, extraction was carried out adding diethyl ether (10 mL). Extractions were further carried out two times with diethyl ether (10 mL), the organic phases were combined, washed with a saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by thin layer chromatography (benzene:hexane=10:1), and the subject compound (6, 22.7 mg) was obtained as a colorless oily substance (yield=75%).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[CH2:27][CH2:28][CH3:29].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1cc(C(=O)O)ccc1OCCCCCCc1cccc(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1cc(C(=O)O)ccc1OCCCCCCc1cccc(O)c1O
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To 1.80 g of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3-propylbenzoic acid in 125 mL of methylene chloride cooled at -70° was added 14 mL of 1M boron tribromide in methylene chloride. After 30 minutes at -70° and 5 hours at -20°, the reaction was worked up as in Example 32 and the product was recrystallized from ether-hexane to give 1.12 g, mp 123°-124° of 4-[6-(2,3-dihydroxyphenyl)hexyloxy]-3-propylbenzoic acid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11](Br)[CH:12]=[CH2:13]>O1CCCC1>[C:3]1([CH2:2][CH2:1][CH2:13][CH:12]=[CH2:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CCBr
Reactant: Br[Mg]CCc1ccccc1
Solvent: C1CCOC1
Product: C=CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of phenethyl magnesium bromide (prepared from 25 l g, 0.135 mol of phenethyl bromide and excess magnesium turnings) in anhydrous tetrahydrofuran (50 ml) was added to a stirred solution of allyl bromide (16.34 g, 0.135 mol) in anhydrous tetrahydrofuran (150 ml) at room temperature and under an atmosphere of dry nitrogen. The mixture was stirred at room temperature for 3 hours and the solvent was then evaporated off under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous solution of ammonium chloride and the solvent was evaporated off under reduced pressure to give an oil which was distilled to give 5-phenylpent-1-ene as a colourless oil (b.p. 40° C., 0.5 mm, Hg).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]([N:15]2[CH2:19][C@@H:18]([N:20]([CH:28]3[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29]3)[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[O:22])[CH2:17][C@H:16]2[C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[O:37])=[O:14])[C@H:10]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[CH2:9]1)(OC(C)(C)C)=O.Cl>C(Cl)Cl>[Cl:51][C:48]1[CH:47]=[CH:46][C:45]([C@@H:10]2[CH2:9][NH:8][CH2:12][C@H:11]2[C:13]([N:15]2[C@H:16]([C:36]([N:38]3[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]3)=[O:37])[CH2:17][C@H:18]([N:20]([CH:28]3[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29]3)[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[O:22])[CH2:19]2)=[O:14])=[CH:50][CH:49]=1
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)C3CCC(C)(C)CC3)CN2C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)C3CCC(C)(C)CC3)CN2C(=O)[C@@H]2CNC[C@H]2c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
1-BOC-(3R,4S)-3-(4-chlorophenyl)-4-({(2S,4S)-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-2-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidin-1-yl}carbonyl)pyrrolidine (1.33 g, 1.83 mmol) obtained in Step A was dissolved in DCM (1 mL) and 4M HCl (1 mL) was added dropwise thereto. The reaction solution was stirred for 1 hour at room temperature and concentrated in vacuo to give the title compound (1.14 g, 99.8%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.Br[C:40]1[CH:41]=[C:42]([S:46]([NH:49][C:50]([CH3:54])([CH3:53])[CH2:51][OH:52])(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1.CCCCCCC>C1(C)C=CC=CC=1>[OH:52][CH2:51][C:50]([NH:49][S:46]([C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)[CH:41]=1)(=[O:48])=[O:47])([CH3:54])[CH3:53]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(CO)NS(=O)(=O)c1cccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.503 g, 0.7 mmol), 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (Example H.4) (0.237 g, 0.77 mmol), tetrakis(triphenyl-phosphine)palladium (0.040 g, 0.030 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (268 mg, 66%). MS (ISP) 585.2 [(M+H)+]; mp 150° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:14]2[CH2:15][NH:16][CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10].CCN(CC)CC.[N+](C1C=CC([O:37][C:38](=O)[O:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=2)=CC=1)([O-])=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:14]2[CH2:15][N:16]([C:38]([O:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=3)=[O:37])[CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: Cn1c(C(=O)Nc2ccccc2N)cc2c1CNCC2
Reactant: COc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(OC(=O)N2CCc3cc(C(=O)Nc4ccccc4N)n(C)c3C2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (1.0 eq) obtained in step IX of example 228, in DMF was added Et3N (3.0 eq.) followed by carbonic acid 3,4-dimethoxy-phenyl ester 4-nitro-phenyl ester (1.0 eq) and stirred at room temperature overnight. Reaction mixture was then quenched with water and extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[C:26]([C:28]6[NH:32][N:31]=[N:30][N:29]=6)[CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]>>[C:38]([CH2:37][CH2:36][S:35][CH:22]1[C:21]2[CH:24]=[CH:25][C:26]([C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:33]=[CH:34][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:40])=[O:39]
Reactant: OC1c2ccc(-c3nnn[nH]3)cc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: O=C(O)CCS
Product: O=C(O)CCSC1c2ccc(-c3nnn[nH]3)cc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-hydroxy-8-(tetrazol-5-yl)-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17]C)=[O:16])=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH2:1]([O:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 2-(benzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylate (390 mg, 0.78 mmol) from Example 51, Step B in methanol (5 mL) was added 5N sodium hydroxide (0.31 mL, 1.56 mmol). The reaction was stirred at rt 20 h and then at 40° C. for 1 h. The reaction was diluted with water, acidified with 2N hydrochloric acid, and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give crude 2-(benzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=1.CC([O-])=O.[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4](=[O:23])[CH:5]=[C:6]([C:28]1[CH:27]=[N:26][C:25]([NH2:24])=[CH:30][CH:29]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:2]
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)C=CCCCCCCc1ccc2cccnc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(CCCCCCc1ccc2cccnc2n1)c1ccc(N)nc1
Temperature: 115 °C

Procedure:
A mixture of 28-4 (0.3 g, 1.0 mmol), 2-amino-5-bromopyridine (0.3 g, 1.9 mmol), KOAc (0.3 g, 2.4 mmol) and Pd(OAc)2 (0.02 g, 0.1 mmol) in 6 mL DMF was purged with argon for 5 min and then heated at 90° C. for 7 hr and 115° C. for 48 hr. It was cooled, treated with 50 mL water and extracted with EtOAc (×3). The combined organic layers were washed with brine and dried over Na2SO4. After solvent removal, the residue was purified using silica gel flash chromatography (100% EtOAc to EtOAc/MeOH 10:1) to afford the desired product 28-5 as an oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[NH:11][C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)#[N:8].[N:24]#[C:25]Br>C1COCC1>[Cl:14][C:13]1[C:9]([C:7]#[N:8])=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:11]([C:25]#[N:24])[C:12]=1[Cl:15]
Reactant: N#CBr
Reactant: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1c(Cl)c(Cl)n(C#N)c1-c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
Potassium t-butoxide (617 mg, 55 mmol) is added in portions to a solution of 3-cyano-4,5-dichloro 2-(3,4-dichlorophenyl)pyrrole (1.52 g, 5 mmol ) in anhydrous THF (20 mL). After 30 minutes, a solution of cyanogen bromide (583 mg, 5.5 mmol) in THF (1 mL) is added. The reaction mixture is stored at room temperature overnight. The solvent is removed in a rotary evaporator. The residue is treated with water and extracted witch ethyl acetate. The organic layer is washed with water and saturated sodium chloride and dried (MgSO4). Evaporation and crystallization of the residue from ethyl acetate gives while crystals (1.07 g); mp 250.5°-252.0° C.; IR (nujol) 2255, 2245 cm-1 (CN) 13C NMR (DMSO-d6) 102.7 (N-CN), 113.7 (3-CN); Mass spectrum 331.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=O)=O.CN(C)P(N(C)C)(N(C)C)=O>O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCOc1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCOc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 17.1 g. of ethyl p-aminobenzoate, 14.6 g. of 3-(4-chlorophenoxy)-1-propanol O-methanesulfonate and 100 ml. of hexamethylphosphoramide is heated at 110°-115° C. for 16 hours. The solution is diluted with 100 ml. of water, allowed to cool and is filtered to give 12.5 g. of solid. Recrystallization from cyclohexane gives 7.8 g. of yellow needles. Chromatography over silica gel gives 6.8 g. of product as white crystals, m.p. 87°-88° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[CH:18]=[C:17]([CH3:25])[N:16]=1>CN(C)C=O>[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH:18]=[C:17]([CH3:25])[N:16]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CN(C)C=O
Product: Cc1cc(NCCCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A solution of tert-butyl 4-aminobutylcarbamate (32.12 g, 170.6 mmol) in N,N-dimethylformamide (200 mL) was added over a period of 90 minutes to a solution of 2,4-dichloro-6-methyl-3-nitropyridine (35.09 g, 169.5 mmol) in N,N-dimethylformamide (500 mL). The reaction mixture was stirred at ambient temperature overnight. The solvent was removed by vacuum distillation using a 24/40 short path distillation head and warm water. The residue was dissolved in ethyl acetate (700 mL), washed with water (3×100 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography (50×450 mm silica gel eluting with 1:1 hexane:ethyl acetate) to provide 59.90 g of tert-butyl 4-[(2-chloro-6-methyl-3-nitropyridin-4-yl)amino]butylcarbamate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[OH:23]>CN(C=O)C.O>[Br:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 115 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
18.2 g (0.13 mol.) of potassium carbonate and 18.74 g (13.03 ml, 0.11 mol.) benzyl bromide is added to 2-bromo-4-chlorophenol (1) (25 g, 0. 12mol) in DMF (25 ml) under nitrogen. The reaction mixture is heated (oil bath temperature 115° C.) for 1.5 hours and then allowed to cool and left to stand overnight at RT. The reaction mixture is diluted with distilled water (100 ml) and then extracted with Et2O (2×100 ml). The organic extracts are combined, washed with 1M sodium hydroxide (100 ml) and concentrated in vacuo to leave a colorless oil. This oil is purified by flash chromatography (SiO2, pentane) to yield a colorless oil which crystallised on standing to give the title compound as a colorless solid, (29.14 g, 81%), m.p. 49-50.5° C. δH (250 MHz, CDCl3), 7.55 (d, J=2.6 Hz, 1H), 7.46 (m, 5H), 7.19 (dd, J=8.9, 2.5 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.13 (s, 2H).