Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][NH2:7].[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:41])[C:20]2[CH:25]=[N:24][C:23](S(C)(=O)=O)=[N:22][C:21]=2[N:30]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[CH:31]=1)=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:41])[C:20]2[CH:25]=[N:24][C:23]([NH:7][CH2:6][C:5]3[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:22][C:21]=2[N:30]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[CH:31]=1)=[O:17])[CH3:14]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCc3cc(OC)cc(OC)c3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1 Step F, the title compound was prepared from 3,5-dimethoxybenzylamine and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (10 mg, 0.02 mmol). 10 mg of 2-(3,5-Dimethoxy-benzylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.27 (s, 1H), 8.47 (s, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.19 (s, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.44 (s, 1H), 6.26 (s, 2H), 5.99 (br, 1H), 4.37 (q, J=7.1 Hz, 2H), 4.28 (d, J=6.2 Hz, 2H), 3.74 (s, 6H), 2.98 (m, 4H), 2.16 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.CC([O-])=O.[Na+].[Br:16]Br>CC(O)=O>[NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][C:5]([Br:16])=[CH:6][N:7]=1
Reactant: BrBr
Reactant: NC(=O)c1nccnc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1nc(Br)cnc1N
Temperature: 50 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred solution of 3-aminopyrazine-2-carboxamide (1 g, 7.24 mmol, prepared according to International Patent Application Publication No. WO2011054922) and NaOAc (200 mg, 2.44 mmol) in HOAc (15 mL) was added Br2 (0.45 mL) dropwise at 0° C. for 1 hour, and then it was stirred at 50° C. for 8 hours. After the mixing, it was poured into ice-water and filtrated, the crude product of 3-amino-6-bromopyrazine-2-carboxamide as brown solid (1.5 g, yield: 95%) was obtained. 1H-NMR (DMSO-d6, 400 MHz) δ 8.30 (s, 1H), 7.93 (s, 2H), 7.66 (s, 2H). MS (M+H)+: 217/219.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(O[CH:17](OCC)[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH3:27])[CH:21]=1)C>FC(F)(F)C(O)=O>[CH2:26]([C:22]1[CH:21]=[C:20]2[C:25]([CH:17]=[CH:18][NH:19]2)=[CH:24][CH:23]=1)[CH3:27]
Reactant: CCOC(CNc1cccc(CC)c1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCc1ccc2cc[nH]c2c1
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
To a solution of trifluoroacetic anhydride (45 mL) in trifluoroacetic acid (45 mL) at 4° C. under N2 was added (2,2-diethoxyethyl)-(3-ethylphenyl)amine (11.47 g, 48.36 mmol). After stirring for 30 min, the cold mixture was diluted with trifluoroacetic acid (60 mL). The mixture was stirred at reflux for 2.5 d, concentrated and extracted with methylene chloride (3×100 mL). The combined organic layers were washed with saturated NaHCO3 (3×60 mL), saturated NaCl (60 mL), dried (MgSO4) and concentrated. Flash chromatography (SiO2, 25% EtOAc/hexanes) gave the title compound (1.6 g, 23%) as a brown crystalline solid. 1H NMR (CDCl3) δ 8.03 (bs, 1H), 7.57 (m, 1H), 7.18 (s, 1H), 7.12 (m, 1H), 6.68 (m, 1H), 6.46 (m, 1H), 2.73 (m, 2H), 1.26 (m, 3H)
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C@@H:6]1[C@H:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:2].C[Si](C)(C)[O:32][CH2:33][CH2:34]O[Si](C)(C)C.C[Si](Cl)(C)C>C(O)CO>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C@@H:6]1[C@H:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10]32[O:32][CH2:33][CH2:34][O:14]3)[CH2:7]1)=[O:5])[CH3:29]
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Reactant: CCN(CC)C(=O)[C@H]1CN2CC[C@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: OCCO
Product: CCN(CC)C(=O)[C@H]1CN2CC[C@H]1C1(OCCO1)C2C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 88.5 %

Procedure:
A mixture of (3R*,4R*)-N,N-diethyl-6-diphenylmethyl-5-oxo-1-azabicyclo[2.2.2]octane-3-carboxamide (10 g, 26 mmol), 1,2-bis(trimethylsiloxy)ethane (6 g, 29 mmol), trimethylsilyl chloride (20 ml) and ethylene glycol (50 ml) was heated at 100° C. for 3 hours. After by-products were removed by distillation (93° C./atmosphere pressure), the mixture was poured into cold aqueous sodium bicarbonate (NaHCO3) (250 ml) and extracted with methylene chloride (CH2Cl2) (100 ml) three times. The combined extracts were dried over sodium sulfate (Na2SO4) and concentrated. The clude was purified by recrystallization from ethyl acetate (EtOAc)/hexane to give 21 (1:2 mixture at 6-position; 23 mmol, 88%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:17]([N:19]([CH3:36])[C@H:20]([C:33]([NH2:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO.[C].[Pd]>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:17]([N:19]([CH3:36])[C@H:20]([C:33]([NH2:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:30])([CH3:32])[CH3:31])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O

Procedure:
To a solution of 183 mg (0.290 mmol) of Z-Phe-Val-N-Me-Tyr(3-tBu)-NH2 in 3 ml of methanol, 100 mg of 10% palladium carbon was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 5 hours. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:methanol=10:1) to yield Phe-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 108 mg (75%). NMR(method g,CDCl3): δ 0.69(3H,dd,J=6.9,17.8 Hz), 0.89(3H,dd,J=6.9,14.5 Hz), 1.36(9/2H,s), 1.39(9/2H,s), 2.67(1H,dd,J=9.6,13.5 Hz), 2.78-2.94(1H,m), 2.97(3/2H,s), 3.09(3/2H,s), 3.12-3.40(2H,m), 3.59(1H,ddd,J=3.6,9.3,10.2 Hz), 4.34-4.42(1/2H,m), 4.68(1/2H,dd,J=6.6,11.1 Hz), 4.79(1/2H,dd,J=7.9,8.9 Hz), 5.18-5.26(1/2H,m), 5.35(1/2H,brs), 5.49(1/2H,brs), 6.60(1H,dd,J=7.9,12.2 Hz), 6.86(1H,ddd,J=1.6,6.3,6.3 Hz), 7.06(1H,s), 7.16-7.34(5H,m), 7.76(1/2H,brs), 7.85(1/2H,d,J=8.9 Hz), 7.95(1/2H,d,J=7.9 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8].[Br:11]N1C(=O)CCC1=O>C(Cl)Cl>[Br:11][C:6]1[N:2]([CH3:1])[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccn1C
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a dry flask is added methyl 1-methyl-1H-pyrrole-2-carboxylate (12.0 g, 86.4 mmol) and 150 mL of dry CH2Cl2, and the flask is wrapped in foil and purged with nitrogen. N-bromosuccinimide (16.2 g, 90.7 mmol) is added in one portion and the mixture is stirred at room temperature for 0.5 h. The reaction mixture is washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. Fractional distillation gives 12.0 g of methyl 5-bromo-1-methyl-1H-pyrrole-2-carboxylate as a yellow oil (64% yield). MS for C7H8NO2Br (ESI) (M)+m/z 217.1.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[CH:6][C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)=[CH:3]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(-n2ccc(Br)c2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccn(-c3ccc(OC(F)(F)F)cc3)c2)cc1
Temperature: 150 °C
Yield: 18.9 %

Procedure:
A suspension of crude 3-bromo-1-(4-trifluoromethoxyphenyl)-1H-pyrrole (356 mg, 1.26 mmol, 1.00 eq), 4-formylphenylboronic acid (283 mg, 1.89 mmol, 1.50 eq), bis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.04 mmol, 0.03 eq), 2 M Na2CO3 (aq) (1.26 mL, 2.52 mmol, 2.0 eq), and 1,4-dioxane (5 mL) were heated at 150° C. in a microwave reaction vessel for 45 min. The cooled solution was then diluted with EtOAc (20 mL), filtered over Celite®, concentrated to dryness, and purified via chromatography (2:2:1, hexane:EtOAc:acetone) to afford the desired intermediate (79 mg, 21%).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:5]2[CH:6]=[C:7]([C:14]3[CH:15]=[N:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][CH:19]=3)[CH:8]=[C:9]([C:10]([NH:12][NH2:13])=[O:11])[N:4]2[N:3]=1.[C:24](Cl)(=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27]>C1COCC1.O1CCOCC1>[CH3:27][CH:26]([CH3:28])[CH2:25][C:24]([NH:13][NH:12][C:10]([C:9]1[N:4]2[N:3]=[C:2]([NH2:1])[N:23]=[C:5]2[CH:6]=[C:7]([C:14]2[CH:19]=[N:18][C:17]([N:20]([CH3:21])[CH3:22])=[N:16][CH:15]=2)[CH:8]=1)=[O:11])=[O:29]
Reactant: CC(C)CC(=O)Cl
Reactant: CN(C)c1ncc(-c2cc(C(=O)NN)n3nc(N)nc3c2)cn1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)CC(=O)NNC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(N)nn12

Procedure:
The product of Step 2 (0.11 g, 0.35 mmol) was combined with isovaleryl chloride (0.04 mL, 0.35 mmol) and 5 mL of a 1:1 solution of THF/dioxane in a tube. The mixture was microwaved at 130° C. for five minutes. The reaction mixture was cooled, then the solid was collected by filtration to give 2-amino-7-(2-dimethylamino-pyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid N′-(3-methyl-butyryl)-hydrazide. MS (APCI+): m/z 398.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:32][C:33]1[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([OH:40])[CH:34]=1.[C:41]([C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50]O)=[CH:45][CH:44]=1)#[N:42]>C(Cl)Cl.CCOCC>[Cl:32][C:33]1[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([O:40][CH2:50][CH2:49][C:46]2[CH:47]=[CH:48][C:43]([C:41]#[N:42])=[CH:44][CH:45]=2)[CH:34]=1
Reactant: N#Cc1ccc(CCO)cc1
Reactant: Oc1cc(O)cc(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1ccc(CCOc2cc(O)cc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
Triphenylphoshine (32 g; 122 mmol) and diethylazodicarboxylate (19.2 mL; 122 mmol) were dissolved in CH2Cl2 (150 mL). Chloro-3,5-dihydroxybenzene (9.1 g; 63 mmol; from step (i) above) and 2-(4-cyanophenyl)ethanol (9.04 g; 61 mmol) were added and the solution was stirred at room temperature overnight. The mixture was diluted with Et2O and filtered through Celite. The solvent was removed in vacuo. Purification, first by flash chromatography (SiO2; CH2Cl2:MeOH), then by preparative HPLC (60% CH3CN:0.1 M NH4OAc/aq), afforded 3.55 g (21%) of the sub-title compound.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[Cl:36][C:37]1[CH:42]=[C:41](B(O)O)[CH:40]=[CH:39][N:38]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:41]4[CH:40]=[CH:39][N:38]=[C:37]([Cl:36])[CH:42]=4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-c4ccnc(Cl)c4)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 120 using (1R,2R,4R)-4-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 117) and 2-chloropyridine-4-boronic acid. Light brown solid. MS (EI): 617.1 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]=[CH:5][CH2:6][C:7]([OH:9])=[O:8].C([NH:20][C@H:21]([C:23](O)=[O:24])[CH3:22])(OC(C)(C)C)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(COC)OC>[NH2:20][C@H:21]([C:23]([NH:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]=[CH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:24])[CH3:22]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC(CC=CCC(=O)O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: C[C@H](N)C(=O)NC(CC=CCC(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 16 h
Yield: 115.2 %

Procedure:
3.9 g of the product of Step D of Example 5 were dissolved in 200 ml of dimethoxyethane and 3.63 g of N-Boc-L-alanine were added. The mixture was cooled to -5°/0° C. and after addition of 3.99 g of dicyclohexylcarbodiimide, the mixture was vigorously stirred for 16 hours at 0° C. followed by filtering and evaporating to dryness. The residue was taken up in dimethoxyethane and filtered, then evaporated to dryness and taken up in methylene chloride. After washing with a saturated solution of sodium bicarbonate, then with salt water, drying and evaporating to dryness, 7.7 g of crude product were obtained which was chromatographed on silica. Elution with a cyclohexane - ethyl acetate mixture (7-3) yielded 5.4 g of the expected product with a specific roation of [α]=-18.5°±1° (c=1.6% in CH2Cl2).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[Cl:23][SiH:24]([Cl:26])[Cl:25]>>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Si:24]([Cl:26])([Cl:25])[Cl:23])=[CH:17][CH:16]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: Fc1ccc(CCl)cc1
Agent: CCCCP(CCCC)CCCC
Product: Fc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 87.6 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 1.08 g (7.5 mmol) of 4-fluorobenzyl chloride, and 5.08 g (37.5 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 1.6 g of (4-fluorobenzyl)trichlorosilane (bp; 56° C./13 mmHg, yield; 96%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([NH:14][C:15]([NH:17]C3C=CC=CC=3)=[O:16])[C:7]=2[CH:24]=1)#[N:2].[CH2:25](N=C=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]([NH:14][C:15]([NH:17][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])[C:7]=2[CH:24]=1)#[N:2]
Reactant: CC1(C)CC(NC(=O)Nc2ccccc2)c2cc(C#N)ccc2O1
Reactant: O=C=NCc1ccccc1
Solvent: CCO
Product: CC1(C)CC(NC(=O)NCc2ccccc2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A solution of the title D compound from Example 8 (0.50 g, 2.47 mmoles) and benzyl isocyanate (0.33 g, 2.47 mmoles) in anhydrous ethanol (4 ml) was heated at reflux for 3 hours and cooled to room temperature. The reaction product precipitated from solution. It was collected by suction filtration; the solid was triturated with diisopropyl ether and dried under vacuum to obtain 0.71 g of the title compound as a white solid, m.p. 168-169° C. 1H NMR (DMSO-d6) δ 7.59 (s, 1 H), 7.56 (s, 1 H), 7.38-7.24 (m, 5 H) 6.89 (d, J=8.21 Hz, 1 H), 6.56 (t, J=5.87 Hz, 1 H), 6.50 (d, J=8.21 Hz, 1 H), 4.94 (M, 1 H), 4.30 (d, J=5.86 Hz, 2 H), 2.10 (m, 1 H), 1.74 (m, 1 H), 1.41 (s, 3 H), 1.28 (s, 3 H). 13C NMR (DMSO-d6) δ 158.11, 157.19, 140.78, 132.25, 132.08, 128.22, 126.93, 126.61, 126.12, 119.18, 118.03, 102.02, 77.28, 43.01, 41.95, 38.81, 29.08, 24.42.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC(C)=O>[CH2:35]([O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])=[CH:4][CH:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CN(C(=O)Cc1ccc(O)c([N+](=O)[O-])c1)[C@H](CN1CCCC1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C(=O)Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound (vi) (3.2 g, 7.62 mmol) in anhydrous acetone (50 mL) was added anhydrous potassium carbonate (4.22 g, 30.5 mmol). The mixture was stirred at room temperature for 30 mins then added dropwise benzyl bromide (1.30 g, 7.62 mmol). The stirring was continued for an additional 48 h and the reaction mixture was filtered off. The cake was washed thoroughly with acetone and the combined-filtrate was evaporated to dryness. The residue was redissolved in CH2Cl2 and the organic layer was washed with water, saturated salt solution and dried over anhydrous sodium sulfate. The removal of the solvent resulted in a yellow foam, and the product was purified on a silica gel column to give (vii) as a solid, 2.5 g (69%); MS 474 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH2:14][CH2:15][CH2:16][C:17]2[C:21]=1[O:20][C:19](=[O:22])[C:18]=2[CH3:23])=[O:12].[K+].C([O-])(=O)C.C1(C)C=CC=CC=1.Cl>O>[CH3:23][CH:18]([C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])[CH:21]=1)[C:19]([OH:22])=[O:20]
Reactant: CC1=C2CCCC(C(=O)c3ccc4ccccc4c3)=C2OC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C(=O)O)c1cccc(C(=O)c2ccc3ccccc3c2)c1
Temperature: 220 °C
Reaction time: 1 h

Procedure:
A mixture of 7-(2-naphthoyl)-3-methyl-5,6-dihydro-2(4H)-benzofuranone (10 g) and acetic acid potassium salt (0.3 g) was added to a reactor and stirred for 1 hr at 220° C. The reaction mixture was cooled down to room temperature. Toluene and water were added to the reaction mixture and acidified to pH 2 with 5% hydrochloric acid. Toluene layer separated was dried over anhydrous MgSO4, filtered and evaporated to give crude product. The crude product was purified by column chromatograph on silica gel by eluting with a mixture of ethylacetate and n-hexane (1:5) to give the desired product (9:42 g, 94 % .
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:35][CH:34]=3)[S:30][C:29]=2[CH:47]=1.[Br-].[Al+3].[Br-].[Br-]>S(Cl)(Cl)=O.CN(C=O)C>[N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([C:32]3[C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:47][C:29]=4[S:30][C:31]=3[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:35][CH:34]=3)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(O[C@@H]2CCCC[C@H]2N2CCCCC2)cc1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Al+3]
Agent: [Br-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3ccc(O[C@@H]4CCCC[C@H]4N4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.698 g (5.60 mmol) of 4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]benzoic acid (Part C) was dissolved in 30 mL of thionyl chloride at room temperature. To this was added 434 μL (5.60 mmol) of DMF as a catalyst. The mixture was stirred for 3 days at room temperature. The thionyl chloride was removed under reduced pressure and the residue was treated with dry benzene to remove azeotropically the residual thionyl chloride and then placed under high vacuum. The crude acid chloride was suspended in 50 mL of anhydrous dichloroethane, and to this was added 1.799 g (5.09 mmol) of 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B). After cooling the slurry to 0° C., aluminum bromide (6.79 g, 25.4 mmol) was added, producing a dark red mixture. The ice bath was removed and the reaction mixture was stirred at room temperature for 6 h. The mixture was poured into 100 mL of cooled (0° C.) 2.0 N NaOH. The aqueous layer was extracted with EtOAc (3×400 mL). The combined organic layers were washed with 300 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified using PrepLC (8% of (10% concd NH4OH in MeOH) in CH2Cl2).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:34][O:35][CH2:36][CH2:37][CH3:38])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]=1[C:10]([O:12]CCC)=[O:11])([CH3:4])[CH3:3]>O.[OH-].[Li+].O1CCOCC1>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:34][O:35][CH2:36][CH2:37][CH3:38])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3]
Reactant: CCCOCc1nc(C(C)(C)O)c(C(=O)OCCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCOCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
394 mg of propyl 4-(1-hydroxy-1-methylethyl)-2-propoxymethyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 90(b)] were dissolved in a solution of 88 mg of lithium hydroxide monohydrate in 10 ml of a 50% v/v aqueous Solution of dioxane, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction solution was concentrated by distillation under reduced pressure, and the dioxane was removed by distillation under reduced pressure. The concentrate was then cooled with ice, and 2.1 ml of 1N aqueous hydrochloric acid were added. The crystals which precipitated were collected by filtration, to give 235 mg of the title compound, melting at 166°-168° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][CH2:16]Cl)=[CH:10][CH:9]=1.[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][CH2:16][N:33]2[CH2:34][CH2:35][CH:30]([C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[CH:20]([CH3:19])[CH3:36])[CH:29]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)=[CH:10][CH:9]=1
Reactant: O=C(CCCl)c1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(=O)c3ccc(Br)cc3)CC2)c1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 1-(4-bromophenyl)-3-chloro-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 457.1 (M+H)+.