Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=O.[N+:12]([CH3:15])([O-:14])=[O:13].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:15][N+:12]([O-:14])=[O:13])[CH:7]=[C:8]([F:11])[C:9]=1[OH:10]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc(F)c(O)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1cc(F)c(O)c(F)c1
Temperature: 110 °C
Yield: 70.8 %

Procedure:
3,5-Difluoro-4-hydroxybenzaldehyde (2.27 g, 14.4 mmol), nitromethane (4.7 mL, 86.4 mmol) and ammonium acetate (4.4 g, 57.6 mmol) were dissolved in acetic acid (22 mL) and the reaction mixture was heated at 110° C. for 1 hour 30 min. The reaction was concentrated under reduced pressure and the residue partitioned between ether and water. The layers were separated and the organic layer was dried with Na2SO4. The organic mixture was filtered and the filtrate concentrated under reduced pressure to afford a crude product. The crude product was purified by flash column chromatography (eluent: EtOAc/hexane 22/78) to afford the title compound (2.05 g, yield: 71%). Electrospray MS M−1 ion=200. 1H-NMR (CDCl3, 200 MHz): 7.84 (d, 1H, J=13.7 Hz), 7.45 (d, 1H, J=13.7 Hz), 7.19-6.99 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]1[CH2:21][NH:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[CH2:17]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:20]2[CH2:21][CH2:16][CH2:17][CH:18]([C:22]([F:25])([F:24])[F:23])[CH2:19]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: FC(F)(F)C1CCCNC1
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC(C(F)(F)F)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and DL-3-(trifluoromethyl)piperidine (9.2 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.2 mg). HRMS calcd for C17H17F3N2O2: 338.1242, found 338.1242.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][N:5]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[C:4]=2[CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)CNc1ccsc1C2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3sccc32)cn1

Procedure:
As described for Example 1, 5, 10-dihydro-4H-thieno[3,2-c][2]benzazepine in dichloromethane in the presence of triethylamine is reacted with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 4-(methanesulfonyl)phenyl acetic acid (43.63 g, 0.204 mol) in methanol (509 mL) was treated slowly with concentrated sulfuric acid (2 mL). The resulting reaction mixture was heated under reflux for 19 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (800 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×200 mL), washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 1/1 hexanes/ethyl acetate) afforded 4-(methanesulfonyl)phenyl acetic acid methyl ester (45.42 g, 98%) as a yellow oil which solidified to a cream colored solid upon sitting over time at 25° C.: mp 78-80° C.; EI-HRMS m/e calcd for C10H12O4S (M+) 228.0456, found 228.0451.
Reaction SMILES: O=[C:2]([C:7](OC)=[O:8])[C:3]([O:5][CH3:6])=[O:4].[S:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:12][C:13]([O:15][CH3:16])=[O:14]>>[OH:8][C:7]1[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:12]([C:13]([O:15][CH3:16])=[O:14])[S:11][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CSCC(=O)OC
Reactant: COC(=O)C(=O)C(=O)OC
Product: COC(=O)c1sc(C(=O)OC)c(C(=O)OC)c1O

Procedure:
The above compound was prepared as in Preparation 7 from dimethyl ketomalonate and dimethyl thiodiacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.Cl[CH2:19][O:20][CH3:21]>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH2:9][O:10][CH2:19][O:20][CH3:21])=[CH:5][N:6]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: COCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOCc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (5,6-dichloropyridin-3-yl)methanol (commercially available) in CH2Cl2 (0.2 M) at 0° C. was added triethylamine (3 eq.) and chloro(methoxy)methane (2 eq.). After stirring at 0° C. for 3 hours the reaction mixture was concentrated and the crude was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford 2,3-dichloro-5-((methoxymethoxy)methyl)pyridine as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[CH:12][CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([S:24][CH2:25][C:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[O:29][CH:30]=2)[N:3]=1.Cl.[CH3:39][NH:40][CH2:41][C:42]([O:44][CH3:45])=[O:43].C(N(CC)CC)C>CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:28]2[O:29][CH:30]=[C:26]([CH2:25][S:24][C:4]3[N:3]=[C:2]([N:40]([CH3:39])[CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:7]([C:8]#[N:9])=[C:6]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[CH:12][CH:11]=4)[C:5]=3[C:22]#[N:23])[N:27]=2)=[CH:32][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)cc1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)c1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
108 mg (0.20 mmol) of the compound from Example 103A are dissolved in 3 ml of dry DMF, and 54 mg (0.39 mmol) of methyl N-methylglycinate hydrochloride and 59 mg (0.59 mmol) of triethylamine are added. The reaction mixture is stirred at RT for 8 h. The solvent is then removed on a rotary evaporator and the residue is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). After removal of the solvent on a rotary evaporator, the product is obtained as a white solid.
Reaction SMILES: [C@@H:1]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.F[C:21](F)(F)C(OC(=O)C(F)(F)F)=O.C[O-].[Na+].Cl.N1C=CC=CC=1>N1C=CC=CC=1.CO>[NH2:17][C:16]1[N:18]=[C:19]2[C:12]([N:11]=[CH:10][N:9]2[C@@H:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)=[C:13]([O:14][CH3:21])[N:15]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COc1nc(N)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 0 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To 2 mmol of deoxyguanosine, dried by evaporation of pyridine and suspended in 10 mL of dry pyridine was added dropwise 2.3 mL (16 mmol) of trifluoroacetic anhydride, with cooling in an ice both. After ten minutes a suspension of 4.3 g of sodium methoxide in 300 mL of methanol was added dropwise. After a further 24 hrs, the mixture was treated with a solution of pyridine hydrochloride (12 mL of pyridine/4 mL conc HCl). The excess acid was destroyed by addition of 2 g of sodium bicarbonate and the mixture was evaporated to dryness. The residue was dissolved in water and purified on a Dynamax reversed-phase hplc column using a gradient of 2-5% acetonitrile in water in 45 min at a flow rate of 6 mL/min. Evaporation of appropriate fractions gave 0.36 g (60%) of pure 2-amino-6-methoxy-9-(2-deoxy-Beta-D-erythro-pentofuranosyl)purine. A crystalline sample was obtained by crystallization from water, mp 155°-7°. UVmax (MeOH) 281 nm; UVmin 281 nm; 1H NMR (DMSO-d6) delta (ppm) 8.07 (s, 1,H8), 6.43 (br s, 2, NH2), 6.20("t", 1, Japp =6.9 Hz, H1'), 5.27 (d, 1, J=3.8 Hz, 3'-OH), 4.98 (t, 1, J=5.5 Hz, 5'-OH) , 4.35 (m,1,H3'), 4.00 (s, 3, OCH3), 3.82 (m, 1, H4'), 3.53 (m, 2, H5',5'), 2.57 & 2.22 (m & m, 1 & 1, H2' & H2"). Anal. Calcd. for C11H15N5O4.H2O: C, 44.15; H, 5.72; N, 23.40. Found: C, 44.15; H, 5.83; N, 23.43.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([CH3:25])(=[O:24])=[O:23])=[N:7][C:8]2[C:13]([CH:14]=1)=[N:12][CH:11]=[C:10]([F:15])[CH:9]=2)(O)C.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O>C1COCC1>[F:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:5]([CH:2]([N:30]3[C:26](=[O:36])[C:27]4[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:29]3=[O:31])[CH3:1])[C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22]([CH3:25])(=[O:23])=[O:24])=[N:7]2)=[N:12][CH:11]=1
Reactant: CC(C)(O)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h

Procedure:
To a mixture of methyl 1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethanol (500 mg, 1.44 mmol) and phthalimide (425 mg, 2.88 mmol) in THF (15 mL) was added triphenylphosphene (757 mg, 2.88 mmol) at 0° C. The reaction mixture was stirred for 10 min at same temperature. Diisopropyl azo-dicarboxylate (0.6 mL, 2.88 mmol) was added to reaction mixture at 0° C. The reaction mixture was stirred for overnight at 0° C. Water was added to reaction mixture and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 2-(1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1, 5-naphthyridin-3-yl)ethyl) isoindoline-1,3-dione: LC-MS (ESI) m/z 476.0 [M+H]+. It was carried on crude for next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:37])[CH2:35][CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:37])[CH2:35][CH3:36])[CH:28]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 61 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 494.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[NH:11][CH:10]=[N:9][C:8]=2[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[NH:4][N:3]=1.[C:18](Cl)(Cl)=[O:19].C1(C)C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[N:6]=[C:5]2[N:4]([C:18](=[O:19])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]3[N:9]=[CH:10][NH:11][C:7]=32)[N:3]=1
Reactant: CCCCCNc1nc[nH]c1-c1nc(C)n[nH]1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCn1c(=O)n2nc(C)nc2c2[nH]cnc21
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of 5-(3-methyl-1H-1,2,4-triazol-5-yl)-N-pentyl-1H-imidazol-4-amine (45 mg, 0.19 mmol) in THF (10 mL) at 0° C. was added phosgene in toluene (0.3 mL, 1.0 mmol). The reaction mixture was slowly warmed to room temperature while stirring. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative LCMS (method A) to provide the desired product (25 mg, 50% yield) as a white powder. LCMS calculated for C12H17N6O (M+H): 261.1. found: 261.1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[F:16])=[O:6]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Nc1ccccc1F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Nc1ncc(Br)cc1C(=O)Nc1ccccc1F
Temperature: 130 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A mixture of 2-Amino-5-bromo-nicotinic acid (1 g, 4.61 mmol) and SOCl2 (5 mL) in toluene (15 mL) was stirred at 130° C. for 2 h. After concentrated, the residue was dissolved in tetrahydrofuran (20 mL), and then 2-fluoro-phenylamine (1.09 g, 9.81 mmol) was added dropwise at 0° C. The reaction mixture was heated to 90° C. for 4 h. After being cooled to room temperature and quenched with saturated aqueous K2 CO3 (10 mL), the mixture was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with silica gel column chromatograph (PE:EtOAc=2:1) to give 2-amino-5-bromo-N-(2-fluorophenyl)nicotinamide (1.0 g, 70% yield) as yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.25˜8.28 (m, 2H), 7.86 (d, J=2.4 Hz, 2H), 7.13˜7.22 (m, 3H), 6.36 (s, 2H). MS (M+H)+: 311/313.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:58]1[CH2:63][CH2:62][CH:61]([N:64]2[CH2:70][CH2:69][C:68]3[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=3[NH:66][C:65]2=[O:75])[CH2:60][CH2:59]1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:58]4[CH2:59][CH2:60][CH:61]([N:64]5[CH2:70][CH2:69][C:68]6[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=6[NH:66][C:65]5=[O:75])[CH2:62][CH2:63]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
(S)-2-(1,4-Dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino [3,4-e]indazol-7-yl)acetic acid (52 mg, 0.104 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). N,N-Diisopropylethylamine (70 μl, 0.402 mmol) was added to the mixture followed by TBTU (34.8 mg, 0.108 mmol). 3-(Piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (35.4 mg, 0.144 mmol) was then added to the mixture. Reaction stirred at room temperature for 1 hour. Reaction was quenched with 50% acetonitrile-water. Material was purified by reverse phase prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 67% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.92 (s, 1H) 8.51 (s, 1H) 7.48 (s, 1H) 6.98-7.08 (m, 3H) 6.76-6.86 (m, 1H) 5.58 (d, J=17.40 Hz, 1H) 5.39 (d, J=17.09 Hz, 1H) 4.49 (d, J=13.12 Hz, 1H) 4.26-4.42 (m, 2H) 4.10-4.24 (m, 1H) 3.90-4.09 (m, 2H) 3.33-3.41 (m, 2H) 3.19 (d, J=16.79 Hz, 1H) 3.05-3.15 (m, 1 H) 2.95-3.02 (m, 1H) 2.83-2.94 (m, 3H) 2.53-2.65 (m, 1H) 2.33-2.46 (m, 1H) 1.58-1.85 (m, 3H) 1.40-1.57 (m, 1H). High resolution MS m/e (M+H)+=725.0720.
Reaction SMILES: CN(C=O)C.[C:6]1([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][NH:15][C:14](=[O:24])[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]>O>[O:24]=[C:14]1[N:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[N:16]=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:13]1
Reactant: O=c1cc(-c2ccccc2)c(-c2ccccc2)n[nH]1
Reactant: COC(=O)CCCCCCCCBr
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Sodium hydride (840 mg of a 60% dispersion in oil, 20 mmol) was washed twice with hexanes, covered with DMF (25 mL) and 5,6-diphenyl-3(2H)-pyridazinone (4 g, 16 mmol), obtained according to P. Schmidt, et al., Helvetica Chim. Acta., 37, 134-140 (1954), added. After gas evolution had ceased, the mixture was stirred at room temperature for 30 minutes before adding methyl 9-bromononanoate (4.45 g, 18 mmol). The mixture was heated briefly to 110° C. to give a solution and then allowed to cool before being stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with diethyl ether (3×). The combined extracts were washed with water, dried over sodium sulfate and concentrated to leave an oil. Chromatography on a column of silica gel afforded methyl 6-oxo-3,4-diphenyl-1(6H)-pyridazine nonanoate (6.44 g, 95%) as an oil.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:31])[N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])=[O:31])=[CH:17][CH:16]=1
Reactant: O=C(NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Yield: 67.4 %

Procedure:
To a degassed solution of [4-(4-{[N,N-bis-(2-hydroxyethyl)carbamoyl]methoxy}phenyl)-butyl]carbamic acid benzyl ester 25 (0.19 g, 0.43 mmol) in ethanol (4 mL) was added 10% palladium on activated carbon (0.1 g, 50% wet). The mixture was hydrogenated overnight at atmospheric hydrogen. The catalyst was filtered through a pad of diatomaceous earth and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 20–5:1:0.1–1 dichloromethane/methanol/concentrated ammonium hydroxide, v/v) to provide 26 (0.09 g, 72%) as a colorless oil. 1H NMR (300 MHz, CD3OD) δ 1.56 (m, 4H), 2.56 (t, 2H), 2.65 (t, 1H), 3.29 (m, 1H), 3.55 (m, 4H), 3.72 (m, 4H), 4.90 (s, 2H), 6.86 (d, 2H), 7.09 (d, 2H). m/z (ESI): 311 [C16H26N2O4+H]+.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([CH2:17][C:18](=O)[CH3:19])/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10].[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[C:21]([CH:23]([CH:18]([CH3:19])[CH2:17][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)C(C)CC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
In 200 ml. of benzene was dissolved 50 g. of geranyl acetone, and then 42 g. of ethyl cyanoacetate, 6 g. of ammonium acetate and 6 g. of acetic acid were added to the solution. The mixture was then refluxed for 8 hours while removing the produced water. The reaction mixture was washed with water and dried. To this was added dropwise a solution of 5.7 g. of sodium borohydride in 40 ml. of ethanol, under stirring and at 10°-20° C. The stirring was continued for 1 hour. Then, 60 ml. of 10% acetic acid was added to the reaction mixture, and the mixture was subsequently washed with water and dried. The solvent was then removed by evaporation and the residue was purified by silica gel column chromatography to obtain 59 g. of the desired oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[NH:23][CH:22]=[N:21]2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:32][O:33][CH2:34][CH2:35]Br>CS(C)=O.O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[N:23]([CH2:35][CH2:34][O:33][CH3:32])[CH:22]=[N:21]2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:5]
Reactant: O=C(NCC1(O)CCCCCC1)c1cc(-n2nc[nH]c2=O)ccc1Cl
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COCCn1cnn(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.9 %

Procedure:
A slurry of 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzamide (44.4 mg, 0.122 mmol) and Cs2CO3 (66.0 mg, 0.202 mmol) were stirred in DMSO (0.813 mL) at ambient temperature for 20 minutes. 2-Bromoethyl methyl ether (17.0 mg, 0.122 mmol) was added and the reaction stirred at ambient temperature for 48 hours. The reaction was diluted with water (15-fold) and the aqueous extracted with CH2Cl2 (3×). The organics were dried over sodium sulfate, and concentrated in vacuo. The crude was purified by reverse phase HPLC reverse phase HPLC using a (25–65% gradient of 0.1% formic acid in acetonitrile and 0.1% formic acid in water) (to give the title compound (18 mg). LCMS (m/z) 423.5 M+1.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:27])[N:10]([CH3:26])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[C:29]1[CH:41]=[CH:40][C:32]([CH:33]=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1.CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([NH:8][C:9](=[O:27])[N:10]([C:11]1[CH:12]=[C:13]([C:29]2[CH:41]=[CH:40][C:32]([CH:33]=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)C=Cc1ccc(Br)cc1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C=CC(=O)OCC)cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
308 mg (0.26 mmol, 5 mol %) of tetrakis(triphenylphosphine)palladium are added to a solution of 2 g (5.34 mmol, 1.0 eq) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]urea and 1.6 g (6.4 mmol, 1.2 eq) of ethyl 4-bromocinnamate in 20 mL of an 8/2 mixture of dimethylformamide and of 2M potassium phosphate solution. The reaction mixture is stirred for 3 hours at 90° C. The reaction is stopped by addition of 50 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 1.69 g of ethyl 3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in oil form are obtained. Yield=75%