Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19]O)[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:10]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:51]>ClCCl>[Br:51][CH2:19][C@@H:16]1[O:17][CH2:18][C@:9]2([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=[C:11]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:12][C@H:13]([CH3:21])[C@@H:14]2[CH2:15]1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CBr)C[C@@H]12
Reaction time: 18 h

Procedure:
A solution of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P2) (150 mg, 0.347 mmol) in dichloromethane (7.5 mL) was cooled to 0° C. Triphenylphosphine (182 mg, 0.694 mmol) was added, followed by carbon tetrabromide (70 μL, 0.69 mmol), and the reaction mixture was removed from the ice bath and stirred for 18 hours. After addition of saturated aqueous sodium chloride solution (15 mL), the mixture was extracted with dichloromethane (2×20 mL); the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 70% ethyl acetate in heptane) provided the product as a white solid. Yield: 77.9 mg, 157 μmol, 45%. 1H NMR (400 MHz, CDCl3) δ 8.15-8.27 (br m, 2H), 7.34-7.57 (m, 4H), 6.84-6.98 (m, 2H), 4.19 (br d, J=12 Hz, 1H), 3.82-3.92 (m, 2H), 3.45-3.52 (m, 1H), 3.39 (dd, J=10.5, 5.8 Hz, 1H), 3.23-3.33 (br m, 1H), 2.89-2.98 (m, 1H), 1.93-2.02 (m, 1H), 1.6-1.73 (m, 1H), 1.28 (d, J=7 Hz, 3H).
Reaction SMILES: S(Cl)(Cl)(=O)=O.C1(C[S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[NH:21][C:22]3[C:27]([C:28](=[O:30])[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)C=CC=CC=1.N12CCN(CC1)CC2>C(Cl)Cl>[CH:23]1[C:22]2[N:21]3[S:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:20]3=[CH:29][C:28](=[O:30])[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: O=c1cc(-c2ccccc2SCc2ccccc2)[nH]c2ccccc12
Agent: C1CN2CCN1CC2
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=c1cc2c3ccccc3sn2c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
Sulfuryl chloride (0. 255 ml, 3.15 mmole, 1.05 equiv.) was added dropwise over 2 min to a solution of 2-[2-[(phenylmethyl)thio]phenyl]-4(1H)-quinolinone (1.03 g, 3 mmole, 1 equiv.) in dry CH2Cl2 (30 ml) at -15° C. The mixture was stirred for 0.5 hr, then 1,4-diazabicyclo[2.2.2]octane (504.8 mg, 4.5 mmole, 1.5 equiv.) was added. Stirring at -15° C. was continued for an additional 10 min, then the mixture was warmed to 25° C. After 0.5 hr at 25° C. the reaction was quenched with 10% aqueous Na2CO3 (30 ml) and extracted with CH2Cl2 . Drying (MgSO4), concentration, and silica gel chromatography (10% MeOH in 50% EtOAc/CHCl3) gave 5H-[1,2]benzisothiazolo[2,3-a]quinoline-5-one (0.28 g, 37%) as a yellow solid. Recrystallization from CHCl3 /EtOAc gave yellow, very fine needles: mp phase change at 244°-245° C., actual mp>300° C.; TLC (10% MeOH in 50% EtOAc/CHCl3) Rf 0.41; 1H NMR (CDCl3) δ8.53(m, 1H), 8.00 (app d, 1H), 7.6-7.8 (m, 3H), 7.4-7.6 (m, 3H), 7.09 (s, 1H); IR (KBr) 1618, 1593, 1571, 1544, 1483, 1464, 1445, 748 cm-1 ; MS (NH3), m/e (%) 252.1 (100, (M+H)+). Anal. Calcd for C15H9NOS: C, 71.69; H, 3.61; N, 5.57; S, 12.76. Found: C, 71.39; H, 3.51; N, 5.43; S, 12.68.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17].Br[CH2:19]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[O:17][CH2:19][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]3[C:10]=2[CH:15]=1
Reactant: BrCBr
Reactant: Oc1ccc(Cl)cc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)-c1nc3ccccc3n1CO2
Temperature: 80 °C
Reaction time: 12 h
Yield: 35.4 %

Procedure:
A mixture of 2-(1H-benzo[d]imidazol-2-yl)-4-chlorophenol (80 mg, 0.33 mmol), dibromo-methane (341 mg, 1.96 mmol), K2CO3 (137 mg, 0.99 mmol) in DMF (6 mL) was allowed to stir at 80° C. for 12 hours. Water (20 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. After being concentrated in vacuo, the resulting resulting residue was purified using prep-HPLC to provide 2-chloro-6H-benzo[e]benzo[4,5]imidazo[1,2-c][1,3]oxazine (30 mg, yield: 36%). 1H-NMR (Methanol-d4, 400 MHz) δ 8.07 (d, J=2.1 Hz, 1H), 7.83˜7.81 (m, 1H), 7.78˜7.75 (m, 1H), 7.63 (dd, J=8.8, 2.2 Hz, 1H), 7.54˜7.52 (m, 2H), 7.30 (d, J=8.8 Hz, 1H), 6.33 (s, 2H). MS (M+H)+: 257.
Reaction SMILES: [Cl:1][CH:2]1[CH:11]([Cl:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([OH:16])=[O:15])[C:9]=2[CH3:13])[S:4](=[O:18])(=[O:17])[CH2:3]1.[CH2:19]([N:21]1[C:25](O)=[CH:24][CH:23]=[N:22]1)[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>C(O)(CC)(C)C>[Cl:1][CH:2]1[CH:11]([Cl:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([O:16][C:25]3[N:21]([CH2:19][CH3:20])[N:22]=[CH:23][CH:24]=3)=[O:15])[C:9]=2[CH3:13])[S:4](=[O:17])(=[O:18])[CH2:3]1
Reactant: Cc1c(C(=O)O)ccc2c1C(Cl)C(Cl)CS2(=O)=O
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCC(C)(C)O
Product: CCn1nccc1OC(=O)c1ccc2c(c1C)C(Cl)C(Cl)CS2(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
1.5 Grams (4.9 mmol) of 3,4-dichloro-5-methyl-6-carboxythiochroman-1,1-dioxide was dissolved in 5 ml of t-amyl alcohol, and 1.1 g (5.3mmol, 1.2 eq.) of 1-ethyl-5-hydroxypyrazole and 1.1 g (5.3 mmol, 1.2 eq.) of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 2.5 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate and hexane, and liberated N,N'-dicyclohexylurea was filtered off. An organic layer was concentrated under reduced pressure and purified by column chromatography (silica gel/ethyl acetate) to give 1.9 g (yield 95%) of 3,4-dichloro-5-methyl-6-(1-ethylpyrazol-5-yl)oxycarbonylthiochroman-1,1-dioxide.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].Cl[CH2:18][CH2:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)(=[O:22])=[O:21].Cl>CN(C=O)C.C(OCC)(=O)C.O>[F:32][C:29]([F:30])([F:31])[C:25]1[CH:24]=[C:23]([S:20]([CH2:19][CH2:18][S:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])(=[O:21])=[O:22])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1cccnc1S
Reactant: O=S(=O)(CCCl)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
683 mg (4.92 mmol) of K2CO3 were added to a suspension of 349 mg (2.25 mmol) of 2-mercaptonicotinic acid in DMF (5 ml), and the mixture was stirred for 30 min at RT. 614 mg (2.25 mmol) of 2-chloroethyl-(3-(trifluoromethyl)phenyl)sulfone were then added, and stirring was continued for a further 72 h at RT. The reaction solution was concentrated in vacuo, the residue obtained was taken up in ethyl acetate, and water was added. The pH was adjusted to 3 with 2 M hydrochloric acid, and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. 778 mg (1.99 mmol, 88%) of 2-(2-(3-(trifluoromethyl)phenylsulfonyl)ethylthio)nicotinic acid were obtained as residue.
Reaction SMILES: C(S([C:6]1[N:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:11][CH:12]=2)[N:7]=1)(=O)=O)C.[NH2:30][C:31]1[CH:40]=[CH:39][C:34]2[NH:35][C:36](=[O:38])[NH:37][C:33]=2[CH:32]=1>C(#N)C>[O:38]=[C:36]1[NH:35][C:34]2[CH:39]=[CH:40][C:31]([NH:30][C:6]3[N:15]=[CH:14][C:13]4[C:8](=[CH:9][C:10]([O:16][CH:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]5)=[CH:11][CH:12]=4)[N:7]=3)=[CH:32][C:33]=2[NH:37]1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: CCS(=O)(=O)c1ncc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2n1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Nc4ccc5[nH]c(=O)[nH]c5c4)nc3c2)CC1
Yield: 50 %

Procedure:
A solution of tert-butyl 4-(2-(ethylsulfonyl) quinazolin-7-yloxy)piperidine-1-carboxylate (1 eq) and 5-amino-1,3-dihydro-benzimidazole-2-one (5 eq) in acetonitrile was heated in sealed tube at 110° C. for 48 h. The product was filtered, washed and dried. A brown solid, yield 50%. ES/MS m/z 477.5 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:13][CH2:14][C:15]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCCl
Reactant: NCCc1ccc(Br)cc1
Product: O=C1CCCN1CCc1ccc(Br)cc1

Procedure:
The title compound was prepared from 4-bromophenethylamine and 4-chlorobutyryl chloride using a similar procedure to that described for Description 28.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1ccc(F)cc1
Product: Nc1nnc(-c2ccc(F)cc2)c(-c2ccccc2)n1
Yield: 46.5 %

Procedure:
6-(4-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (99 mg, 46%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 4-fluorophenylboronic acid (0.112 g, 0.80 mmol) according to the general procedure of Example 1.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1F>CN(C=O)C>[C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:30]2[CH:29]=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][C:25]=2[F:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1cc(C)c(C(=O)c2ccccc2)n1C
Temperature: 0 °C
Yield: 83.7 %

Procedure:
Ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate (5.0 g, 17.5 mmol) [prepared as in Example 1, Step (a)], was dissolved in DMF (50 ml) and the solution was cooled in an ice bath to 0° C. under an argon atmosphere. Sodium hydride, 50% /mineral oil, (1.3 g, 27.1 mmol) was added, and after 5 min 3,4-difluoronitrobenzene (3.36 g, 21.1 mmol) was added to the reaction mixture. After 1 h the reaction mixture was poured into 10% HCl/ice and the product was extracted into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and evaporated to dryness. Purification on a Florisil® column (hexane-ethyl acetate, 9:1) gave ethyl 2-(5-benzoyl-1,4-dimethylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)acetate (6.22 g, 84%) as a solid. ##STR20##
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[C:23]([CH3:29])[NH:24]2.C(N(C(C)C)C(C)C)C>C(O)CCC>[CH3:29][C:23]1[NH:24][C:25]2[C:21]([N:22]=1)=[C:20]([NH:18][C@H:16]([C:8]1[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=1)[CH3:17])[N:28]=[CH:27][N:26]=2
Reactant: Cc1nc2c(Cl)ncnc2[nH]1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc2c(N[C@@H](C)c3nc4ccccc4n3-c3ccccc3)ncnc2[nH]1
Yield: 32.7 %

Procedure:
A solution of (1S)-1-(1-phenyl-1H-1,3-benzodiazol-2-yl)ethan-1-amine from Example 4 (150 mg, 0.62 mmol, 1.00 equiv, 98%), 6-chloro-8-methyl-9H-purine (150 mg, 0.87 mmol, 1.41 equiv) and ethylbis(propan-2-yl)amine (0.3 mL, 98%) in butan-1-ol (6 mL) was stirred overnight at 130° C. The resulting mixture was concentrated under vacuum. The residue was purified on a C18 column eluted with water/acetonitrile to give 75 mg (30%) of 158 as a white solid. LC-MS (ES, m/z) 370 [M+H]+. H-NMR (300 MHz CD3OD, ppm) δ 8.04 (s, 1H), 7.69 (d, 1H), 7.55 (m, 5H), 7.30 (m, 2H), 7.11 (d, 1H), 5.63 (s, 1H), 2.55 (s, 3H), 1.71 (d, 3H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[C:7](Br)=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>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.[Cu]I.O>[CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[C:7]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccnc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)Nc1cccnc1C#C[Si](C)(C)C
Temperature: 100 °C

Procedure:
A mixture of (2-bromo-pyridin-3-yl)carbamic acid ethyl ester described in Preparation Example S-2 (395 mg, 1.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.028 mmol), triethylamine (0.25 mL, 1.8 mmol), copper(I)iodide (10 mg, 0.05 mmol) and trimethylsilylacetylene (0.131 mL, 2.4 mmol) was placed in a sealed tube, and heated at 100° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into water, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then evaporated, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), and the title compound (0.42 g, 1.6 mmol, quantitatively) was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][CH:3]=1.CN(C)[CH:20]=[O:21].O.P(Cl)(Cl)[Cl:25]>>[Cl:25][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH:20]=[O:21]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)csc21
Reactant: CN(C)C=O
Reactant: ClP(Cl)Cl
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)c(C=O)sc21
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (4.00 g) in phosphorus trichloride (80 ml) was added dimethylformamide (1.5 ml) dropwise with stirring. The solution was heated for 18 hours at 100° C. under nitrogen. Once the solution had cooled to room temperature it was added dropwise to acidified warm water (1 ml of 2M hydrochloric acid in 500 ml of water at 50° C.) and then allowed to cool. The solution was extracted with ethyl acetate (3×200 ml). The organic phase was washed with brine and then dried over magnesium sulfate, filtered and evaporated to leave a dark brown oil. Chromatography, eluting with dichloromethane, gave a solid which was triturated with diethyl ether to give the subtitle compound as a pale yellow solid (1.76 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCOCCN)CCCC3
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCNC(=O)Nc1ccccc1)CCCC3
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (919 mg, 2.76 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. The reaction mixture was then treated with phenyl isocyanate (300 μL, 2.76 mmol) and Et3N (0.77 mL, 5.51 mmol) and allowed to warm slowly to room temperature. After stirring overnight, the reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The solid was triturated with Et2O (30 mL) and a few drops of MeOH. The solid was isolated by filtration and dried under vacuum to give 460 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea as a white powder. m.p. 180-182° C.;
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([C:21]#[C:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(C#CCOC2CCCCO2)cc1F
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F

Procedure:
2,3,4-Trifluorobenzoic acid and 2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]aniline were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, followed by purification by chromatography on silica gel (50% EtOAc/PE as eluant), 3,4-difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}benzoic acid was isolated as a cream-yellow solid (68%); m.p. (Et2O/hexane) 164–166° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.60 (v br s, 1 H), 9.27 (br s, 1 H), 7.83 (ddd, J=8.2, 6.1, 1.9 Hz, 1 H), 7.36 (dd, J=12.0, 1.7 Hz, 1 H), 7.21–7.11 (m, 2 H), 6.96 (td, J=8.8, 5.5 Hz, 1 H), 4.80 (br s, 1 H), 4.47 (d, J=16.0 Hz, 1 H), 4.38 (d, J=16.0 Hz, 1 H), 3.79–3.71 (m, 2H), 3.51–3.45 (m, 2 H), 1.77–1.61 (m, 2 H), 1.56–1.44 (m, 4 H). Anal. calcd. for C21H18F3NO4: C, 62.2; H, 4.5; N, 3.5. Found C, 62.5; H, 4.4; N, 3.6.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=[O:7])([O-])=O>CCOC(C)=O.CCO.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:13][CH:14]=1)=[O:7]
Reactant: O=C(Nc1cnc(-c2ccccc2)nc1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 2-nitro-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (100 mg, 0.25 mmol, 1.00 equiv) in EtOAc/EtOH (5/5 mL). The mixture was treated with Pd/C (10 mg) and stirred under a hydrogen atmosphere for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 90 mg (97%) of product as a yellow solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:47])[CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:47])[CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cccc(C(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3-isopropylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.04 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.41 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.66 g, 57%).
Reaction SMILES: CN(C=O)C.[CH2:6]([C:10]1[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:35][CH:34]=2)[C:13]2[C:14](=[O:30])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH2:7][CH2:8][CH3:9].[Cl-].C([NH+](CC)CC)C.[N-:55]=[N+:56]=[N-:57].[Na+]>O.C(OCC)(=O)C>[CH2:6]([C:10]1[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[NH:57][N:56]=[N:55][N:46]=3)=[CH:35][CH:34]=2)[C:13]2[C:14](=[O:30])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH2:7][CH2:8][CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2ccn(Cc3ccccc3C(=O)OCC)c(=O)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc2ccn(Cc3ccccc3C(=O)OCC)c(=O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 1450 ml of DMF, 219.7 g of 2-butyl-3-(2'-cyano-biphenyl-4-ylmethyl)-4,5-dihydro-4-oxo-5-(o-ethoxycarbonyl-benzyl)-3H-imidazo[4,5-c]pyridine, 166.5 g of triethylammonium chloride and 78.6 g of sodium azide is heated to 120° for 22 hours. After cooling, the mixture is worked up conventionally with ethyl acetate and water, the crude product is purified several times by suspending it in ethanol and filtering, and 2-butyl-4,5-dihydro-4-oxo-3-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-5-(o-ethoxycarbonyl-benzyl)-3H-imidazo[4,5-c]-pyridine is obtained; m.p. 203-20°.