Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[F:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1ccccc1F
Temperature: 50 °C
Yield: 38.2 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 444 mg, 2 mmol), 2-fluorophenylboronic acid (Matrix; 274 mg, 2.01 mmol), copper(II) acetate (363 mg, 2.0 mmol) and triethylamine (280 μL, 2.0 mmol) in 1,2-dichloroethane (3 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-benzyl-N′-(2-fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (242 mg, 38%) as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(Cc1ccccc1)Nc1ccc2ccc(Cl)nc2n1
Temperature: 4 °C
Yield: 63.1 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with phenylacetic acid (10.9 g), N,N'-carbonyldiimidazole (13 g) and 2-amino-7-chloro-1,8-naphthyridine (10.8 g). The product obtained by precipitation in water (13.5 g; m.p. 184° C.) is dissolved in boiling acetonitrile (210 cc). After cooling for 1 hour at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (10 cc) and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)phenylacetamide (11.3 g), m.p. 187° C., is obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35](CO)[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.O>[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35]([CH2:20][Cl:24])[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2cc(CCl)cc(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
To a solution of triphenylphosphine (2.8 g, 10.6 mmol) in anhydrous tetrahydrofuran (16 mL) was added carbon tetrachloride (5 mL). After the mixture was stirred at room temperature for 10 minutes, (4-benzyloxy-6-fluoro-naphthalen-2-yl)-methanol (1.5 g, 5.3 mmol) was added as a solid under a nitrogen atmosphere. After being stirred at reflux for 2 hours, the resulting mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL×2). The combined aqueous layers were extracted with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (elution with 5% ethyl acetate in petroleum ether) to afford 1-benzyloxy-3-chloromethyl-7-fluoro-naphthalene (1.4 g, 87.5%) as a white solid.
Reaction SMILES: [Cl-].[NH4+].[B-](F)(F)(F)F.CCOC(C(C#N)=[N:14]OC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[CH3:34][C:35]1[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:49]([C:51]3[N:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]4=[C:53]([C:60]4[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=4)[C:63]([OH:65])=O)[N:52]=3)=[O:50])[CH:41]=2)[N:36]=1>CN(C=O)C>[CH3:34][C:35]1[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:49]([C:51]3[N:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]4=[C:53]([C:60]4[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=4)[C:63]([NH2:14])=[O:65])[N:52]=3)=[O:50])[CH:41]=2)[N:36]=1
Reactant: CCCn1c(C)nc2ccc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)cc2c1=O
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCn1c(C)nc2ccc(C(=O)c3nc(-c4cccc(C(N)=O)c4)c4ccccn34)cc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.4 %

Procedure:
0.107 g (2 mmol) of ammonium chloride, 0.328 g (1 mmol) of TOTU and 0.517 g (4 mmol) of N,N-diisopropylethylamine are added, at ambient temperature under an inert atmosphere, to 0.233 g (0.5 mol) of 3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid in 30 ml of DMF. The reaction medium is stirred for 5 hours at ambient temperature and then concentrated under reduced pressure. 50 ml of a saturated solution of sodium hydrogen carbonate are added to the residue. The precipitate obtained is filtered off, and then dried under reduced pressure at 50° C. overnight. 0.230 g of a yellow solid is obtained.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.Cl[C:14]1[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=1.C(N(C(C)C)C(C)C)C.[Na+].[I-]>CC(N(C)C)=O>[CH2:20]([C:17]1[CH:16]=[N:15][C:14]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[N:19][CH:18]=1)[CH3:21]
Reactant: CCc1cnc(Cl)nc1
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCc1cnc(N(C)[C@H]2CC[C@H](C#CCO)CC2)nc1

Procedure:
A solution of 0.24 g (1.44 mmol) of trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, 0.7 ml (5.74 mmol) of 2-chloro-5-ethylpyrimidine, 0.83 ml (4.88 mmol) N-ethyldiisopropylamine and a catalytic amount of NaI in 1.5 ml DMA was heated in the microwave oven for 3.75 h at 120° C. The reaction was cooled and partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (hexane/EtOAc 9:1 to 1:1) gave 0.24 g (61%) of trans-3-{4-[(5-Ethyl-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, MS: 274 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[CH2:11]([C:13]1[C:18]([CH2:19][NH2:20])=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:12].CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:20][CH2:19][C:18]2[C:13]([CH2:11][CH3:12])=[N:14][CH:15]=[N:16][CH:17]=2)[N:7]=1
Reactant: CCc1ncncc1CN
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1ncncc1CNc1ncc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
To a mixture of 2,4-dichloropyrimidine-5-carbonitrile (1.0 equiv. 61.4) and (4-ethylpyrimidin-5-yl)methanamine (1.0 equiv.) in isopropanol (0.2 M) was added DIEA (2.0 equiv.). The mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with a solution of ammonium chloride and concentrated under vacuum to give crude product, which was purified by silica gel chromatography (30% ethyl acetate in petroleum ether) to afford the title compound (11.4% yield) as brown solid. 1H-NMR (400 MHz, CD3OD) δ (ppm) 9.95 (d, J=3.2 Hz, 1H), 8.64 (d, J=12.0 Hz, 1H), 8.58 (d, J=19.6 Hz, 1H), 4.70 (d, J=20.4 Hz, 2H), 2.97-2.87 (m, 2H), 1.33-1.27 (m, 3H); MS (ESI) m/z 275.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[C:11]([C:16]([OH:18])=O)=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22]>ClCCCl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:23][CH2:20][CH2:21][N:22]2[C:16](=[O:18])[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9]3)=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: O=C(Cc1cccnc1C(=O)O)c1ccc(F)cc1
Solvent: ClCCCl
Solvent: CO
Product: O=C1c2ncccc2CC2(c3ccc(F)cc3)NCCN12
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a suspension of 3-[2-(4-fluorophenyl)-2-oxoethyl]pyridine-2-carboxylic acid (1.5 g, 5.8 mmol) in 1,2-dichloroethane (100 mL) was added ethylenediamine (8 mL, 120 mmol) and the resulting solution heated at reflux for 1 hour. The resulting suspension was then allowed to cool to room temperature before being concentrated in vacuo to yield a thick, orange gum. The gum was suspended in methanol with the aid of sonication and filtered. The filtrate was adsorbed onto silica and purified by flash chromatography (5 to 7.5% methanol-dichloromethane) to yield 10a-(4-fluorophenyl)-2,3,10,10a-tetrahydroimidazo[2,1-g][1,7]naphthyridin-5(1H)-one as a pale yellow solid (1.1 g, 67% yield). ESI-MI m/z [M+H]+ 284.04. 1H NMR (400 MHz, CDCl3) δ 8.66 (brd, J=4.7 Hz, 1H), 7.36 (brd, J=7.7 Hz, 1H), 7.30 (dd, J=8.9, 5.2 Hz, 2H), 7.23 (dd, J=7.7, 4.7 Hz, 1H), 6.89 (t, J=8.7 Hz, 2H), 4.02-3.89 (m, 1H), 3.70-3.60 (m, 1H), 3.47 (d, J=15.2 Hz, 1H), 3.42 (d, J=15.2 Hz, 1H), 3.35 (ddd, J=12.4, 7.9, 2.8 Hz, 1H), 2.86-2.74 (m, 1H), 2.49 (brs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH2:19])[CH:13]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Nc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cccc(Nc2ccc(Br)cc2[N+](=O)[O-])c1
Temperature: 120 °C
Yield: 63.2 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitro-benzene (1.14 ml, 9.25 mmol), benzene-1,3-diamine (1.96 g, 18.1 mmol) and DIPEA (1.93 ml, 11.1 mmol) in dry NMP (5 ml) was deoxygenated by evacuate/fill N2 (×3), then stirred and heated at 120° C. under N2 for 18 hours. After cooling to RT the mixture was partitioned between EtOAc and 0.5N HCl. The organic layer was washed with H2O (×1), brine (×1) then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (10→40% EtOAc/petrol) to give the title compound (1.8 g) as a red solid. 1H NMR (400 MHz, DMSO-d6): 9.28 (1H, s), 8.20 (1H, d), 7.63 (1H, dd), 7.14 (1H, d), 7.07 (1H, t), 6.49 (1H, s), 6.48-6.39 (2H, m), 5.24 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])=[O:10].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Br)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.2 %

Procedure:
To a stirred solution of methyl 3-bromo-4-[N′-(2-bromophenyl)ureido]phenylacetate (770 mg, 1.74 mmol) in THF (10 ml) was added 0.25 N NaOH (10 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 3-bromo-4-[N′-(2-bromophenyl) ureido]phenylacetic acid (702 mg, 94%) as colorless powder. 1H-NMR (DMSO-d6) δ 3.56 (s, 2H), 6.99 (dt, J=7.8, 1.5 Hz, 1H), 7.21 (dd, J=8.3, 1.7 Hz, 1H), 7.33 (dt, J=7.1, 1.5 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.62 (dd, J=8.1, 1.5 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.93 (dd, J=8.1, 1.5 Hz, 1H), 8.82 (s, 1H), 8.86 (s, 1H), 12.39 (s, 1H); MS (ESI) m/z 428 (M++1), 430(M++3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:28]([N:11]([CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:9])=[O:10])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3cccc(Cl)c3)s2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(C(=O)c3ccccc3)S(=O)(=O)c3cccc(Cl)c3)s2)c1

Procedure:
In analogy to example 6, 3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide (example 7, step 2) was reacted with benzoyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give N-benzoyl-3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 563.2 ([M+NH4]+)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Se](=O)=[O:13]>>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[CH:11][C:2]=1[CH:1]=[O:13]
Reactant: O=[Se]=O
Reactant: Cc1cnc2ccccc2n1
Product: O=Cc1cnc2ccccc2n1

Procedure:
This compound can also be prepared by oxidation of 2-methylquinoxaline with selenium dioxide, as described by Landquist et. al J. Chem. Soc. 2052 (1956).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)[CH2:20][C@@:19]2([CH3:30])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:31])[CH2:16][C@@:15]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=O)[CH3:13])[CH2:3]1.[NH2:33][CH2:34][CH2:35][OH:36].C1(C)C=CC=CC=1>O>[OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)[CH2:20][C@@:19]2([CH3:30])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:31])[CH2:16][C@@:15]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[N:33][CH2:34][CH2:35][OH:36])[CH3:13])[CH2:3]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: NCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=NCCO)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
The (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (8.0 g), 2-aminoethanol (40 ml), toluene (200 ml) and Dowex 50-W resin (0.8 g) were added to a flask fitted with a water separator. The mixture was heated under reflux for 10 h, by which time approximately 15 ml of a distillate had collected in the water separator. The contents of the flask were filtered while still hot and the residue was rinsed with hot toluene. The filtrate was washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure to give (2β,3α,5α)-3-hydroxy-20-[(2-hydroxyethyl)imino]-2-(2,2-dimethyl-4-morpholinyl)pregnan-11-one. δ (CDCl3) 0.50 (s,3H), 1.05 (s,3H), 1.21 (s,3H), 1.23 (s,3H) and 2.36 (s,2H).
Reaction SMILES: [IH:1].CS[C:4](=[NH:8])[NH:5][CH2:6][CH3:7].[OH:9][C:10]1([CH2:21][NH2:22])[CH2:16][O:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[O:12][CH2:11]1>C(O)C>[IH:1].[OH:9][C:10]1([CH2:21][NH:22][C:4]([NH:5][CH2:6][CH3:7])=[NH:8])[CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[O:15][CH2:16]1
Reactant: NCC1(O)COc2ccccc2OC1
Reactant: CCNC(=N)SC
Agent: I
Solvent: CCO
Product: CCNC(=N)NCC1(O)COc2ccccc2OC1

Procedure:
A mixture of S-methyl-N-ethylisothiourea hydriodide (2.46 g., 10 millimoles), 3-hydroxy-3-aminomethyl-3,4-dihydro-2H-1,5-benzodioxepin 1.95 g. (10 millimoles) from Example 1, Step E, and 20 ml. of ethanol is refluxed for four hours. The solution then is evaporated to a small volume and diluted with ether to afford 3-hydroxy-3-(3-ethylguanidinyl)methyl-3,4-dihydro-2H-1,5-benzodioxepin hydriodide.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:21]4[CH:20]=[CH:19][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5ccccc5c4)cc3CC[C@@H]12
Yield: 54.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2-naphthylboronic acid (168 mg, 0.98 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80° for 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatagraphy (ethyl acetate eluent) to give 126 mg (55%) of the title compound as a white solid. mp 221°-223°. FDMS: m/e=355. α[D]589 =+73.58 (C=1.06, chloroform).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.C(O)(C)C.[OH-].[Na+]>O>[C:26]1([C:24]2[N:23]=[C:22]([NH2:32])[N:21]=[C:20]([NH:14][C:13]3[CH:15]=[CH:16][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[N:8]=4)=[CH:11][CH:12]=3)[CH:25]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc(Oc2ccnc(C(F)(F)F)n2)cc1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(Oc3ccnc(C(F)(F)F)n3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.5 %

Procedure:
4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}aniline (1.0 g, 3.9 mmol) and 4-chloro-6-phenylpyrimidin-2-amine (806 mg, 3.9 mmol) were suspended in water (39 mL) and isopropanol (13 mL) and the mixture was heated at 95° C. for 17 h. After cooling to rt, the mixture was neutralized with 1 N aqueous sodium hydroxide and stirred for 20 min. The precipitate were collected by filtration to afford 6-phenyl-N4-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine (1.2 g, 72%) as a yellow solid. 1H NMR (DMSO-d6) δ 9.35 (s, 1H), 8.85 (d, 1H), 7.85-7.91 (m, 4H), 7.42-7.47 (m, 3H), 7.30 (d, 1H), 7.18 (d, 2H), 6.48 (s, 1H), 6.38 (brs, 2H); MS ES 425 (M+H)+, calcd 425, RT=2.53 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[C:17]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36]Cl)[N:35]=2)=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)=[CH:4][CH:3]=3)[N:35]=2)=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccccc1)c1ccc(-c2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Product: O=C(c1ccccc1)c1ccc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)cc1
Yield: 64 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 2-(4-benzoylphenyl)-4-chloromethyloxazole to give 2-(4-benzoylphenyl)-4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole. The yield was 64%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 91-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2)[C:10]([F:13])([F:12])[F:11].[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1>>[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][O:26][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:15]=3[CH:16]=[CH:17][N:18]=[CH:19]4)[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:35][CH:36]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cccc2cnccc12)C(F)(F)F
Product: COC(=O)Cc1ccc(COc2ccc(C(C)C(O)(c3cccc4cnccc34)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 140, step 6, 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl-propyl)-phenol (Example 147, step 5) was reacted with (4-bromomethyl-phenyl)-acetic acid methyl ester to give {4-[3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl-propyl)-phenoxymethyl]-phenyl}-acetic acid methyl ester. This compound was hydrolyzed in analogy to Example 141 to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=528.0 [M-−H+].
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][C:12]([NH2:14])=[O:13])[N:6]=1.[N:17]([C:20]1[CH:33]=[CH:32][C:23]([O:24][CH2:25][CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[CH:22][CH:21]=1)=[C:18]=[S:19].O>C1COCC1>[N:27]1([CH2:26][CH2:25][O:24][C:23]2[CH:32]=[CH:33][C:20]([NH:17][C:18](=[S:19])[CH:11]([C:7]3[N:6]=[C:5]([C:4]([F:3])([F:15])[F:16])[CH:10]=[CH:9][N:8]=3)[C:12]([NH2:14])=[O:13])=[CH:21][CH:22]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: NC(=O)Cc1nccc(C(F)(F)F)n1
Reactant: S=C=Nc1ccc(OCCn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C(C(=S)Nc1ccc(OCCn2ccnc2)cc1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Sodium hydride (0.531 g of a 60 wt % dispersion in oil, 13.3 mmol) was added in portions to a stirred solution of 2-(4-trifluoromethylpyrimidin-2-yl)acetamide (0.911 g; 4.43 mmol) in THF (20 mL) over 10 min. A solution of 1-[2-(4-isothiocyanatophenoxy)ethyl]-1H-imidazole (1.21 g; 4.92 mmol) in THF (10 mL) was then added over 15 min. The mixture was stirred at room temperature for a further 1 hr, and then water (1 mL) was added and the mixture was concentrated under reduced pressure. Water (75 mL) was added to the residue, the pH adjusted to 7 with 2N hydrochloric acid, and the mixture was extracted three times with EA. The combined EA extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 3-{-4-[2-(1H-imidazol-1-yl)ethoxy]phenylamino}-3-thioxo-2-(4-trifluoromethylpyrimidin-2-yl)propanamide (1.47 g) as an orange semi-solid.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:18](=[O:20])[CH3:19]>C(Cl)Cl>[F:10][C:11]1[C:16]([N+:6]([O-:9])=[O:7])=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)c1c(F)cccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a −40° C. mixture of concentrated H2SO4 (100 mL) and fuming HNO3 (100 mL) was added 1-(2,6-difluorophenyl)ethanone (20 g, 128 mmol) dropwise. The resulting mixture was stirred at −40° C. for 2 h then poured slowly onto ice. That mixture was diluted with DCM and the phases were separated. The aqueous layer was neutralized with sat. aq. NaHCO3 and then extracted with DCM. All organic portions were combined, dried over MgSO4, filtered, and concentrated to give 1-(2,6-difluoro-3-nitrophenyl)ethanone (26.3 g, 131 mmol, >theoretical) that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[NH2:16][C:17]([NH2:19])=[S:18]>>[CH3:1][O:2][C:3]([C:4]1[N:16]=[C:17]([NH2:19])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:15]
Reactant: NC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1F
Product: COC(=O)c1nc(N)sc1-c1ccccc1F

Procedure:
prepared by reaction of 3-chloro-3-(2-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.76 min; [M+H]+=253.2.