Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O.O1CCOCC1>[ClH:30].[NH2:8][C@@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[CH:20][CH:21]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 194 %

Procedure:
A solution of the compound of Intermediate 2 (70 g, 0.146 mol) in EtOAc (500 ml) and 1,4-dioxan (50 ml) was treated with a solution of HCl in EtOAc (500 ml, 3M), and stirred at room temperature for 4 h. The reaction was concentrated in vacuo to give a yellow solid which was triturated with Et2O then recrystallised (EtOAc/hexane) to give the title compound (59.3 g, 92%). δH (DMSO d6), 11.10 (1H, s), 8.70 (2H, s), 7.55 (2H, d, J 8.4 Hz), 7.25 (2H, d, J 8.4 Hz), 4.10 (3H, m), 3.10 (2H, m), 1.10 (3H, m); m/z (ES+, 70V) 382 (MH+).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]1(=O)[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH:1]([NH:4][C:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C1CCCC(=O)C1
Reactant: CC(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)NC1=CC(=O)CCC1

Procedure:
Equimolar amounts of isopropylamine and cyclohexane-1,3-dione were dissolved in benzene and heated with addition of p-toluenesulfonic acid to boiling with a water trap. After the trapping of water was complete, the mixture was thoroughly washed with water, the solvent was stripped off, and the residue was recrystallized.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[N:4]([C:9](Cl)=[O:10])[O:5][C:6]=1[CH2:7][Cl:8].[CH3:13][NH:14][CH3:15].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:12])[N:4]([C:9](=[O:10])[N:14]([CH3:15])[CH3:13])[O:5][C:6]=1[CH2:7][Cl:8]
Reactant: CNC
Reactant: O=C(Cl)n1oc(CCl)c(Cl)c1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)C(=O)n1oc(CCl)c(Cl)c1=O
Temperature: 25 °C
Yield: 62.5 %

Procedure:
254 mg of 4-chloro-2-chlorocarbonyl-5-chloromethyl-4-isoxazolin-3-one were dissolved in 5 ml of benzene, and then a solution of 48 mg of dimethylamine and 107 mg of triethylamine in 2 ml of benzene were added, with stirring, at room temperature. The mixture was stirred for a further 10 minutes, after which it was washed, in turn, with 2 ml of 0.1N sulphuric acid and water (twice, 5 ml each time). The organic phase was dried over anhydrous sodium sulphate and the solvent was distilled off. The residue was purified by column chromatography through silica gel eluted with a 20:1 by volume mixture of benzene and acetone. The solvent was distilled from the eluate and the residue was recrystallized from diisopropyl ether, to give 159 mg (yield 62.8%) of the title compound in the form of crystals, melting at 107°-108° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21](OC=C(C#N)C#N)C>C(O)(C)C>[C:1]1([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[C:13]3[N:14]=[CH:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC=C(C#N)C#N
Reactant: Nc1c(-c2ccccc2)ccnc1Nc1ccccc1
Solvent: CC(C)O
Product: c1ccc(-c2ccnc3c2ncn3-c2ccccc2)cc1
Yield: 75 %

Procedure:
0.70 mol of N2,4-diphenylpyridine-2,3-diamine and 2.56 mol of ethoxymethylene malononitrile were added in 10 ml of isopropanol, and refluxed for 6 hours. The solution was removed and was purified by using column chromatography to thereby produce a solid crystalline product at a yield of 75%.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].[C:33]1([CH2:39][CH2:40][CH2:41]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]([CH2:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]=[CH:9][NH:10][C:11]=3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(CNc2ccc3c(c2)ncn3C(=O)OC(C)(C)C)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(CCCc2ccccc2)c2ccc3nc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N1-Boc-N-(4-Methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K2CO3 (166 mg; 1.2 mmol; 1.2 eq.) and phenylpropylbromide (0.183 ml; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The remains were taken up with THF (5 ml), treated with 5 N NaOCH3 and stirred for 2 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.015 g (4.0%); MS m/z: 372.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.84-1.90 (m, 2H); 2.62 (t, 2H, 3J=7.6 Hz); 3.39 (t, 2H, 3J=7.6 Hz); 3.39 (s, 3H); 4.45 (s, 2H); 6.71 (br s, 1H); 6.73 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 6.83-6.85 (m, 2H); 7.12-7.14 (m, 2H); 7.16-7.19 (m, 3H); 7.24-7.27 (m, 2H); 7.36 (d, 1H, 3J=8.9 Hz); 8.08 (s, 1H); HPLC (METHOD [A]): rt 16.97 min (93.2%)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[Cl:24])[C:12]1=[O:25])[CH2:8]2.[OH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:30]4[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=4)=[CH:19][C:18]=3[Cl:24])[C:12]1=[O:25])[CH2:8]2
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1C2CC3CC(C2)CC1C3
Product: O=C1C(Cc2ccc(-c3ccc(O)cc3)cc2Cl)CCN1C1C2CC3CC(C2)CC1C3
Yield: 70.7 %

Procedure:
Using the procedure to synthesize Example 81 and using reagents 1-adamantan-2-yl-3-(4-bromo-2-chloro-benzyl)-pyrrolidin-2-one (Example 76) (1.0 g, 2.4 mmol) and 4-hydroxyphenylboronic acid (980 mg, 7.1 mmol) affords 740 mg (72%) of the title compound: Mass spectrum (apci) m/z=436.2 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[O-]S([O-])(=O)=O.[Mg+2].[C:12]1([CH3:18])[CH:17]=CC=C[CH:13]=1>>[CH:12]([CH:18]1[NH:1][CH2:2][CH2:3][CH2:4][O:5]1)([CH3:17])[CH3:13]
Reactant: Cc1ccccc1
Reactant: NCCCO
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(C)C1NCCCO1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 3-aminopropanol (91 g, 65.4 mmol) in toluene (100 mL) was added isobutraldehyde (9.0 mL, 99.1 mmol, 1.5 equiv.) and MgSO4 (7.5 g) to generate an exotherm. The slurry was stirred for 30 min. and an additional portion of MgSO4 was added (7.5 g), and the slurry was stirred overnight. The resulting mixture was filtered and concentrated under reduced pressure. The condensate was again concentrated under reduced pressure and the two residues were combined to afford 2isopropyltetrahydro-1,3-oxazine as a colorless oil (5.18 g, 61%) 1H NMR (CDCl3) δ0.84-0.88 (m, 6H), 1.24-1.29 (m, 1H), 1.51-1.66 (m, 3H), 2.77-2.87 (m, 1H), 3.07-3.13 (m, 1H), 3.60-3.76 (m, 2H), 4.00-4.05 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[O:13][CH:14]=[C:15]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]2)[N:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[O:13][CH:14]=[C:15]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]2)[N:16]=1
Reactant: CCOC(=O)c1cnn(Cc2coc(-c3cccc(C(F)(F)F)c3F)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnn(Cc2coc(-c3cccc(C(F)(F)F)c3F)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
A mixture of the compound (0.44 g) obtained in Example 105b, 4N sodium hydroxide (3 mL), ethanol (8 mL) and tetrahydrofuran (2 mL) was stirred at room temperature for 16 hr. The reaction mixture was adjusted to pH 5 with 1N hydrochloric acid, and the precipitate was collected by filtration, dried under reduced pressure and recrystallized from ethanol-hexane to give the title compound (0.32 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[Mg].C1O[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=O)[O:17]C1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:21]2[CH2:22][CH2:23][C:18](=[O:17])[CH2:19][CH2:20]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: O=C1CCCCC12OCCO2
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1CCC(c2ccc(OC(F)(F)F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To Grignard reagent prepared from 3-fluoro-4-trifluoromethoxy bromobenzene 70.0 g (270 mmol) and magnesium in dried THF 300 ml at room temperature, a THF (200 ml) solution of cyclohexanedione monoethyleneketal 42.1 g (270 mmol) was added dropwise at room temperature, and the mixture was stirred for 3 hours at room temperature. The reactant was added to one liter of 6N-hydrochloric acid, and the product was extracted with diethylether. The extract was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue, para-toluene sulfonic acid 5 g and toluene 500 ml were added. The mixture was refluxed with heating for 3 hours while removing water formed with Dien-Stark. The reactant was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=4/1). Such obtained purified material was hydrogenated in the presence of 5% palladium carbon 5 g as a catalyst in ethanol 300 ml. The catalyst was filtered off, the solvent was distilled off under reduced pressure, formic acid 20 g and toluene 200 ml were added to the residue, and the mixture was refluxed for 3 hours. After cooling, water 300 ml was added to the reactant, and the organic layer was fractionated, washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1) to obtain 4-(3-fluoro-4-trifluoromethoxyphenyl)cyclohexanone 22.0 g (84.5 mmol). The yield was 31.3% from 3-fluoro-4-trifluoromethoxybromobenzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:39][CH3:40])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][CH2:39][CH3:40])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCCc1ccccc1O/C(=C/C(=O)OCC)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)OC)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (623 mg, 0.003 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (1.98 g, 0.015 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2-propyl-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0440 mg, 34%) as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([C:15]1[C:16]([NH:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:17][C:18]([NH:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([CH2:39][OH:40])=[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])[N:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:23])=[N:19][CH:20]=1)#[N:14]>C1COCC1>[CH3:8][S:9]([O:40][CH2:39][C:30]1[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])=[N:32][C:33]2[N:24]([C:22](=[O:23])[NH:21][C:18]3[CH:17]=[C:16]([NH:41][CH2:42][CH2:43][O:44][CH3:45])[C:15]([C:13]#[N:14])=[CH:20][N:19]=3)[CH2:25][CH2:26][CH2:27][C:28]=2[CH:29]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CO)c(C(OC)OC)nc32)ncc1C#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCNc1cc(NC(=O)N2CCCc3cc(COS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (120 μL, 0.866 mmol) and methanesulfonyl chloride (57 μL, 0.731 mmol) were added to solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 171, 300 mg, 0.657 mmol) in THF (11 ml) at 0° C. The reaction mixture was stirred for approximately 2.5 h at 0° C. and filtered to remove solid impurities. The solid residue was washed with THF and the filtrate was concentrated to yield the title compound as beige solid which was used directly in the next step. (UPLC-MS) ESI-MS 535.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 13.67 (br s, 1H), 8.24 (s, 1H), 7.67 (s, 1H), 7.55 (s, 1H), 5.47 (s, 3H), 5.33 (br s, 1H), 4.08-4.00 (m, 2H), 3.63 (t, 2H), 3.53-3.45 (m, 8H), 3.41 (s, 3H), 3.07 (s, 3H), 2.88 (t, 2H), 2.09-1.94 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])=[O:23].[O-]CC.[Na+].[CH:29]([S:31]([CH2:34][CH3:35])(=O)=[O:32])=[CH2:30]>C(O)C>[CH2:29]([S:31]([CH2:34][CH2:35][O:21][N:20]=[CH:19][C:4]1[C:3]([S:22]([CH3:24])=[O:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=1)=[O:32])[CH3:30]
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: C=CS(=O)(=O)CC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCS(=O)CCON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O

Procedure:
In a manner similar to that employed in Example 12 an ethanol solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime was reacted with sodium ethoxide and ethyl vinyl sulfone to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-[2-(ethylsulfinyl)ethyl]oxime, m.p.144-148° C. Compound 27.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[CH3:13].[CH2:14]([O:16][C:17](=[O:22])[CH:18](Cl)[S:19][CH3:20])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:22])[CH:18]([O:12][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=1)[N:4]=[CH:3][C:2]([I:1])=[CH:11]2)[S:19][CH3:20])[CH3:15]
Reactant: Cc1cc(O)cc2cc(I)cnc12
Reactant: CCOC(=O)C(Cl)SC
Product: CCOC(=O)C(Oc1cc(C)c2ncc(I)cc2c1)SC

Procedure:
In a similar procedure to Stage 2, Step 1 of Example 5, 3-iodo-8-methyl-quinolin-6-ol, was reacted with chloro-methylsulfanyl-acetic acid ethyl ester to give (3-iodo-8-methyl quinolin-6-yloxy)-methylsulfanyl-acetic acid ethyl ester as a yellow coloured solid (MH+ 418).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]>CS(C)=O>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: COc1ccccc1OCCCCCCl
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1OCCCCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Cyanophenol (742 g, 6.23 mol) is dissolved in dimethyl sulfoxide (7.30 L) and to this solution is added powdered anhydrous potassium carbonate (883 g, 6.30 mol), potassium iodide (1.05 kg, 6.30 mol) and finally 1-(5-chloropentoxy)-2-methoxybenzene (1.44 kg, 6.29 mol). This suspension is heated at 80°-82° C. for 7 hours and the heating bath is then removed. After stirring overnight at room temperature, the mixture is poured onto cold water (29 L) and the product precipitates. This mixture is then extracted with ethyl acetate (3×20 L). The organic extracts are washed with potassium hydroxide solution (0.50N, 4×8 L), brine (2×10 L), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a yellow oil which crystallizes on standing. This is then dissolved in 2-propanol (5.6 L) with warming and the resulting solution is filtered gravimetrically, washing the funnel with 1.2 L of hot 2-propanol. The combined filtrate is cooled to 10° C. in an ice bath and the solid mass is broken up and filtered. The filter cake is washed with 2-propanol (2×800 mL), dried in vacuo to give 4-[5-(2-methoxyphenoxy)pentoxy]benzonitrile, m.p. 66°-68° C. which is >99.5% pure by glc analysis.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([B:21]([OH:26])[OH:22])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of 4-tert-butyldimethylsilyloxybromobenzene (11.49 g) in tetrahydrofuran (100 ml) was added a solution of n-butyllithium in n-hexane (1.59M, 32.7 ml) dropwise at −55° C. under a nitrogen atmosphere, and the mixture was stirred for 1 hour at −60° C. To the reaction mixture was added triisopropyl borate (12.84 ml), and the mixture was stirred at −60° C. for 1 hour. The reaction mixture was warmed to ambient temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The solid was triturated with n-hexane, filtered and washed with n-hexane to give 4-tert-butyldimethylsilyloxyphenylboronic acid (7.45 g).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:27])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[CH:12]=1.[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:3][O:4][C:5](=[O:27])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:36]([NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])[CH:12]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1
Reactant: O=C=NCc1ccccc1
Agent: Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)NCc1ccccc1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester, dihydrochloride and benzyl isocyanate were reacted as described in Example 2, Step 3, to provide {5-[2-(3-benzyl-1-ethyl-ureidomethyl)-4-trifluoromethyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester. The ester was hydrolyzed to the acid as described in Example 12, Step 4.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12]P(=O)(OC)OC)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[Li+].CC([N-]C(C)C)C.[C:33]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=[C:43]3[CH2:44][CH2:45][N:40]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:41][CH2:42]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: COP(=O)(Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(C=C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a cold (−78° C.) suspension of dimethyl (2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methylphosphonate (0.35 g, 0.93 mmol) in THF (8.0 mL) was added a 2.0M solution of LDA in THF (0.49 mL). The resulting solution was allowed to warm to room temperature before the addition of a solution of 1-Boc-4-piperidone (0.19 g, 0.95 mmol) in THF (3 mL). The reaction mixture was then stirred at room temperature for 2 hours, and partitioned between brine and DCM. The organic layer was isolated, washed with brine, dried over MgSO4 and concentrated. The crude residue was then purified by flash chromatrography (0-75% EtOAc in heptane) to give the title compound (0.38 g, 91%). LCMS m/z: 449.2 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:9]([NH:10][OH:11])=[CH:8][C:6](=[O:7])[N:5]([CH3:12])[C:3]1=[O:4].[C:13](OC(=O)C)(=O)[CH3:14]>>[CH3:13][C:14]1[O:11][N:10]=[C:9]2[C:8]=1[C:6](=[O:7])[N:5]([CH3:12])[C:3](=[O:4])[N:2]2[CH3:1]
Reactant: Cn1c(NO)cc(=O)n(C)c1=O
Reactant: CC(=O)OC(C)=O
Product: Cc1onc2c1c(=O)n(C)c(=O)n2C

Procedure:
One gram of 1,3-dimethyl-6-hydroxyaminouracil is boiled with 10 ml of acetic anhydride at 140° C. for 1 hour and, when hot, the insolubles are filtered off. The filtrate is concentrated to dryness to recover 0.7 g of the captioned compound as colorless needles. As recrystallized from ethanol, the compound melts at 200°-202° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.[C:41]1([NH2:48])[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH2:47]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[NH:48][C:8](=[O:10])[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:13]([OH:14])=[C:12]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:11]=1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: Nc1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)Nc2ccccc2N)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a solution of 3,5-di-t-butyl-4-hydroxybenzoic acid (5.0 g) in methylene chloride (20 ml) was added dicyclohexylcarbodiimide (2.17 g) and the mixture was stirred overnight at room temperature. Subsequently, triethylamine (2.1 ml), 4-dimethylaminopyridine (0.37 g) and o-phenylenediamine (1.08 g) were added and the mixture was stirred overnight at room temperature. The insolubles was filtered off and the filtrate was concentrated to dryness. The residue was purified by a silica gel column chromatography (chloroform:ethyl acetate=20:1) and crystallized from diisopropyl ether to give N-(2-aminophenyl)-3,5-di-t-butyl-4-hydroxybenzamide (1.10 g, 32%).