Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:4]=1[C:16]1[C:17]([CH3:25])=[C:18](C(O)=O)[O:19][C:20]=1[CH3:21])=[O:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>N1C2C(=CC=CC=2)C=CC=1.CN1C(=O)CCC1>[CH3:21][C:20]1[O:19][CH:18]=[C:17]([CH3:25])[C:16]=1[C:4]1[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][N:7]([CH3:8])[C:3]=1[CH:1]=[O:2]
Reactant: Cc1oc(C(=O)O)c(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C=O
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CN1CCCC1=O
Solvent: c1ccc2ncccc2c1
Product: Cc1coc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C=O
Yield: 51.9 %

Procedure:
A mixture of 4-(5-formyl-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)-3,5-dimethylfuran-2-carboxylic acid (45 mg, 0.13 mmol), phenantroline (9.53 mg, 0.05 mmol) and Cu2O (3.78 mg, 0.026 mmol) in quinoline (0.73 ml) and NMP (2.19 mL) was flushed with N2 and irradiated in the microwave at 190° C. for 15 min. HCl (1M) and CH2Cl2 were added and the phases were separated. The crude product was purified on preparative HPLC to give 4-(2,4-dimethylfuran-3-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (20.0 mg, 51%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]([O:25]C)=[O:24])[C:12]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:22][C:23]([OH:25])=[O:24])[C:12]2=[O:27])[CH2:28][CH2:29]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(CC(=O)O)CN2c1ccccc1
Yield: 81.3 %

Procedure:
A stirred mixture of 2.96 g (7.8 mmol) of methyl 8-(t-butoxycarbonyl)-4-keto-1-phenyl-1.3.8-triazaspiro[4.5]decan-3-acetate, 2.03 g (14.7 mmol) of potassium carbonate, 30 ml of methanol and 10 ml of water was heated under reflux for 2 hours. The mixture was concentrated to about one-third of its original volume, diluted with 20 ml of water and acidified with 2N HCl at 0° C. The mixture was extracted with ethyl acetate and the extracts were washed with water and brine, dried, and concentrated in vacuo. Recrystallization of the residual solid from ethanol afforded 2.47 g (86%) of colorless crystals, mp 200°-201° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:10]([OH:12])[OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[NH:13]([CH2:17][CH2:18]O)[CH2:14][CH2:15]O>>[F:1][C:2]1[CH:3]=[C:4]([B:10]2[O:11][CH2:18][CH2:17][NH:13][CH2:14][CH2:15][O:12]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: OCCNCCO
Product: Fc1cc(B2OCCNCCO2)cc(F)c1F
Yield: 70 %

Procedure:
The title compound (70%, crystals) was prepared from 3,4,5-trifluorophenylboronic acid and diethanolamin.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([C:44](Cl)=[O:45])=[CH:40][CH:39]=1>C1COCC1>[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([C:44]([N:8]2[C:9]3[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:45])=[CH:40][CH:39]=1
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 240 mg, 1.09 mmol) in THF (10 mL) at room temperature is added 0.5 M KHMDS in toluene (4.0 mL, 2.0 mmol). After 30 min, 4-chlorocarbonyl-benzoic acid methyl ester (400 mg, 2.0 mmol) is added. The mixture is stirred under N2 for 1 h. The reaction is quenched with aqueous sodium bicarbonate and the volatiles are removed in vacuo. Purification by silica gel flash chromatography using a heptane-ethyl acetate gradient affords 4-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid methyl ester. 1H NMR (400 MHz, MeOD) δ ppm 3.90 (s, 3H), 7.12 (s, 1H), 7.26 (dd, J=8.0, 4.9 Hz, 1H), 7.63-7.72 (m, 3H), 7.77-7.81 (m, 1H), 7.91-7.96 (m, 3H), 8.17 (d, J=1.5 Hz, 1H), 8.32 (dd, J=4.8, 1.5 Hz, 1H), 8.56 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 382.1186 [(M+H)+ Calcd for C23H16N3O3: 382.1192].
Reaction SMILES: [OH-].[K+].[C:3]([NH:7][C:8]([C:10]1[S:14][C:13]([S:15][CH3:16])=[N:12][C:11]=1[C:17]([O:19]CC)=[O:18])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.O.C(O)C>[C:3]([NH:7][C:8]([C:10]1[S:14][C:13]([S:15][CH3:16])=[N:12][C:11]=1[C:17]([OH:19])=[O:18])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1nc(SC)sc1C(=O)NC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc(C(=O)O)c(C(=O)NC(C)(C)C)s1

Procedure:
0.82 g (14.6 mmol) of potassium hydroxide in 10 ml of water was added to a solution of 4.00 g (13.2 mmol) of 4-ethoxycarbonyl-2-methylthiothiazole-5-carboxylic acid-tert-butylamide in 50 ml of water/ethanol (2:1), and the mixture was refluxed for 2 hours. The solvent mixture was then removed under reduced pressure and the residue was taken up in 50 ml of water and acidified with concentrated hydrochloric acid. The precipitated product was filtered off and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.CN([CH:25]=[O:26])C.O=P(Cl)(Cl)Cl>>[CH3:1][C:2]1[CH:7]=[C:6]([CH:25]=[O:26])[C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C)c(N2CCN(Cc3ccccc3)CC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(N2CCN(Cc3ccccc3)CC2)c(C)cc1C=O
Temperature: 0 °C
Yield: 81.1 %

Procedure:
The 4-(2,5-dimethylphenyl)-1-benzylpiperazine (10 g, 36 mmol) was dissolved in anhydrous DMF (30 mL, 390 mmol) and cooled to 0° C. Fresh POCl3 (70 mL, 750 mmol) was added drop wise with stirring. Once the addition was completed the dark mixture was warmed to 75° C. for five hours or until TLC analysis indicated the disappearance of the starting material. The excess phosphorous oxychloride was distilled off and the entire mixture was diluted with ethyl acetate and added slowly to 500 mL of ice-chips. The solution was neutralized and made basic with concentrated NaOH. The neutralization and basification must be done at low temperatures to avoid creating by-products. The formylated product was extracted with ethyl acetate (5×). The organic layer was washed with water (2×), brine, dried over magnesium sulfate and purified by silica gel column chromatography using gradient hexane/ethyl acetate (10/0 to 8/2). The product (9 g, 81%) was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:14]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1
Reactant: OB(O)c1ccncc1
Reactant: NC(=O)c1cnc(Cl)cc1NCc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cnc(Cl)cc1NCc1cccc(-c2ccncc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a solution of 6-chloro-4-(3-iodobenzylamino)nicotinamide (200 mg, 0.50 mmol) in Dioxane (2 mL) was added pyridine-4-boronic acid (92 mg, 0.75 mmol) and Pd(PPh3)2Cl2 (56 mg, 0.08 mmol), followed by a solution of Na2CO3 (173 mg, 1.63 mmol) in H2O (1 mL). After stirring at 100° C. for 2 h, it was concentrated and purified by preparative HPLC to give 6-chloro-4-(3-(pyridine-4-yl)benzylamino)nicotinamide (56 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH3:11])=[CH:4][C:3]=1[OH:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH:59](O)[CH3:60]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH3:11])=[CH:4][C:3]=1[O:19][CH:59]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][N:53]=1)[CH3:60]
Reactant: CC(O)c1ccccn1
Reactant: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1cc(CN[C@H](C)c2cccc(Cl)c2)ccc1Cl)c1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a solution of (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 96 (130 mg, 439 μmol) in 5 mL of THF under N2 was added triphenylphosphine (127 mg, 483 μmol). The solution was chilled to 0° C. in an ice bath and then diisopropyl azodicarboxylate (94 μL, 483 μmol) was added dropwise to the reaction. After stirring for 15 min 0° C., a solution of 1-(pyridin-2-yl)ethanol (59 mg, 483 μmol) in THF was added to the reaction. The reaction was allowed to warm to room temperature and it was stirred for 10 h. The reaction was concentrated and diluted with EtOAc. The solution was extracted with saturated NaHCO3, water, and then brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 5% to 90% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give (1R)—N-(4-chloro-3-(1-(pyridin-2-yl)ethoxy)benzyl)-1-(3-chlorophenyl)ethanamine 98 (67 mg, 38% yield) as a colorless oil and as a mixture of diastereomers. 1H NMR (400 MHz, d4-methanol) δ ppm 1.60 (d, J=6.65 Hz, 2.1H) 1.73 (d, J=5.28 Hz, 3H) 1.83 (d, J=6.46 Hz, 3H) 3.90 (d, J=11.15 Hz, 1H) 4.16 (d, J=12.72 Hz, 1H) 4.45-4.54 (m, 1H) 5.18-5.28 (m, 0.7H) 5.99 (m, 1H) 7.05 (d, 1H) 7.48 (m, 5H) 7.63 (m, 1H) 7.99 (m, 1.7H) 8.08 (m, 0.7H) 8.20 (d, 1H) 8.59 (m, 1.7H) 8.73 (m, 0.7H) 8.83 (d, 1H). Mass spectrum: calculated for C22H22Cl2N2O 401.3. found 402.4 (M++1).
Reaction SMILES: [CH2:1]([C@@:5]1([C:34]([OH:36])=[O:35])[CH2:9][C@H:8]([CH2:10][O:11][CH2:12][CH:13]=[CH2:14])[C@H:7]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:6]1[C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[C:23]([O:31][CH3:32])[CH:22]=1)[CH:2]([CH3:4])[CH3:3].[H][H]>C(O)C.[Pd]>[CH2:1]([C@@:5]1([C:34]([OH:36])=[O:35])[CH2:9][C@H:8]([CH2:10][O:11][CH2:12][CH2:13][CH3:14])[C@H:7]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:6]1[C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:28])([CH3:30])[CH3:29])=[C:23]([O:31][CH3:32])[CH:22]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: C=CCOC[C@H]1C[C@@](CC(C)C)(C(=O)O)N(C(=O)c2ccc(C(C)(C)C)c(OC)c2)[C@H]1c1nccs1
Agent: [Pd]
Solvent: CCO
Product: CCCOC[C@H]1C[C@@](CC(C)C)(C(=O)O)N(C(=O)c2ccc(C(C)(C)C)c(OC)c2)[C@H]1c1nccs1

Procedure:
A solution of Example 40 (10 mg) in ethanol (4 mL) was added to 10% palladium on carbon (50 mg) and stirred under 1 atmosphere pressure of hydrogen at 20 degrees for 4 h. Catalyst was removed by filtration and washed with ethanol (10 mL). Filtrate and washings were combined and solvent was removed to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:41]1([S:47](Cl)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:41]1([S:47]([CH:2]([NH2:1])[C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]3[O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:5][CH:4]=2)(=[O:49])=[O:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CN)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(N)S(=O)(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A solution of 47 mg (0.105 mmol) of tert-butyl (3RS,4RS)-4-(4-aminomethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 2 ml of methylene chloride was treated with 18 μl (1 2.7 mg, 0.1 26 mmol, 1.2 eq.) of triethylamine and cooled to 0° C. 15 μl (20.4 mg, 0.116 mmol, 1.1 eq.) of benzenesulphonyl chloride were added dropwise, the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was partitioned between methylene chloride and 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. There were obtained 47 mg of crude tert-butyl (3RS,4RS)-4-[4-(phenylsulphonyl-amino-methyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, which was used in the following step without further purification and characterization.
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>>[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1
Reactant: Cc1ccccc1CBr
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Solvent: NCc1ccccc1
Product: Cc1ccccc1CN1CCC(COc2cccc3nc(N)nc(N)c23)CC1
Yield: 89 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (75 mg; 0.27 mmol) and 2-methylbenzyl bromide (65 mg; 0.35 mmol) via Method BB to yield 91 mg. (89% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.34 (t, J=8.0 Hz, 1H), 7.21 (m, 3H), 7.14 (m, 3H), 6.76 (d, J=8.0 Hz, 1H), 6.52 (d, J=8.4, 11H), 5.94 (br s, 2H), 3.98 (d, J=6.4 Hz, 2H), 3.41 (s, 3H), 2.83 (br, d, J=11.6 Hz, 2H), 2.32 (s, 3H), 2.00 (t, J=10.4 Hz, 2H), 1.9 (m, 1H), 1.73 (d, J=12.8 Hz, 2H), 1.31 (m, 2H). MS m/z (ESI) 378 (M+H)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[O:14]([CH2:21][C:22](O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:14]([CH2:21][C:22]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)COc1ccccc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: c1ccc(OCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
The compound was synthesized starting from Benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and Phenoxyacetic acid (153 mg; 1 mmol) as described in method 2 but purified by flash chromatography on silica using a CHCl3/MeOH gradient; yield: 0.049 g (16.8%); MS m/z: 293.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): □5.48 (s, 2H); 7.00-7.03 (m, 1H); 7.11-7.13 (m, 2H); 7.32-7.36 (m, 2H); 7.78 (d, 1H, 3J=8.3 Hz); 7.86 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 8.20 (br s, 1H); 8.40 (s, 1H); 12.82 (br s, 1H); HPLC (METHOD [A]): rt 11.29 min (100%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:13][C:7]=3[C:6]=2[CH:21]=1.[ClH:22].[C:23]([Cl:31])(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[ClH:31].[ClH:22].[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[CH:12]1[CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[CH:21][C:6]=3[C:7]=2[CH2:13]1)[CH2:16][CH3:17]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCCN(CCC)C1CCc2oc3ccc(N)cc3c2C1
Agent: Cl
Product: CCCN(CCC)C1CCc2oc3ccc(NC(=O)c4ccncc4)cc3c2C1
Yield: 80.7 %

Procedure:
Beginning with 0.072 gm (0.20 mMol) 8-amino-1,2,3,4-tetrahydro-2-dipropylaminodibenzofuran and 0.054 gm (0.30 mMol) isonicotinoyl chloride hydrochloride, 0.075 gm (81%) of the title compound were recovered as a yellow solid by the procedure described in Example 17.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([CH:16]2[CH2:18][CH2:17]2)[N:3]=1.[NH2:19][CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].C([O-])(O)=O.[Na+].O1CCOCC1>O>[CH:16]1([C:4]2[N:3]=[C:2]([NH:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[N:5]=2)[CH2:18][CH2:17]1
Reactant: NC[C@H](O)c1ccccc1
Reactant: Clc1cc(-c2ccc(Cl)c(Cl)c2)nc(C2CC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O[C@@H](CNc1cc(-c2ccc(Cl)c(Cl)c2)nc(C2CC2)n1)c1ccccc1
Yield: 81.9 %

Procedure:
A mixture of 4-chloro-2-cyclopropyl-6-(3,4-dichloro-phenyl)-pyrimidine (108 mg, 0.364 mmol), (R)-(−)-2-amino-1-phenylethanol (67.2 mg, 0.490 mmol), and NaHCO3 (190.1 mg, 2.26 mmol) and 1,4-dioxane was refluxed for 48 h. The mixture was poured into water and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound as a white solid (119.4 mg, 82%). MS (ESI): mass calcd. for C21H19Cl2N3O, 399.09; m/z found, 400.1 [M+H]+. 1H NMR (CD3OD): 8.13-8.05 (m, 1H), 7.85-7.79 (m, 1H), 7.64-7.58 (m, 1H), 7.45-7.31 (m, 4H), 7.30-7.23 (m, 1H), 6.68-6.59 (m, 1H), 4.93-4.85 (m, 1H), 3.81-3.65 (m, 1H), 3.56-3.48 (m, 1H), 2.16-2.01 (m, 1H), 1.16-1.09 (m, 2H), 1.02-0.94 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)=[O:8].Cl[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[OH-].[Na+].O>CS(C)=O>[F:1][C:2]([F:16])([F:17])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1)=[O:8]
Reactant: O=C(CCCCC(F)(F)F)c1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(CCCCC(F)(F)F)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of 3-(6,6,6-trifluorohexanoyl)phenol (6.8 g, 27 mmol) and 2-chloromethylquinoline (4.4 g, 25 mmol) in DMSO (75 ml) containing 2N NaOH solution (14 ml) was stirred at room temperature overnight (13 hrs.). The dark reaction mixture was poured into water (200 ml) and the aqueous solution was extracted with ethyl acetate (4×30 ml). The organic extract was washed with 1N NaOH solution, water and brine and then dried over MgSO4. After removal of all volatiles, a dark liquid was obtained which solidified on standing (7.2 g). This solid was chromatographed (3% ethanol in toluene on silica gel) to obtain a beige color solid (4.5 g; mp 83°-4° C.), which was chromatographed again (15% acetone in hexanes on silica gel) to get a white solid (3.1 g; mp 86°-87° C.). This pure material was recrystallized from hexanes-acetone (trace) to leave the desired compound as a colorless, crystalline solid (2.4 g), mp 88°-88.5° C. (first crop; second crop mp 87°-88° C.).
Reaction SMILES: [CH:1]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[NH:3][C:2]=1Cl.[SH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH-].[K+]>C(O)C>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][C:2]2[NH:3][C:4](=[O:5])[NH:6][C:7](=[O:8])[CH:1]=2)=[CH:12][CH:13]=1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Reactant: Oc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=c1cc(Sc2ccc(O)cc2)[nH]c(=O)[nH]1
Yield: 77.6 %

Procedure:
A mixture of 4-chlorouracil (0.87 g, 6.0 mmol), 4-mercaptophenol(0.834 g, 6.6 mmol) and KOH (0.435 g, 6.6 mmol) in ethanol (36 ml) was heated to reflux for 24 h. The reaction was allowed to cool, was concentrated in vacuo, and acidified with 1 n HCl. The solids were collected, washed with water and dried to give 6-[(4-hydroxyphenyl)thio]-2,4(1H,3H)-pyrimidinedione (1.1 g, 80%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[NH:5][CH2:6][CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][C:28](=[O:33])[CH:29](Cl)[CH2:30][CH3:31]>O>[Cl:27][C:28](=[O:33])[CH:29]([N:5]([CH2:6][CH:7]=[O:8])[C:4]1[C:9]([O:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:1][CH3:2])[CH2:30][CH3:31]
Reactant: CCc1cccc(OC)c1NCC=O
Reactant: CCC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCc1cccc(OC)c1N(CC=O)C(CC)C(=O)Cl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-ethyl-6-methoxyanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-chlorobutanoyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chlorobutanoyl-2-ethyl-6-methoxyanilino)acetaldehyde.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (example E.28) (0.300 g, 0.86 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.356 g, 1.029 mmol) according to the general procedure VI. Obtained as a white solid (0.110 g, 24%). MS (ISP) 532.1 [(M+H)+]; mp 225° C.