Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:13]=[C:11]1[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:18])[N:12]1[CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1
Reactant: N#CC1(CO)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CC1(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.3 %

Procedure:
A solution of 1-(hydroxymethyl)-cyclopropanecarbonitrile (5.52 g, 56.8 mmol), phthalimide (9.20 g, 62.5 mmol), and triphenylphosphine (16.4 g, 62.5 mmol) in THF (550 mL) was treated with DEAD (9.90 mL, 62.5 mmol) and stirred at room temperature for 17 hours. The reaction mixture was then concentrated and the resulting solids were triturated in diethyl ether (150 mL), and collected by filtration. Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM) afforded 1-((1,3-dioxoisoindolin-2-yl)methyl)-cyclopropanecarbonitrile (8.8 g, 38.8 mmol, 68%) as a white solid: LCMS (m/z) 227.0 (MH+), tR=0.66 minute; 1H NMR (300 MHz, CDCl3) δ 7.90 (dd, J=5.4, 3.1 Hz, 2H), 7.77 (dd, J=5.4, 3.1 Hz, 2H), 3.81 (s, 2H), 1.30-1.44 (m, 2H), 1.28 (d, J=3.8 Hz, 2H).
Reaction SMILES: [CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33])(=O)[O:4][CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36]>>[CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33])(=[S:36])[O:4][CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2]
Reactant: CCP(=O)(OCOC(=O)C(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: CCP(=S)(OCOC(=O)C(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 2,2-dimethylpropionyloxymethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (4.7 mmol) and phosphorus pentasulfide (1.2 mmol) is heated to 150°-160° under nitrogen for 3-4 hours. After cooling, the residue is purified by prep. TLC (20% ethyl acetate/hexane) to give O-(2,2-dimethylpropionyloxymethyl) P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinothioate.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([OH:15])[C:7](=[O:16])[C:6](=[O:17])[NH:5]2.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>CN(C=O)C>[OH:15][N:8]1[C:9]2[C:4](=[CH:3][C:2]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:6](=[O:17])[C:7]1=[O:16]
Reactant: c1c[nH]cn1
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2n(O)c1=O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(-n3ccnc3)c([N+](=O)[O-])cc2n(O)c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
A mixture of 370 mg of 6-fluoro-1-hydroxy-7-nitroquinoxaline-2,3-(1H,4H)-dione, 320 mg of imidazole and 37 ml of DMF was stirred at 100° C. for 4 hours. The reaction mixture was concentrated and, then, diluted with water. The aqueous layer was neutralized with hydrochloric acid and the resulting crystals were recovered by filtration and washed with water to provide 214 mg of 1-hydroxy-6-(1-imidazolyl)-7-nitroquinoxaline-2,3-(1H,4H)-dione 1/2 hydrate.
Reaction SMILES: [C]=O.C=O.[C:5]([OH:11])(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].C([O:18][CH2:19][C:20]([OH:22])=[O:21])(=O)CCCC>O>[C:20]([OH:22])(=[O:21])[CH2:19][OH:18].[C:5]([OH:11])(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(=O)OCC(=O)O
Agent: C=O
Agent: [C]=O
Solvent: CCCCC(=O)O
Solvent: O
Product: O=C(O)CO

Procedure:
Use of a hydrophobic solvent for extraction of the carboxylic acid from the hydrolyzed mixture is necessary if the carboxylic acid and aqueous glycolic acid does not phase separate and may be helpful to improve the separation even if not required to form two phases. In a second embodiment of the invention as set forth in FIG. 2, Carbon Monoxide Stream 1, Aqueous Formaldehyde Stream 2, and Valeric Acid Stream 3 are fed to Hydrocarboxylation Reactor 50 which comprises a fixed bed, solid catalyst (not shown). The Effluent Stream 4 comprises the esters of glycolic and valeric acid including 2-valeryloxyacetic acid. Effluent Stream 4 and Water Stream 8 are fed to Hydrolyzer 55. Hydrolyzer 55 is operated at sufficient temperature, pressure, and residence time to produce Hydrolyzed Mixture Stream 9 comprising glycolic acid, valeric acid, and water. Hydrolyzed Mixture Stream 9 is separated into two phases in Decanter 65. The organic phase is recycled to Hydrocarboxylation Reactor 50 as Valeric Acid Stream 3. Aqueous Glycolic Acid Stream 12 exits Decanter 65 and is fed, along with First Ethylene Glycol Stream 13 to Esterification Unit 80. Water Stream 14 and Glycolate Ester Oligomer Stream 15 exit Esterification Unit 80. Glycolate Ester Oligomer Stream 15 is hydrogenated using Hydrogen Stream 16 in Hydrogenation Unit 90. Hydrogenation Unit 90 produces Second Ethylene Glycol Stream 17 which can be split into Ethylene Glycol Product Stream 18 and First Ethylene Glycol Stream 13 which is recycled to Esterification Unit 80.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1CCOCC1

Procedure:
The product of Example 8A (2.9 mmol), triethylamine (1.2 mL, 8.7 mmol) and methanesulfonyl chloride (0.34 mL, 4.4 mmol) in 10 mL tetrahydrofuran (THF) were reacted and the product isolated as in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Product: CC(C)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(4-fluorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 375) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.051 g, 18%). Yellow oil. 1H NMR (300 MHz, DMSO d6) δ 0.80 (d, J=5 Hz, 6H), 1.47 (m, 3H), 4.42 (t, J=6 Hz, 2H), 7.37 (m, 2H), 7.50 (m, 1H), 7.65 (m, 2H), 7.83 (m, 2H), 7.93 (m, 2H), 8.18 (s, 1H), 8.60 (bs, 1H). MS (DCI/NH3) m/z 432 (M+H)+, 449 (M+NH4)+. Anal. calc. for C21H22FN3O4S: C, 58.46; H, 5.14; N, 9.74. Found: C, 58.16; H, 5.21; N, 9.57.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([OH:15])=O)[CH2:8][CH2:7][CH2:6]2.[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH:20]=[N:19]1)[CH3:17]>>[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[C:13]([CH:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:15])[CH:20]=[N:19]1)[CH3:17]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: COc1ccc2c(c1)CCCC2C(=O)O
Product: CCn1cc(CN(C(=O)C2CCCc3cc(OC)ccc32)c2ccc(C(C)C)cc2)cn1
Yield: 69.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.45 g) was obtained. melting point: 111-113° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1>>[CH3:28][O:27][C:21]1[CH:22]=[C:23]([O:25][CH3:26])[N:24]=[C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[N:20]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(OC)nc(N)n1
Product: COc1cc(OC)nc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 2-amino-4,6-dimethoxypyrimidine (27 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.65 (brs, 1H), 8.71–8.70 (m, 2H), 7.54 (brs, 1H), 7.44 (dd, J=7.8, 4.8 Hz, 1H), 7.25 (s, 1H), 7.04 (s, 1H), 6.07 (t, J=5.4 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=2)[C:6]1=[O:19].Cl.C(N(CC)CC)C.[CH3:28][C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:28][C:29]([CH3:34])([CH3:33])[C:30]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=2)[C:6]1=[O:19])=[O:31]
Reactant: COC(=O)c1ccc2ccn(CCCN)c(=O)c2c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2ccn(CCCNC(=O)C(C)(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of methyl 2-(3-aminopropyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.13 g, 0.44 mmol) dissolved in methylene chloride (8 mL) was added triethylamine (0.18 mL, 1.3 mmol) and 2,2-dimethylpropanoyl chloride (0.08 mL, 0.66 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was then concentrated to dryness and the residue was purified by flash silica gel chromatography (40% to 90% EtOAc/hexanes) to afford methyl 2-{3-[(2,2-dimethylpropanoyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.14 g, 92%). LC-MS: (FA) ES+ 345.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([CH3:21])[NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][N:34]=[C:35]=[S:36].O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:20][C:35]([NH:34][CH2:33][C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[S:36])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: S=C=NCc1ccco1
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=S)NCc1ccco1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Yield: 76.8 %

Procedure:
(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine (50 mg, 0.14 mmol), as described in Example 1, is dissolved in 0.89 mL dichloromethane and furylmethylisothiocyanate (19.3 mg, 0.14 mmol) is dropwise added. After stirring for 90 min at r.t. water (5 mL) is added and the reaction mixture extracted once with ethyl acetate (50 mL). The organic phase is washed with water (10 mL) and dried over Na2SO4. After filtration the solvent is removed and the residue purified by chromatography (silicagel, eluents: hexane/ethylacetate). 53.8 mg (77.7%) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:29])=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30]>C(Cl)Cl.CC(O)C>[NH2:30][C:20]1[C:19]2[N:18]([C:17]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[F:29])[CH:23]=[CH:22][N:21]=1
Reactant: Fc1c(OCc2ccccc2)cccc1-c1nc(C2CCC2)n2ccnc(Cl)c12
Reactant: N
Solvent: CC(C)O
Solvent: ClCCl
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3F)c12
Temperature: 125 °C
Yield: 75 %

Procedure:
1-(3-Benzyloxy-2-fluoro-phenyl)-8-chloro-3-cyclobutyl-imidazo[1,5-a]pyrazine (500 mg, 1.2 mmole) in methylene chloride was placed in a Parr pressure reactor, cooled in ice salt bath and charged with a saturated solution of NH3 in 2-propanol (10 mL). The pressure reactor was heated at 125° C. overnight. The reaction was cooled to room temperature and the crude reaction mixture was evaporated and triturated with methylene chloride and filtered. The filtrate was evaporated to dryness and purified by silica-gel column chromatography [eluant CH2Cl2:hexane (70:30)] to afford the title compound (350 mg, 75%); FAB-MS: m/z 388.9 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].C(N(C(C)C)CC)(C)C>[I-].[K+].O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[CH3:14])=[O:4])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: COc1ccc(C)c(NC(=O)CCl)c1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C)c(NC(=O)CNc2ccc(F)c(Cl)c2)c1
Yield: 86.7 %

Procedure:
2-Chloro-N-(5-methoxy-2-methylphenyl)-acetamide (3 g), 3-chloro4-fluoroaniline (7.56 g), diisopropylethylamine (13.8 ml), potassium iodide (0.005 g) and anhydrous tetrahydrofuran (20 ml) were heated together at 105° C. in a sealed tube for 19 hours. The mixture was then cooled and concentrated. Purification of the residue by silica gel chromatography (eluting with 1:1 iso-hexane/ethyl acetate) gave the sub-title compound (3.93 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:14]2[C:15]3[C:20](=[CH:19][C:18]([C:22]([N:24]4[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]4)=[O:23])=[CH:17][CH:16]=3)[CH:21]=[C:13]2[C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[O:12])[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC4(CC2)OCCO4)n3-c2cccc(Cl)c2)CC1
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 66, from (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 196), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (50%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[Cl:10].CC1(C)C(C)(C)OB([C:19]2[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])O1.O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.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.CC1(C)C(C)(C)OB(C2C=CC=CC=2C(OCC)=O)O1>[Cl:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:19]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(Br)c(Cl)c1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(OC)cc1Cl
Temperature: 120 °C
Reaction time: 7 h
Yield: 116.4 %

Procedure:
Under an argon atmosphere, 1-bromo-2-chloro-4-methoxybenzene (44.3 g) was dissolved in toluene (220 ml), ethyl 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoate (60.8 g), water (132 ml), sodium hydrogen carbonate (33.6 g) and dichlorobis(triphenylphosphine)palladium(II) (2.8 g) were added, and the mixture was stirred at an oil bath temperature of 120° C. for 7 hr. To the reaction mixture was added ethyl 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoate (5.2 g), and the mixture was further stirred for 2 hr. The reaction mixture was cooled to room temperature, toluene (100 ml) and water (200 ml) were added, and the mixture was stirred overnight. To the reaction mixture was added activated carbon (3 g), and the mixture was further stirred for 1 hr. The insoluble material was filtered off through celite, and the insoluble material was washed with toluene (100 ml) and water (200 ml). The obtained filtrates were combined to allow for layer separation. The obtained organic layer was washed with water (100 ml), and the solvent was evaporated to give the title compound (67.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:18][S:19]([O:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][CH2:31]CS([O-])(=O)=O)[CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:20]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:31][CH2:30][CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][S:19]([CH3:18])(=[O:21])=[O:20])[CH:24]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CS(=O)(=O)Oc1cccc(CCCCS(=O)(=O)[O-])c1
Product: CCOC(=O)C(Cc1ccc(OCCCc2cccc(OS(C)(=O)=O)c2)cc1)OCC

Procedure:
2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) was alkylated with 3-(3-methanesulfonyloxyphenyl)propylmethanesulfonate using the same method as in example 1 (b) to give 2-ethoxy-3-{4-[3-(3-methanesulfonyloxyphenyl)propoxy]-phenyl}propanoic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCCCCC>[CH3:28][N:25]1[CH2:24][CH2:23][CH:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[O:42])=[CH:30][CH:29]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:27][CH2:26]1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyridine (80.7 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.96 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (73.7 mg, 66%) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:14])[NH:12][CH3:13])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:14])[NH:12][CH3:13])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Solvent: ClCCl
Product: CNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 2,6-dichloro-4-(methylcarbamoyl)benzoic acid (400 mg, 1.6 mmol) and thionyl chloride (1.91 g, 16 mmol) in dichloromethane (10 mL) was stirred at 50° C. for 5 hours. The reaction mixture was concentrated under rotary evaporator and used as such for next step.
Reaction SMILES: [N+](C1C=CC([C:10]2[C:18]([CH2:19][C@H:20]3[C@@H:25]([OH:26])[C:24]4[CH:27]=[C:28]([O:31][CH2:32][C:33]5[S:34][C:35]6[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:36]=6[N:37]=5)[CH:29]=[CH:30][C:23]=4[O:22][CH2:21]3)=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O-])=[O:13])=CC=1)([O-])=O.[H-].[Na+].[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47]>>[F:42][C:39]1[CH:40]=[CH:41][C:35]2[S:34][C:33]([CH2:32][O:31][C:28]3[CH:29]=[CH:30][C:23]4[O:22][CH2:21][C@@H:20]([CH2:19][C:18]5[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=5)[C:12]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:13])[C@@H:25]([OH:26])[C:24]=4[CH:27]=3)=[N:37][C:36]=2[CH:38]=1
Reactant: O=C([O-])c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1-c1ccc([N+](=O)[O-])cc1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)NC(=O)c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1

Procedure:
Synthesis was carried out as in example 1, but using 1.7 grams optically pure (+)cis-4-nitrophenyl-3-[[6-[(5-fluoro-2-benzothiazolyl)methoxy]-3,4-dihydro -4-hydroxy-2H-1-benzopyran-3-yl]methyl]benzoate, 410 milligrams sodium hydride and 1.65 grams methanesulfonamide. 187 milligrams of product was obtained. αD =33.4°; c=0.005 in tetrahydrofuran.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N+]=[N-])=[CH:4][CH:3]=1.[CH:18]([CH:20]=[CH2:21])=[O:19]>ClCCl.CCCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:21][CH:20]2[CH:18]=[O:19])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C=CC=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=CC1CC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of bis(4-fluorophenyl)diazomethane, prepared as in Example 84 from the action of activated manganese dioxide (59.7 g) on 4,4'-difluorobenzophenone hydrazone (42.81 g) in dichloromethane (195 mL), was added to a solution of acrolein (15.7 mL) in heptane (150 mL). The deep purple reaction mixture, after being stirred at 40° C. for 2 hours then at 53° C. for 30 minutes, faded to a pale amber color. Evaporation of the solvents afforded 46 g of 2,2-bis(4-fluorophenyl)cyclopropanecarboxaldehyde as an oil. The material was used without further purification in subsequent reactions.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]OS(C1C=CC(C)=CC=1)(=O)=O.[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:21]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]([O:19][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCCCOc1ccccc1-c1ccccc1

Procedure:
1-Chloro-6-(p-toluenesulphonyloxy)hexane (100 g), 2-hydroxybiphenyl (59 g) and potassium carbonate (60 g) were heated with stirring in dimethylformamide at 70° for 16 hours. The solution was cooled and added to water, then extracted with ether. The extract was washed with water, dried and evaporated, and the residue was chromatographed on silica gel (1800 g) eluting with 99:1 hexane; ethyl acetate, so as to afford the title compound as an oil.