Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].[CH:19]([C:22]1[N:23]=[C:24]([C:27](O)=[O:28])[S:25][CH:26]=1)([CH3:21])[CH3:20].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:16]([C:3]1[C:2]([NH:1][C:27]([C:24]2[S:25][CH:26]=[C:22]([CH:19]([CH3:21])[CH3:20])[N:23]=2)=[O:28])=[C:7]([Cl:8])[C:6]([O:9][CH2:10][CH:11]([O:12][CH3:13])[O:14][CH3:15])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Reactant: CC(C)c1csc(C(=O)O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1Cl)OC
Temperature: -10 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
1-[2-amino-3-chloro-4-(2,2-dimethoxy-ethoxy)-phenyl]-ethanone (1.89 g, 6.92 mmol) and 4-isopropyl-thiazole-2-carboxylic acid (1.77 g, 10.38 mmol) was dissolved in pyridine (20 mL) and was cooled to −10° C. POCl3 (0.823 mL, 8.99 mmol) was added dropwise. The reaction was stirred at −10° C. for 2 hours. The reaction was quenched with CH3OH (5 mL). After 15 minutes, the reaction was taken up in EtOAc and extracted with 2N HCl(aq). The organic layer was dried with Na2SO4, filtered and was concentrated. 4-Isopropyl-thiazole-2-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)-phenyl]-amide (2.84 g, 96%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[H-].[Na+].[NH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12](Cl)[N:11]=1>C1COCC1.C(#N)C>[NH2:9][C:10]1[N:15]=[C:14]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[CH:13]=[C:12]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[N:11]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Temperature: 62 °C
Yield: 95.5 %

Procedure:
To a solution of trifluoroethanol (9.0 mL, 125 mmol) in anhydrous THF (100 mL) at 0° C. in a 3-neck round bottom flask under an atmosphere of dry N2 was added NaH (4.8 g, 120 mmol, 60% dispersion in mineral oil) over ca. 1 min. After gas evolution ceased and the solution became clear (ca. 20 min), 2-amino-4,6-dichloropyrimdine (8.2 g, 50 mmol) was added. The flask was fitted with a reflux condenser and heated to 62° C. overnight (ca. 15 h). An NMR of a quenched aliquot from the reaction mixture demonstrated the reaction was complete. After the reaction mixture was cooled to ambient temperature it was quenched by addition of 1 N HCl and diluted with EtOAc. The separated organic layer was washed with brine, sat. aq. NaHCO3 and then brine. After drying over MgSO4, filtering and concentrating, the oil thus obtained was dissolved in acetonitrile and washed with hexanes (2×, to remove mineral oil) and concentrated to afford the desired amine as an orange oil (13.9 g, 96% yield): Kugelrohr distillation (high vacuum, 90° C. bath temperature, ice bath for receiving flask) afforded the product as a white solid: m.p. 34-35° C.; 1H NMR (CDCl3) δ 5.69 (s, 1H), 4.95 (br s, 2H), 4.69 (q, 4H, J=8.1 Hz); GCMS (EI, 70 eV) m/z 291 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:14][C:15]([F:32])([F:31])[C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH2:26][CH2:25]3)=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:10]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([C:19]4[CH:20]=[N:21][C:16]([C:15]([F:31])([F:14])[F:32])=[CH:17][CH:18]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CCN3)cn1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)nc4)ccc32)cc1Cl
Temperature: 80 °C

Procedure:
1.18 g of commercially available 3-Chloro-4-cyano-benzenesulfonyl chloride were dissolved in 30 ml dichloromethane. Then 880 mg 5-(6-Trifluoromethyl-pyridin-3-yl)-2,3-dihydro-1H-indole were added followed by 15 ml pyridine and 407 mg 4-dimethylaminopyridine. The mixture was stirred at 80° C. for thirty minutes. The mixture was diluted with 100 ml of dichloromethane and washed with 100 ml water and 100 ml saturated NaHCO3 solution. The organic layer was then separated and dried over MgSO4. The solvent was removed in vacuo to obtain 1.49 g 2-Chloro-4-[5-(6-trifluoromethyl-pyridin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C(N(C(C)C)CC)(C)C.[Na+].[I-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:14]([CH3:16])([C:13]([O:12][CH2:10][CH3:11])=[O:18])[CH3:15])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Nc1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 61.9 %

Procedure:
A 15-mL sealed tube equipped with a magnetic stirring bar was charged with 3,4-dichloroaniline (1.63 g, 10.0 mmol) and treated with ethyl-2-bromoisobutyrate (1.6 mL, 11 mmol), diisopropylethylamine (1.9 mL, 11.0 mmol), and NaI (824 mg, 0.600 mmol). The vessel was sealed tightly, heated to 110° C. and maintained at that temperature for 48 h. After allowing the reaction mixture to cool to room temperature, the reaction was diluted with THF and the solids were filtered off. The filtrate was collected and concentrated under vacuum. The crude oil was purified by silica gel chromatography (35 g Redisep column, silica 40 um, 35 mL/min, A: CH2Cl2, B: MeOH, B: 0% for 20 min, 5% for 5 min, 10% for 5 min; detection at 214 nm) to give 1.71 g (55%) of ethyl N-(3,4-dichlorophenyl)-2-methylalaninate as a brown oil. MS (ES) m/z 276 [M+H]+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:6]2[N:5]=[C:4]3[N:3]=[CH:2][NH:1][C:9]3=[CH:8][CH:7]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc2[nH]cnc2n1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]cnc2n1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 57 %

Procedure:
The title compound is prepared from 1H-imidazo[4,5-b]pyridine-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 57% of theory; LC (method 3): tR=2.10 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH:13]O.[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([NH2:12])=[O:13])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: OO
Reactant: N#Cc1cc(Br)c2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1cc(Br)c2cc[nH]c2c1
Yield: 97.6 %

Procedure:
A solution of 4-bromo-1H-indole-6-carbonitrile (1 g, 4.50 mmol) in methanol (10 mL) was treated with 30% aqueous hydrogen peroxide (2.7 mL, 4.95 mmol) and a 1 M aqueous sodium hydroxide solution (5 mL) then heated at 40° C. for 1 h. The reaction mixture was cooled, treated with water and cooled in an ice-bath. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to obtain 4-bromo-1H-indole-6-carboxylic acid amide (1.05 g, 97%), which was transformed into the title boronic ester by the general method (Scheme 1) (0.80 g, 67%).
Reaction SMILES: [CH2:1]([C:3]([C:7]1[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=1)([CH3:6])[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:10]1[N:11]=[N:12][C:7]([C:3]([CH2:4][CH3:5])([CH3:6])[CH2:1][CH3:2])=[CH:8][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(C)(CC)c1ccc(=O)[nH]n1
Product: CCC(C)(CC)c1ccc(Cl)nn1

Procedure:
To 34 g. of 6-(1-ethyl-1-methylpropyl)-3-pyridazinone was added 175 ml. of phosphorus oxychloride, and the mixture was stirred under reflux for 30 minutes. It was then cooled, excess phosphorus oxychloride was removed under vacuum, and the residual oil was poured into ice water. The residue was made basic to pH 9 with ammonia, and triturated. The aqueous mixture so prepared was extracted with two one-liter portions of diethyl ether, and the combined organics were dried and evaporated under vacuum to obtain 35 g. of the desired product, identified by mass spectroscopy, which showed a molecular ion having a weight of 198.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a mixture of tetrahydro-2H-pyran-4-carboxylic acid (4.8 g) and potassium carbonate (7.6 g) and DMF (73 mL) was added dropwise benzyl bromide (4.6 mL) at 0° C. The reaction mixture was stirred at room temperature for one day, diluted with ice water, and extracted with ethyl acetate. The extract was washed with water, 0.5N hydrochloric acid, water and saturated brine, dried and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (solvent gradient; 0→20% ethyl acetate/hexane) to give benzyl tetrahydro-2H-pyran-4-carboxylate (7.6 g, 94%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)=[CH:9][N:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[CH:17]=[N:16][N:15]=1)[N:7]=3>C(#N)C.[Pd]>[CH:19]([N:18]1[CH:17]=[N:16][N:15]=[C:14]1[N:8]1[N:7]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[CH:2][CH:23]=[CH:22][C:5]=32)=[CH:9]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1cnnc1-n1cc2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd]
Solvent: CC#N
Product: CC(C)n1cnnc1-n1cc2c(n1)-c1ccccc1OCC2
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Alternatively, a degassed solution of 8-bromo-2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (122 mg, 0.326 mmol) in IMS (10 mL) was added 10% Pd/C (15 mg), the reaction mixture stirred under an atmosphere of hydrogen for 1 h before the reaction mixture was filtered and the filtrate concentrated in vacuo. The resultant residue was dissolved in DCM and the solution washed with water, the organic layer dried (Na2SO4), filtered and concentrated in vacuo to give a residue. The residue was dissolved in acetonitrile and water and the solution freeze dried to give 2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene as a white solid (54 mg, 56%). 1H NMR (400 MHz, CDCl3): δ 8.27-8.23 (m, 2H); 8.12 (t, J=1.02 Hz, 1H); 7.30-7.24 (m, 1H); 7.14-7.06 (m, 2H); 5.38-5.29 (m, 1H); 4.36 (t, J=5.10 Hz, 2H); 3.16 (td, J=5.10, 1.06 Hz, 2H); 1.63-1.54 (d, J=6.59 Hz, 6H). LCMS: RT=10.29 min, M+H+=296
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].C(N[C:18]1[CH:27]=[C:26]([NH:28][C:29](=[O:33])[CH2:30][CH2:31][CH3:32])[C:25]([O:34]C(=O)CCC)=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH3:40])=[N:23]2)(=O)CCC.[OH2:41]>C(O)(=O)C>[C:29]([NH:28][C:26]1[C:25](=[O:34])[C:24]2[N:23]=[C:22]([CH3:40])[CH:21]=[CH:20][C:19]=2[C:18](=[O:41])[CH:27]=1)(=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(=O)Nc1cc(NC(=O)CCC)c2ccc(C)nc2c1OC(=O)CCC
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCCC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Yield: 77 %

Procedure:
This compound was prepared by the oxidation of the corresponding acylamido with potassium dichromate in glacial acetic acid. In a 500 ml. round-bottomed flask equipped with a magnetic bar, 5,7-dibutyramido-8-butyroxy-2-methylquinoline (34) (prepared as described in Examples 31-34) (3.29 g., 8.25 mmol) was suspended in 122 ml of glacial acetic acid. A solution of potassium dichromate (8.8 g., 0.03 mol) in 115 ml. of water was added and stirred. The stirred suspension began to dissolve but, after two hours, more solid continued to precipitate. Dichloromethane (70 ml.) was added to promote solution. The resulting two-phase solution mixture was stirred at room temperature overnight. The two-phase solution mixture was extracted with dichloromethane (12×50 ml.). The organic extracts were washed with a 3% sodium bicarbonate solution (200 ml.), dried with magnesium sulfate, and rotoevaporated to yield an orange-yellow solid. After vacuum drying, the solid weighed 1.65 g. (a yield of 77%). The product was recrystallized from ethyl acetate: mp. 188-189 EC; 1H NMR (CDCl3)*1.00 (3H, t, J=7.4 Hz, C—7NHCOCH2CH2CH3), 1.69-1.82 (2H, m, C—7NHCOCH2CH2CH3), 2.48 (2H, t, J=7.4 Hz, C—7NHCOCH2CH2CH3), 2.74 (3H, s, C—2CH3), 7.53 (1H, d, J=8.0 Hz, C—3H), 7.90 (1 H, s, C—6H), 8.28 (1H, d, J=8.0 Hz, C—4H), 8.36 (1H, br. s, C—7NH); IR (KBr) vmax 3338, 3275, 2964, 2935, 2875, 1711, 1682, 1654, 1644, 1615, 1588, 1502, 1323, 1310, 1133 cm−1; EIMS, m/e (relative intensity) 258 (81), 215 (7), 188 (base), 161 (66); HRMS, m/e for C14H14N2O3 calculated 258.100442, found 258.100227; analysis for C14H14N2O3 calculated C, 65.11; H, 5.46; N, 10.85; found C, 65.22; H, 5.51; N 10.01.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(/C=C/C2C=CC=CC=2)C=CC=CC=1.C1(CCC2C=CC=CC=2)C=CC=CC=1>[Pd].C(O)C>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=C\c1ccccc1)\c1ccccc1
Agent: [Pd]
Agent: C(=C/c1ccccc1)\c1ccccc1
Solvent: CCO
Solvent: c1ccc(CCc2ccccc2)cc1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The relevant reactions are shown in equations below. the first step, hydrogenation of the triple bond to form an olefin, can give two isomeric products, designated cis or trans depending on the orientation of the substituents about the double bond. These molecules can be further hydrogenated to the saturated product as also shown in such equations ##STR5## The palladium-loaded pyridyl catalyst of Example 6 hydrogenated diphenylacetylene under only 50 psig pressure of H2 : an ethanol solution of the substrate was 100% converted to a product mixture consisting of 80.7% cis-stilbene, 16.1% trans-stilbene, and 3.2% 1,2-diphenylethane. The low pressure used in this experiment made it difficult to monitor the course of the reaction, for the pressure gauge on the Parr bomb is not very sensitive or accurate in this regime. No pressure decrease was observed when the reaction mixture was stirred at room temperature for 3 hrs. and upon warming to 80° C. the pressure increased to 60 psig (the ideal gas law predicts 59 psig if no reaction occurred). No pressure increase was observed when the temperature was next raised to 100° C., and it remained steady on holding the reactor at this temperature for 1 hr. Upon cooling to room temperature the pressure was found to be 35 psig; it thus appears that the reaction occurred during the warming from 80° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH2:39]([S:41][C:42]1[C:51]([C:52](O)=[O:53])=[C:50]([CH3:55])[C:49]2[C:44](=[CH:45][C:46]([C:56]([F:59])([F:58])[F:57])=[CH:47][CH:48]=2)[N:43]=1)[CH3:40]>C1COCC1.CCCCCC>[CH2:39]([S:41][C:42]1[C:51]([C:52]([NH:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:53])=[C:50]([CH3:55])[C:49]2[C:44](=[CH:45][C:46]([C:56]([F:59])([F:57])[F:58])=[CH:47][CH:48]=2)[N:43]=1)[CH3:40]
Reactant: CCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Reactant: NCc1cccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1cccs1
Temperature: 50 °C
Yield: 63.8 %

Procedure:
134 μl (1.3 mmol) thiophenemethanamine, 438 mg (1.1 mmol) HATU and 420 μl (3.0 mmol) NEt3 were added in succession to a solution of 330 mg (1.05 mmol) 2-(ethylthio)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid (VVV08) in THF (8 ml) and the mixture was then heated for 24 h at 50° C. Then it was diluted with EE and washed with a 4M aqueous NH4Cl solution, a 1M aqueous Na2CO3 solution and brine. The organic phase was dried over MgSO4 and then filtered through a silica layer. Column chromatography (hexane/EE 7:3) of the residue yielded 277 mg (0.67 mmol, 65%) 2-ethylsulfanyl-4-methyl-N-(thiophen-2-yl-methyl)-7-(trifluoromethyl)-quinoline-3-carboxamide. MS: m/z 411.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccnc3)ccn2c1=O
Yield: 88 %

Procedure:
Methyl 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-3-yl)-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and pyridin-3-ylboronic acid (63 mg, 0.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (100 mg, 87%). ESI-MS m/z: 335 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)nc(Br)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Product: Cc1cc(C)nc(-c2cc(C)c(Cl)c(C)c2)c1

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-4,6-dimethyl-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.89 min; Mass spectrum (ESI+): m/z=246/248 (Cl) [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([S:21]([NH:24][C:25]([NH:14][C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[O:26])(=[O:22])=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: O=C=NS(=O)(=O)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NS(=O)(=O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and benzenesulfonyl isocyanate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[CH:27][CH:26]=3)[C:16]=2[C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)[C:16]=2[C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(OCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 4-{2-{6-(4-tert-butylbenzenesulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy]ethoxy}phenoxyacetate (1.25 g) in dichloromethane (120 ml) are added anisole (2.09 g) and trifluoroacetic acid (20 ml) under ice-cooling. The mixture is stirred at room temperature for five hours, washed with water, and extracted with 10% aqueous sodium hydroxide solution. The aqueous layer is washed with chloroform, and acidified with 10% hydrochloric acid under ice-cooling. The mixture is extracted with ethyl acetate, and the extract is washed, dried, and evaporated to remove the solvent. The residue is crystallized from ethyl acetate/diisopropyl ether to give 4-{2-[6-(4-tert-butylbenzenesulfonylamino )-5-(4-methylphenyl)pyrimidin-4-yloxy]ethoxy}phenoxyacetic acid (1.14 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[NH2:14][N:15]1[C:19]([NH2:20])=[N:18][N:17]=[C:16]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(O)CO>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:20][C:19]2=[N:18][N:17]=[C:16]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[N:14]=1
Reactant: O=C1Nc2ccc(O)c(Cl)c2C1=O
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Solvent: OCCO
Product: Oc1ccc(Cc2nnc3nc4[nH]c5ccc(O)c(Cl)c5c4nn23)cc1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
According to a cyclization procedure for Example 30, 0.60 mmol of 4-chloro-5-hydroxy-1H-indole-2,3-dione (118.5 mg) and 0.70 mmol of 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (144 mg) in 2 mL of ethylene glycol was stirred at 125° C. overnight (16 hr).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][S:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[C:4]([O:22][CH3:23])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O>CN(C=O)C>[CH3:23][O:22][C:4]1[CH:3]=[C:2]([O:1][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:7]=[CH:6][C:5]=1[C:8](=[O:21])[CH2:9][S:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][CH:12]=1
Reactant: CCCCCCBr
Reactant: COc1cc(O)ccc1C(=O)CSc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccc(C(=O)CSc2ccnc3ccccc23)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
4-[2-(4-Hydroxy-2-methoxyphenyl)-2-oxoethylthio]-quinoline (Compound 12; 83 mg, 0.25 mmol) and potassium carbonate(42 mg, 0.25 mmol) were suspended in dry DMF (2.0 ml). Hexylbromide (0.041 ml, 0.28 mmol) was addded at -15° C. to the suspension and stirred at room temperature overnight. The reaction mixture was added with water under ice cooling, extracted with ethyl acetate, washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed by silica gel chromatography (n-hexane:ethyl acetate=1:4) to obtain 82.1 mg of the titled compound (80.3%).