Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[N:18]3[N:19]=[C:20]([NH2:22])[N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(N(C)C)=O.O1CCOCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[N:18]3[N:19]=[C:20]([NH:22][C:24]4[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]5[CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:36][CH:37]=4)[N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: Nc1nc2cccc(-c3cnn(Cc4ccccc4)c3)n2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: c1ccc(Cn2cc(-c3cccc4nc(Nc5ccc(OCCN6CCCC6)cc5)nn34)cn2)cc1
Temperature: 130 °C

Procedure:
A microwave vial containing 5-(1-benzyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (6.42 g, 22.1 mmol), 1-(2-(4-bromophenoxy)ethyl)pyrrolidine (5.1 mL, 24.3 mmol), tris(dibenzylideneacetone)dipalladium (0.633 g, 1.11 mmol), xantphos (1.28 g, 2.22 mmol), sodium tert-butoxide (4.34 g, 44.2 mmol) and 1,4-dioxane (50 mL) was heated under microwave irradiation (130° C., 15 min). Dimethylacetamide (2.5 mL) was added to assist with microwave absorption. The volatiles were removed under rotary evaporation, and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organics washed with water followed by brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo and after trituration with the minimum amount of dichloromethane in diethylether afforded a pale yellow solid. Yield: 8.12 g, 77%; LCMS method: 2, RT: 2.52 min, MI: 480 [M+1].
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CCO>[N+:11]([C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([O-:13])=[O:12]
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCO
Product: O=C(O)c1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.4 %

Procedure:
3-Fluoro-4-nitrobenzoic acid (Combi-Blocks CA-4022, 5 g; 27.01 mmol) was dissolved in EtOH (30 mL) to which was added piperidine (8.02 mL; 81.03 mmol). The reaction mixture was stirred at RT for 24 hours, then concentrated and the residue was taken up in water (300 mL). The aqueous phase was washed with Et2O then the aqueous phase was acidified with acetic acid until pH 5. The aqueous phase was extracted with Et2O (900 mL). The combined organic phases were dried over MgSO4 and concentrated affording the title compound as an orange solid (6.18 g, 91%). 1H NMR (DMSO-d6, 300 MHz) δ 13.55 (br s, 1H), 7.89-7.86 (d, J=8.42 Hz, 1H), 7.77-7.76 (d, J=1.40 Hz, 1H), 7.60-7.57 (dd, J=8.42 Hz, 1.50 Hz, 1H), 3.23-2.98 (m, 2H), 3.21-3.05 (m, 4H), 1.63-1.58 (m, 6H). HPLC (Method A) Rt 3.88 min (Purity: 99.9%).
Reaction SMILES: C([CH2:4][N:5]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12]C(O)=O)[CH2:7][C:6]1=[O:16])(O)=O.FC(F)(F)S(O)(=O)=O.O1P2[O:31][P:32]3[O:34]P(O2)OP1[O:33]3.[C]=O>O>[P:32]([CH2:4][N:5]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][P:32]([OH:31])([OH:33])=[O:34])[CH2:7][C:6]1=[O:16])([OH:34])([OH:33])=[O:31]
Reactant: O1P2OP3OP1OP(O2)O3
Reactant: O=C(O)CN1CC(=O)N(CC(=O)O)CC1=O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [C]=O
Solvent: O
Product: O=C1CN(CP(=O)(O)O)C(=O)CN1CP(=O)(O)O
Temperature: 75 °C
Reaction time: 16 h

Procedure:
In a round-bottom flask equipped with a mechanical stirrer, a thermometer, a condenser 4.00 g (17.2 mmole) N,N′-bis(carboxymethyl)-2,5-diketopiperazine was mixed with 25 ml trifluoromethanesulfonic acid. Subsequently, the reaction mixture was heated to 75° C. and 1.89 g (8.6 mmole) tetraphosphorus hexaoxide was added slowly. Afterwards the reaction mixture was stirred for 16 hour at 75° C. During the addition and during the reaction time the evolution of carbon monoxide was observed. At ambient temperature 30 ml of water was added to the reaction mixture which subsequently was heated to 95° C. for 6 hour. A white solid precipitated that was removed by filtration at ambient temperature (yield: 4.35 g). The solid consisted of N,N′-bis(phosphonomethyl)-2,5-diketopiperazine at 98.9% by weight.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]2[CH2:17][O:16][C:15](=[O:18])[O:14]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:32][O+](C)C>>[O:18]=[C:15]1[O:14][CH:13]([CH:12]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:11][CH2:10][CH2:9][CH:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([O:1][CH3:32])=[N:8]2)[CH2:17][O:16]1
Reactant: C[O+](C)C
Reactant: CC(C)(C)OC(=O)NC(CCCC1CCCCC(=O)N1)C1COC(=O)O1
Agent: F[B-](F)(F)F
Product: COC1=NC(CCCC(NC(=O)OC(C)(C)C)C2COC(=O)O2)CCCC1

Procedure:
The product of EXAMPLE 270 is reacted with trimethyloxonium tetrafluoroborate by the method of EXAMPLE 26 to produce the title material.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[C:10]([CH3:20])=[N:9]1.[OH-].[Na+].O.Cl>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]([CH3:20])=[N:9]1
Reactant: COC(=O)CCc1c(C)nn(-c2ccccc2O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nn(-c2ccccc2O)c(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 26.4 %

Procedure:
29.9 mg of methyl 3-(1-(2-hydroxyphenyl)-3,5-dimethyl-1Hpyrazol-4-yl)propanoate was dissolved in 0.6 ml of methanol, and to the mixture was added 0.29 ml of 1N-sodium hydroxide and stirred at room temperature for 3.5 hours. To the reaction mixture was added 20 ml of water, neutralized with 1N-hydrochloric acid, and extracted with 20 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 7.5 mg of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[OH:17])[NH:8][CH:7]=1)=[O:5])C>[OH-].[Na+]>[OH:17][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][NH:8]2
Reactant: CCOC(=O)c1c[nH]c2cccc(O)c2c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2cccc(O)c2c1=O
Yield: 87.7 %

Procedure:
A mixture of 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (700 mg, 3 mmol) in 10% NaOH (20 mL) was heated at reflux overnight. After cooling, the mixture was extracted with ether. The aqueous phase was separated and acidified with conc. HCl to pH 1-2. The resulting precipitate was collected via filtration to give 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-3) (540 mg, 87%). 1H NMR (DMSO-d6) δ 13.7 (br, 1H), 13.5 (br, 1H), 12.6 (s, 1H), 8.82 (s, 1H), 7.68 (t, J=8.1 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H); ESI-MS 205.9 m/z (MH+).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:8]1[S:9][CH:10]=[C:11]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:12]=1)(OCC)=[O:4]>C(O)C>[CH:13]1([C:11]2[N:12]=[C:8]([CH2:3][OH:4])[S:9][CH:10]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1nc(C2CCCCCC2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1nc(C2CCCCCC2)cs1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
Sodium borohydride (6.4 g) was added in one portion to an ice cold solution composed of 25.4 g of 2-carboethoxy-4-cycloheptylthiazole and 200 ml of ethyl alcohol. The ice bath was removed after 30 min and the reaction mixture was allowed to warm to room temperature. After 16 hr the reaction mixture was diluted with 400 ml of ice water and extracted with methylene chloride. The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to yield 18.6 g of 4-cycloheptyl-2-thiazolemethanol as an oil.
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([CH3:16])[C:10]=1[CH3:17].[CH3:18][S:19]SC>[Cu]>[CH3:17][C:10]1[C:11]([CH3:16])=[C:12]([S:19][CH3:18])[CH:14]=[CH:15][C:9]=1[Br:8]
Reactant: Cc1c(N)ccc(Br)c1C
Reactant: CSSC
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1ccc(Br)c(C)c1C
Temperature: 77.5 °C
Reaction time: 9 h

Procedure:
603 g (5.85 mol) of tert-butyl nitrite and 375 g of copper powder (5.9 mol) are initially charged in 3000 ml of dimethyl disulfide, and 761 g (3.75 mol) of 4-bromo-2,3-dimethylaniline are added dropwise at 50-58° C. The mixture is then stirred at 75-80° C. for 9 hours. For work-up, the mixture is cooled, the residue is filtered off and the filtrate is washed with saturated aqueous NaHCO3 solution. For purification of the product, the organic phase is separated by distillation. Initially, excess dimethyl disulfide is removed under atmospheric pressure. 1870 g of dimethyl disulfide (purity>97% according to GC) are recovered. The residue is then subjected to fractional distillation under reduced pressure (0.1 mbar).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[C:5]1(=[O:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH2:6]1.[OH-].[Na+]>CS(O)(=O)=O>[NH:1]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6][C:5]1=[O:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CC=Cc2ccccc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCCc2ccccc2N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
Sodium azide (1.95 g, 30 mmol) was added in small portions to a solution of 3,4-dihydro-[(2H)-naphthalenone (2.92 g, 20 mmol) in CH3SO3H (50 mL) at 0° C. The mixture was stirred at 0° C. for 15 min, 1 hr at room temperature, poured into ice (400 mL), basified until pH>8 with 1N NaOH at 0° C. and extracted with ether (3×100 mL). The combined organic layer was dried (MgSO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/1:1) gave 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (2.71 g, 85%) as a white solid.]H NMR (CDCl3, 300 MHz) δ 2.18–2.32 (m, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 6.99 (d, J=8.1 Hz, 1H), 7.13 (td, J=7.6, 1.5 Hz, 1H), 7.22 (d, J=7.0 Hz, 2H), 8.10 (br, 1H) ppm.
Reaction SMILES: C[O-].[Na+].[CH2:4]([OH:7])[CH2:5][OH:6].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH2:11]Br>O>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH2:11][O:6][CH2:5][CH2:4][OH:7]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: OCCO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: OCCOCc1c(Cl)cccc1Cl
Temperature: 57.5 °C
Reaction time: 1.5 h

Procedure:
Sodium methoxide (104.4 g, 1.93 mol) was added portionwise to ethylene glycol (3.74 L) under N2, keeping the temperature below 35° C. After 1-2 h, 2,6-dichlorobenzylbromide (400 g, 1.67 mol) was added and the mixture heated to 55-60° C. for 1 h. On cooling to 20° C. water (2.14 L) was added and the mixture extracted with ethyl acetate (2.14 L). The aqueous layer was separated and extracted twice with ethyl acetate (2.14 L, 1.28 L). The combined organic extracts were washed with water (2.14 L) then evaporated to dryness to afford a colourless oil (371.8 g)-LC RT=4 min. This may be chromatographed on silica (Biotage) eluting with 10% ethyl acetate in 60/80 petrol to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:18][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(N2CCC(CO)CC2)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(N2CCC(CBr)CC2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(6′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-methanol (300 mg, 1.35 mmol) is dissolved in methylene chloride (10 mL). carbon tetrabromide (561 mg, 1.69 mmol) is added and dissolved. The solution is cooled to 0° C. and triphenylphoshine (529 mg, 2.02 mmol) is added portionwise. The reaction is allowed to come to r.t. and is stirred for 30 min. The volume is then reduced under vacuum to ˜2 ml and purified by flash chromatography on silica gel using 2% methanol/methylene chloride as the eluent to provide 4-bromomethyl-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl. 1H NMR (300 MHz, CD3OD) δ 7.74 (d, 1H), 7.43 (dd, 1H), 6.72 (d, 1H), 3.83 (s, 3H), 3.54 (m, 2H), 3.38 (d, 2H), 2.65 (dt, 2H), 1.94 (m, 2H), 1.75 (m, 1H), 1.44 (m, 2H); MS (EI) 284 (M)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]([O:15][CH3:16])(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>>[CH3:16][O:15][C:10](=[O:14])/[CH:11]=[C:12](/[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)\[CH3:13]
Reactant: C/C=C/C(=O)OC
Reactant: OCc1ccc(Br)cc1
Product: COC(=O)/C=C(\C)c1ccc(CO)cc1

Procedure:
For the above synthesis, (E)-3-{4-[3-(4-nitrophenyl)-2H-oxo-2-pyridin-1-yl]phenyl}but-2-enoic acid methyl ester was prepared from P3 and (E)-3-(4-methanesulfonyloxymethylphenyl)but-2-enoic acid methyl ester by the method of Preparation 7, and (E)-3-(4-methanesulfonyloxymethylphenyl)but-2-enoic acid methyl ester was prepared from (E)-3-(4-hydroxymethylphenyl)but-2-enoic acid methyl ester and methanesulfonyl chloride analogously to the method of Preparation 6 (in this case mostly the mesylate was isolated rather than the chloride). (E)-3-(4-hydroxymethylphenyl)but-2-enoic acid methyl ester was prepared analogously to the method of Preparation 4 from 4-bromobenzyl alcohol and methyl crotonate.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.[BH3-]C#N.[Na+].Cl>CO.C(O)(=O)C>[C:1]1([CH2:7][CH2:8][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CCN2CCCc3ccccc32)cc1
Reaction time: 1 h

Procedure:
To phenylacetaldehyde (6.0 g, 0.050 mol), 1,2,3,4-tetrahydroquinoline (13 g, 0.1 mol) and acetic acid (0.5 ml) in methanol (50 ml) was added NaBH3CN (1.18 g). After stirring for 1 hour, the mixture was poured into 800 ml 1N HCl and extracted 3×100 ml ether. The combined organic layers were washed 1×100 ml 1N HCl and 2×100 ml H2O, dried (K2CO3) and concentrated to 100 ml. The concentrate was perfused with excess HCl gas to form an oily hydrochloride salt of title product. The solvent was decanted and the residual washed 2×50 ml ether. The washed salt was distributed between excess 5% K2CO3 and ether, and the organic layer separated, dried (K2CO3) and stripped to yield title product as an oil, 6.5 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]([CH2:21][CH2:22][NH2:23])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.O>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:12][C:11]([CH2:21][CH2:22][NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a stirred solution of 3-amino-6-(2-amino-ethyl)-4-cyclopentylmethoxy-benzo[b]thiophene-2-carboxylic acid amide (11) (HCl salt form, 0.100 g, 0.270 mmol) in pyridine (1 mL) at 0° C. was added methanesulfonyl chloride (0.08 mL, 1 mmol). It was allowed to warm to room temperature and stirred overnight. It was diluted with water, extracted with dichloromethane, washed with brine, dried with sodium sulfate, and concentrated. The residue was purified by preparatory thin layer chromatography to afford the title compound (0.021 g, 19%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(O)(=[O:22])C.S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C#Cc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
To 12.2 g (46 mmol) of 4-fluoro-4'-trifluoromethyltolane, 60 ml of water, 60 ml of acetic acid, 40 ml of sulfuric acid and 13.6 g (46 mmol) of mercuric sulfate were added, and the mixture was stirred at 90° C. for 3.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/9) to obtain 5.1 g of 4'-fluoro-2- (4-trifluoromethylphenyl)acetophenone having a melting point of from 87° to 89° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:10](=[O:18])[N:11]([CH3:17])[C:12](=[S:16])[N:13]([CH3:15])[N:14]=2)=[C:4]([F:19])[CH:3]=1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>CS(C)=O>[Cl:1][C:2]1[C:7]([O:8][C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:6][C:5]([C:9]2[C:10](=[O:18])[N:11]([CH3:17])[C:12](=[S:16])[N:13]([CH3:15])[N:14]=2)=[C:4]([F:19])[CH:3]=1
Reactant: Cn1nc(-c2cc(O)c(Cl)cc2F)c(=O)n(C)c1=S
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CS(C)=O
Product: Cn1nc(-c2cc(Oc3ncccn3)c(Cl)cc2F)c(=O)n(C)c1=S
Yield: 83.4 %

Procedure:
A mixture 6-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,4-dimethyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine (0.200 g), 2-chloropyrimidine (0.084 g), potassium carbonate (0.113 g), 2-butanone (10 ml), and dimethyl sulfoxide (2.5 ml) was heated at refluxed for 10 hours. The reaction was partitioned between water and ethyl acetate and the aqueous phase extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford the desired material (0.21 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C:17]2=[CH:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[CH3:23][O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C:17]2=[CH:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C:11](=[CH2:23])[C:12]2=[O:22])[CH:4]=1
Reactant: C[O-]
Reactant: COC1=CC2=CC[C@@H]3C(=CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1C[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)C3=CC[C@]2(C)C1=O
Reaction time: 1 h

Procedure:
3-Methoxyandrosta-3,5,9(11)-trien-17-one (I, 20 g) in THF (220 ml) was combined with dimethyloxylate (11.8 g) and sodium methoxide (25%, 18.4 ml) at 0° under nitrogen. After the reactants were combined, the ice was removed. After one hour, TLC shows the reaction has gone cleanly. Triethylamine (7.0 ml), acetic acid (1.0 ml), paraformaldehyde (3 g), and methanol (28 ml) were added and the mixture stirred overnight at 20°-25°. TLC showed the reaction had gone to completion. The reaction mixture was washed with phosphate buffer (121 ml) and water (202 ml). The mixture was extracted with methylene chloride (48 ml) and again with methylene chloride (40 ml). The methylene chloride extracts were combined and back-extracted with water (80 ml) and saline (10 ml). The organic mixture was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.N1CCCCC1.C(O)(=O)C>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]2[CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:8](=[O:14])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)CC(=O)c1ccccc1O
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)C1C(=O)c2ccccc2OC1c1cccc(Cl)c1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A mixture of methyl 3-(2-hydroxyphenyl)-3-oxopropanoate (prepared according to Cushman, M. et al., J. Med. Chem. 1991, 34, 798; 250 mg, 1.29 mmol) and 3-chlorobenzaldehyde (146 μL, 1.29 mmol) in isopropanol (5.0 mL) was treated with piperidine (13 μL, 129 μmol) and acetic acid (7.4 μL, 129 μmol) and heated to reflux for 17 h. After this time, the mixture was cooled to rt. The cooled solution was concentrated under vacuum and the resulting residue was purified by rotary TLC, eluting with 9:1 hexane-ethyl acetate, to provide a colorless gum. The colorless gum was crystallized from a hot isopropanol/water solution to provide methyl 2-(3-chlorophenyl)-4-oxochroman-3-carboxylate as an off-white solid (173 mg, 42%). The NMR indicated predominantly the enolic form. 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 6.21 (s, 1 H) 6.82 (d, J=8.1 Hz, 1 H) 6.97 (t, J=7.9 Hz, 1 H) 7.18-7.32 (m, 4 H) 7.34 (m, 1 H) 7.69 (dd, J=7.9, 1.8 Hz, 1 H) 12.28 (br. s, 1 H). High resolution mass spec (M+H)+ calc. 317.0581, found 317.0597.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]2[C:19]([CH3:24])=[N:20][O:21][C:22]=2[CH3:23])=[CH:5][CH:4]=1.O(C1C=CC(C(C2C=CC(OC#N)=CC=2)(C)C)=CC=1)[C:26]#[N:27].CS(C)=O.CCN(CC)CC>[Cl-].[Na+].O>[CH3:24][C:19]1[C:18]([C:10]2[N:11]([C:26]#[N:27])[C:12]3[C:17]([C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: CC(C)(c1ccc(OC#N)cc1)c1ccc(OC#N)cc1
Reactant: COc1ccc(-c2c(-c3c(C)noc3C)[nH]c3ccccc23)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2c(-c3c(C)noc3C)n(C#N)c3ccccc23)cc1
Temperature: 120 °C

Procedure:
4-(3-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole (37 mg, 0.12 mmol) and 2,2-bis-(4-cyanatophenyl)propane (0.6 eq) were mixed in a vial. 1.8 ml DMSO and Et3N (3 eq) were added and the mixture was heated at 120° C. in microwave. 2,2-bis-(4-cyanatophenyl)propane (5.7 eq) and Et3N (40 eq) were added and the mixture was heated at 150° C. for 25 min in microwave. Brine was added and the aqueous layer was extracted with EtOAc 6×. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was taken up in DCM, filtered through cotton wool and purified on silica (EtOAc/n-Heptane 1:9-2:8). 25.7 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile was obtained as a yellowish solid.