Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][CH:30]([CH3:39])[CH:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[OH:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:29][CH:30]([CH3:39])[CH:31]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:35][CH2:34]1)[OH:32]
Reactant: CC(C)C(O)C1CCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(O)C(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.5 %

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.53 mmol), 2-methyl-1-piperidin-4-yl-propan-1-ol (125 mg, 0.79 mmol) and 4 Å molecular sieves (1.0 g) in 1,2-dichloroethane (10 mL) was stirred at RT under nitrogen atmosphere for 1.5 h. Sodium triacetoxyborohydride (167 mg, 0.79 mmol) was added and the resulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PCC, MeOH:DCM: gradient 0:100 to 5:95) followed by a further purification (Si—PCC, acetone:cyclohexane: gradient 10:90 to 40:60). The solvents were reduced in vacuo to afford 346 as a white solid (114 mg, 41%). LCMS (Method G): RT 6.81 min, [M+H]+ 519. 1H NMR (400 MHz, CH3OH-d4): δ 8.06-8.05 (1 H, m), 7.56-7.55 (1 H, m), 7.25-7.24 (2 H, m), 4.29 (4 H, br s), 3.84 (3 H, s), 3.81 (4 H, t, J=4.74 Hz), 3.74 (2 H, s), 2.98-2.95 (3 H, m), 2.86 (3 H, s), 2.11 (2 H, m), 1.84 (1 H, m), 1.72-1.71 (1 H, m), 1.57-1.20 (4 H, m), 0.87 (6 H, dd, J=15.35, 6.73 Hz)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=[CH:11][C:12]=1[CH3:13].[Cl:27][C:28]1[CH:33]=[C:32](Cl)[N:31]=[CH:30][N:29]=1.C(N(CC)C(C)C)(C)C>CC(O)CC>[Cl:27][C:28]1[N:29]=[CH:30][N:31]=[C:32]([N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[NH:6][C:7]2[CH:8]=[C:9]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[CH:10]=[CH:11][C:12]=2[CH3:13])[CH:33]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nccn1-c1cc(Cl)ncn1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of N-[3-(1H-Imidazol-2-ylamino)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (330 mg, 0.92 mmol), 4,6-dichloropyrimidine (409 mg, 2.75 mmol), N,N-diisopropylethyl amine (500 μL, 2.87 mmol) in 2-butanol (20 mL) is heated at 110° C. After 16 hours, the reaction mixture is concentrated. The solid is washed with saturated sodium carbonate, water, ethyl acetate, and dried to give the title compound. 1H NMR 600 MHz (DMSO-d6) δ 10.71 (s, 1H), 10.50 (s, 1H), 9.09 (s, 1H), 8.80 (s, 1H), 8.33 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.84 (s, 1H), 7.77 (t, J=8.4 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.95 (s, 1H), 2.38 (s, 3H); MS m/z 473.3 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[C:13]4[C:19]5[C:32]([CH2:33][CH2:34][C:12]4=[CH:11][C:10]=3[CH:9]=[N:8]2)=[C:31]([O:35][CH3:36])[C:30]2[C:29](=[O:37])[C:28]3[C:23](=[CH:24][C:25]([OH:40])=[C:26]([CH3:39])[C:27]=3[OH:38])[C:22](=[O:41])[C:21]=2[C:20]=5[OH:42])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:46]([O:48][CH3:49])=[O:47].C(O)(=O)C>O>[C:1]1([N:7]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[C:13]4[C:19]5[C:32]([CH2:33][CH2:34][C:12]4=[CH:11][C:10]=3[CH:9]=[N:8]2)=[C:31]([O:35][CH3:36])[C:30]2[C:29](=[O:37])[C:28]3[C:23](=[CH:24][C:25]([O:40][C:46]([O:48][CH3:49])=[O:47])=[C:26]([CH3:39])[C:27]=3[OH:38])[C:22](=[O:41])[C:21]=2[C:20]=5[OH:42])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1c2c(c(O)c3c1C(=O)c1c(cc(O)c(C)c1O)C3=O)-c1c(cc3cnn(-c4ccccc4)c(=O)c3c1O)CC2
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Oc1cc2c(c(O)c1C)C(=O)c1c(OC)c3c(c(O)c1C2=O)-c1c(cc2cnn(-c4ccccc4)c(=O)c2c1O)CC3
Yield: 84 %

Procedure:
A solution of 281.2 mg (0.5 mmol) of 2-phenyl-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one (5) in 2 m of 2 M sodium hydroxide solution is diluted with 5 m of water. This solution is equilibrated at 5° C. and, while stirring, 2 m of methyl chloroformate are added. The mixture is subsequently stirred at room temperature for 30 min and then neutralized with acetic acid. The precipitated product is filtered off with suction to obtain 260 mg of the product. The yield is 84% of theory.
Reaction SMILES: [Se](=O)=O.[O:4]1CCOCC1.[CH2:10]([S:13]([NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1)(=[O:15])=[O:14])[CH2:11][CH3:12]>O>[CH2:10]([S:13]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[O:4])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1)(=[O:15])=[O:14])[CH2:11][CH3:12]
Reactant: CCCS(=O)(=O)Nc1nc(CC(=O)OCC)cs1
Reactant: C1COCCO1
Agent: CCCS(=O)(=O)N=c1[nH]c(CC(=O)OCC)cs1
Agent: O=[Se]=O
Solvent: O
Product: CCCS(=O)(=O)Nc1nc(C(=O)C(=O)OCC)cs1

Procedure:
To a solution prepared by stirring a mixture of selenium dioxide (6.2 g.), dioxane (320 ml.) and water (6.4 ml.) at 50° to 60° C. was added ethyl 2-(2-propanesulfonylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (16.3 g.), and the mixture was refluxed for 1 hour. To the mixture was added selenium dioxide (0.6 g.), and the mixture was further refluxed for 30 minutes and selenium dioxide (0.3 g.) was added thereto, and then the mixture was further refluxed for 30 minutes. After the reaction, the reaction mixture was filtered, and then dioxane was distilled off. The residue was dissolved in ethyl acetate under heating and then treated with activated charcoal. The solvent was distilled off, and the residue was washed with a small amount of ethyl acetate and diethyl ether in turn and dried to give ethyl 2-(2-propanesulfonylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (12.5 g.), mp 132° to 134° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](O)=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[NH2:35][CH2:36][CH2:37][OH:38]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:28])[NH:35][CH2:36][CH2:37][OH:38])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: NCCO
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)NCCO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 55.9 %

Procedure:
(3S)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.5 g, 0.9 mmol) was reacted with 2-aminoethanol (72 mg, 1.2 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.3 g, 56%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[N:11]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=1)=[O:9])(=[NH:3])[NH2:2].FC1C([O:30][C:31]([C:33]2[NH:34][C:35]3[C:40]([CH:41]=2)=[CH:39][C:38]([C:42](=[O:54])[NH:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:37][CH:36]=3)=O)=C(F)C(F)=C(F)C=1F>>[C:50]([O:49][C:47](=[O:48])[NH:46][CH2:45][CH2:44][NH:43][C:42]([C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:31](=[O:30])[NH:15][C:13]1[CH:14]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][CH2:5][CH2:4][C:1](=[NH:3])[NH2:2])[N:11]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:12]=1)=[CH:41]2)=[O:54])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)NCCCC(=N)N
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2c1
Product: CC(C)CCn1cc(NC(=O)c2cc3cc(C(=O)NCCNC(=O)OC(C)(C)C)ccc3[nH]2)cc1C(=O)NCCCC(=N)N
Yield: 58 %

Procedure:
1-(3-Methyl-butyl)-4-nitro-1H-pyrrole-2-carboxylic acid (3-carbamimidoyl-propyl)-amide (prepared by the methods described in Dyatkina et al. J. Med. Chem., 45:805–817, 2002) was reduced to its amine by hydrogenation according to the procedure for 97. The amine was then coupled with compound 33 according to the similar procedure for preparation of compound 95 to give compound 101 in 58% yield. MS: 609.33 (M+H+).
Reaction SMILES: [CH2:1]([OH:8])[CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][OH:6].CO[C:11](OC)([CH3:13])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:12][C:11]1([CH3:13])[O:7][CH:2]([CH2:3][CH2:4][CH2:5][OH:6])[CH2:1][O:8]1
Reactant: COC(C)(C)OC
Reactant: OCCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OCC(CCCO)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pentane-1,2,5-triol (5.00 g) was dissolved in acetone (150 mL), 2,2-dimethoxypropane (10.5 mL) and 4-methylbenzenesulfonic acid (794 mg) were added, and the mixture was stirred at room temperature for 1.5 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound (3.79 g) as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1F)[C:11]([O:13][CH3:14])=[O:12].[CH3:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[N:23]1[CH2:24][CH2:25][CH:20]([CH3:19])[CH2:21][CH2:22]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(F)c(F)c1
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCC(C)CC2)c(F)c1
Temperature: 60 °C

Procedure:
0.076 g of potassium carbonate was added to a solution of 0.086 g of methyl 3,4-difluorobenzoate and 0.050 g of 4-methylpiperidine in 0.5 ml of DMF. The reaction was heated at 60° C. for 2 days, filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 251.3 (C14H18FNO2); MS (ESI): 252 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:19]=[CH:18][C:10]([O:11]/[CH:12]=[CH:13]/[C:14]([O:16]C)=[O:15])=[CH:9][C:8]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22].Cl>C(OCC)(=O)C>[F:3][C:4]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:19]=[CH:18][C:10]([O:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:9][C:8]=1[NH:20][S:21]([CH3:24])(=[O:22])=[O:23]
Reactant: COC(=O)/C=C/Oc1ccc(Oc2ccc(F)cc2F)c(NS(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(O/C=C/C(=O)O)ccc1Oc1ccc(F)cc1F
Reaction time: 1 h
Yield: 86.4 %

Procedure:
24 ml of a 1N aqueous sodium hydroxide solution was added to 1.2 g of methyl trans-3-[4-(2,4-difluorophenoxy)-3-methylsulfonylaminophenoxy]acrylate. The mixture was stirred for 1 hour at 20°-25° C. 30 ml of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.0 g (yield: 87.0%) of oily trans-3-[4-(2,4-difluorophenoxy)-3methylsulfonylaminophenoxy]acrylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:42][Si:43]([CH3:50])([CH3:49])[CH2:44][CH2:45][O:46][CH2:47]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[N:37]([CH2:47][O:46][CH2:45][CH2:44][Si:43]([CH3:50])([CH3:49])[CH3:42])[C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (268 mg, 0.4 mmol) was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (142 μL, 0.8 mmol) to give 5-{-4-[2-(4′-bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-2-(2-trimethylsilanyl-ethoxymethyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: C([O:5][C:6](=[O:48])[CH:7]([NH:14][C:15](=[O:47])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](=[O:46])[NH:31][CH:32]([C:39]([O:41]C(C)(C)C)=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>CCOCC.CCCCCC>[C:6]([CH:7]([NH:14][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([NH:31][CH:32]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]([OH:41])=[O:40])=[O:46])=[O:47])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([OH:48])=[O:5]
Reactant: CC(C)(C)OC(=O)C(NC(=O)c1ccccc1SSc1ccccc1C(=O)NC(C(=O)OC(C)(C)C)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(C(=O)O)c1ccccc1)c1ccccc1SSc1ccccc1C(=O)NC(C(=O)O)c1ccccc1
Yield: 42.5 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [R-(R*,R*)] (2-{2-[(tert-butoxycarbonyl-phenyl-methyl)-carbamoyl]-phenyldisulfanyl}-benzoylamino)-phenyl-acetic acid tert-butyl ester (0.2 g, 0.3 mmol) from Example 38, 10 mL dichloromethane, and 10 mL trifluoroacetic acid. The crude product was stirred with ether/hexane and filtered to afford 73.0 mg of the title compound, mp 231°-232° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:12]1([C:18]#[C:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9](=[O:11])[CH3:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)Cc1ccccc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)Cc1ccccc1C#Cc1ccccc1
Yield: 80.8 %

Procedure:
A solution of 28.3 g (112 mmole) of 2-bromophenyl-2-propanone, 14.7 ml (134 mmole) of phenylacetylene, 1.8 g (2.24 mmole) of bis(triphenylphosphine)palladium (II) chloride and 0.85 g (4.48 mmole) of copper (I) iodide in 250 ml of triethylamine under nitrogen was heated under reflux for 31/2 hours. An additional 3.6 ml of phenylacetylene, 0.36 g of palladium complex and 0.1 g copper (I) iodide were added. The mixture was heated under reflux for 31/2 hours. An additional 5.0 ml of phenylacetylene, 0.36 g of palladium complex and 0.17 g of copper (I) iodide were added. The mixture was heated under reflux for 2 hours. An additional 5.0 ml of phenylacetylene was added. The mixture was heated under reflux for 31/2 hours. The solvent was evaporated in vacuo and the residue taken up in ether. The ether was washed with water and brine, dried (K2CO3) and the solvent evaporated in vacuo. The residue was flash chromatographed on silica gel with ethyl acetate:hexane, 9:1, as eluant. The solvent was evaporated from the major compound bearing fraction to afford 21.2 g (81% yield) of 1-[2-(phenylethynyl)phenyl]-2-propanone as an oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]([F:27])([F:26])[C:13]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([OH:18])[C:14]([F:17])([F:16])[F:15].O>N1C=CC=CC=1>[F:11][C:12]([F:26])([F:27])[C:13]([C:19]1[CH:25]=[CH:24][C:22]([NH:23][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:21][CH:20]=1)([OH:18])[C:14]([F:15])([F:17])[F:16]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1
Temperature: 100 °C

Procedure:
Add 4.22 g (24 mmole) of benzenesulfonyl chloride dropwise to 5.18 g (20 mmole) of 4-(hexafluoro-2-hydroxy-2-propyl)aniline in 25 ml of pyridine and heat to 100° C. for 8 hours. Pour the reaction into H2O and extract with Et2O. Wash with 1N HCl and extract with 1H NaOH. Acidify the NaOH and extract with Et2O. Dry, concentrate and recrystallize from Et2O and hexane to obtain 4'-(hexafluoro-2-hydroxy-2-propyl)-benzenesulfonanilide; m.p. 117°-118° C.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)(=O)[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].BrCC[CH2:29][OH:30]>CO>[OH:30][CH2:29][CH2:2][CH2:1][S:4][CH2:5][C:6]1([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: OCCCBr
Reactant: COC(=O)C1(CSC(C)=O)CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(CSCCCO)CCOCC1
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
To a stirred solution of Intermediate 7 (2.50 g) in methanol (100 ml) under nitrogen at 0° C. was added a solution of sodium hexamethyldisilazide (1M in THF, 11.3 ml) and the resulting mixture was stirred for 10 mins, then a solution of 3-bromopropanol (1.5 g) was added. The mixture was stirred for 6 h, then evaporated and the residue treated with water (100 ml) and extracted with dichloromethane (4×50 ml). The combined dichloromethane extracts were washed with water (2×50 ml), brine (50 ml), dried over MgSO4 and evaporated. The residue was purified on silica gel eluting with 2:1 ethyl acetate/hexane, to give the title compound (2.41 g) as a colourless oil. TLC Rf0.26 (2:1 ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=S)[NH:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1.[NH3:32].C(OO)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18]([NH2:32])=[N:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1
Reactant: N
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4cc(Cl)ccc4o3)c(F)cc2F)C1(F)F
Agent: CC(C)(C)OO
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(-c3nc4cc(Cl)ccc4o3)c(F)cc2F)C1(F)F
Yield: 43 %

Procedure:
In a manner analogous to that described in Example 2c), the ammonolysis of (R)-5-[5-(5-chloro-benzo oxazol-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (35 mg, 74 μmol) with ammonia (7M in methanol; 0.73 ml) and tert-butylhydroperoxide (70% in water; 71 μl) yielded the title compound (14 mg, 43% yield). MS (ISP): m/z=456.3 [M+H]+ and 458.2 [M+2+H]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][C:16]1[CH:17]=[C:18]([NH2:31])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].O>CN(C)C(=O)C>[CH3:15][C:16]1[CH:17]=[C:18]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Cc1cc(N)ccc1S(=O)(=O)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.72 g, 4.5 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.54 g, 4.5 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 3-Methyl-4-(phenylsulfonyl)-benzeneamine (0.75 g, 3.0 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution filtered to yield a brown solid which was purified by flash column chromatography (5% v/v ethyl acetate/methylene chloride). Trituration of the resulting solid with hexane yielded the title propanamide as a white solid (0.95 g, 82%); mp 141°-143° C. 1H-NMR (300 MHz, d6-DMSO): 1.58 (s, 3H, CH3) 2.32 (s, 3H, ArCH3) 7.55-7.70 (m, 4H, aromatic) 7.79-7.85 (m, 3H, aromatic) 7.92 (dd, 1H, J=8.8, 1.9 Hz, aromatic) 8.10 (d, 1H, J=8.8 Hz, aromatic) 10.30 (s, 1H, NH). MS (CI, CH4): 388 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[O:15][C:16]1[CH:17]=[C:18]([CH:19]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1cccc(Oc2cc(Cl)cc(Cl)c2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2cc(Cl)cc(Cl)c2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-(3,5-dichlorophenoxy)-benzaldehyde in an analogous manner to that described in Example 1 to give 9-[3-(3,5-dichlorophenoxy)-phenyl]-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a yellow crystalline solid of melting point 254-255° C.